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Excess comorbidities associated with malignant hyperthermia diagnosis in pediatric hospital discharge records
Abstract
Case reports have linked malignant hyperthermia (MH) to several genetic diseases.
The objective of this study was to quantitatively assess excess comorbidities associated with MH diagnosis in pediatric hospital discharge records.
Data for this study came from the Kids' Inpatient Database (KID) for the years 2000, 2003, and 2006. The KID contains an 80% random sample of patients under the age of 21 discharged from short-term, non-Federal hospitals in the United States, with up to 19 diagnoses recorded for each patient. Using all pediatric inpatients as the reference, we calculated the standardized morbidity ratios (SMRs) and 95% confidence intervals (CIs) for children with MH diagnosis according to major disease groups and specific medical conditions.
Of the 5,916,989 nonbirth-related hospital discharges studied, 175 had a recorded diagnosis of MH. Compared with the general pediatric inpatient population, children with MH diagnosis were significantly more likely to be diagnosed with diseases of the musculoskeletal system and connective tissue (SMR 5.7; 95% CI: 3.9-7.9), diseases of the circulatory system (SMR 3.3; 95% CI: 2.1-4.8), and congenital anomalies (SMR 3.2; 95% CI: 2.3-4.4). The specific diagnosis that was most strongly associated with MH was muscular dystrophies (SMR 31.3; 95% CI 12.6-64.6).
Diseases of the musculoskeletal system and connective tissue are significantly associated with MH diagnosis in children. Further research is warranted to determine the clinical utility of these comorbidities in assessing MH susceptibility in children.
... Il rischio è tuttora presente in tutti i casi in cui, durante l'anestesia generale, siano somministrati alogenati e succinilcolina cloruro. 3,4 Ad oggi il calo della mortalità in anestesia generale è stato reso possibile innanzitutto dall'identificazione dei soggetti a rischio, da una diagnosi precoce e dal trattamento tempestivo; inoltre, la scoperta e l'introduzione del dantrolene sodico 5 La mortalità a livello internazionale è del 7%, una volta che la sindrome si è manifestata a livello intraoperatorio. 4 Le Linee guida 3,4 evidenziano l'importanza di una visita pre-operatoria completa ed accurata e, prima dell'induzione all'anestesia generale, l'eventuale profilassi con il dantrolene sodico (Dantrium®), perchè aiuta a diminuire l'incidenza dell'esordio della crisi. ...
... Case history reports a risk at all ages and for all types of surgery. 5 The international mortality rate is 7% once the syndrome manifests itself at intra-surgery level. 4 The guidelines 4 evidence the importance of a complete and accurate preoperative visit before induction to general anesthesia, and the eventual prophylaxis with dantrolene sodium (Dant-rium®), which helps reduce the incidence at the onset of the crisis. ...
Introduzione: la sindrome da Ipertermia Maligna o Malignant Hyperthermia (MH) è una rara e gravissima complicanza dell’anestesia generale, che si presenta in soggetti geneticamente predisposti in seguito all’esposizione a fattori scatenanti (gas alogenati e succinilcolina cloruro). È un’emergenza medica che non presenta un quadro clinico di chiara identificazione. Tutti gli infermieri, specie quelli d’anestesia, dovrebbero essere formati per essere pronti a gestirla.
... Il rischio è tuttora presente in tutti i casi in cui, durante l'anestesia generale, siano somministrati alogenati e succinilcolina cloruro. 3,4 Ad oggi il calo della mortalità in anestesia generale è stato reso possibile innanzitutto dall'identificazione dei soggetti a rischio, da una diagnosi precoce e dal trattamento tempestivo; inoltre, la scoperta e l'introduzione del dantrolene sodico 5 La mortalità a livello internazionale è del 7%, una volta che la sindrome si è manifestata a livello intraoperatorio. 4 Le Linee guida 3,4 evidenziano l'importanza di una visita pre-operatoria completa ed accurata e, prima dell'induzione all'anestesia generale, l'eventuale profilassi con il dantrolene sodico (Dantrium®), perchè aiuta a diminuire l'incidenza dell'esordio della crisi. ...
... Case history reports a risk at all ages and for all types of surgery. 5 The international mortality rate is 7% once the syndrome manifests itself at intra-surgery level. 4 The guidelines 4 evidence the importance of a complete and accurate preoperative visit before induction to general anesthesia, and the eventual prophylaxis with dantrolene sodium (Dant-rium®), which helps reduce the incidence at the onset of the crisis. ...
Introduction: The Malignant Hyperthermia (MH) syndrome is a serious complication which develops in MH-susceptible patients subjected to general anesthesia and triggered by exposure to certain drugs used during surgery (Succinylcholine and all volatile halogenated inhalational anesthetic agents). It is a medical emergency that does not present a typical clinical presentation. All nurses, especially those in the anesthesia team, should be trained to handle this condition. The low probability of the onset of a MH crisis and the patient’s survival depend on adequate preventive measures, early recognition and prompt treatment.
Objective: Through the analysis and comparison of international scientific documents and guidelines, this review aimed to reach a deeper understanding of the role of nurses in the care of patients with this syndrome.
Materials and Methods: In May 2014, we conducted and revised a literature review through the Medline data base. The latest national, European and Canadian guidelines on the topic were chosen from 20 different sources and were then analyzed and compared.
Results: Analysis of the material demonstrated that the role of nurses has assumed greater importance in the management, prevention and treatment of MH
Prevention consists in the training of nurses to provide them with the necessary skills to educate the patients and their families to cooperate with the doctor in the preoperative setting to ensure utmost safety for the patients (identifying the patients at risk and preparing them for surgery); it is the responsibility of the nurses to ensure that the anesthesia equipment is free from anesthetic vapors, and check the proper functioning of
the monitor and that all the drugs indicated for the treatment of a possible Malignant Hyperthermia crisis are at hand in the operating room. In the preoperative setting, early recognition of the clinical events of Malignant Hyperthermia is vital to allow the immediate implementation of the relevant procedures should a crisis arise.
Conclusions: The key elements for the survival of MH-susceptible patients are training and continuing ducation of OR nurses, to ensure greater awareness and competencies for the early recognition, prevention, and treatment of this syndrome.
Key words: Malignant Hyperthermia, dantrolene, total anesthesia complications.
... The most cited figure is less than 5%; however, this figure has been challenged, and case fatality rates of 1.4, 4.6, 10, and 11.7% have been cited in the literature. 1,[11][12][13][14][15][16] A base case fatality rate of 10% was used as a conservative estimate for this study. 3. The true case fatality rate without dantrolene is uncertain. ...
... Decision tree representing the clinical timeline for a malignant hyperthermia (MH) episode in ambulatory surgery centers (ASCs).[1][2][3]6,[11][12][13][14][15][16] The square represents a decision node and indicates the choices we are evaluating; in this case whether the ASC administers dantrolene to treat an MH episode. ...
Malignant hyperthermia (MH) is a rare hypermetabolic syndrome of the skeletal muscle and a potentially fatal complication of general anesthesia. Dantrolene is currently the only specific treatment for MH. The Malignant Hyperthermia Association of the United States has issued guidelines recommending that 36 vials (20 mg per vial) of dantrolene remain in stock at every surgery center. However, the cost of stocking dantrolene in ambulatory surgery centers has been a concern. The purpose of this analysis is to assess the cost-effectiveness of stocking dantrolene in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States.
A decision tree model was used to compare treatment with dantrolene to a supportive care-only strategy. Model assumptions include the incidence of MH, MH case fatality with dantrolene treatment and with supportive care-only. Sensitivity analyses were performed to assess the robustness of the estimated cost-effectiveness.
The estimated annual number of MH events in ambulatory surgery centers in the United States was 47. The incremental effectiveness of dantrolene compared with supportive care was 33 more lives saved per year. The incremental cost-effectiveness ratio was $196,320 (in 2010 dollars) per life saved compared with a supportive care strategy. Sensitivity analysis showed that the results were robust for the plausible range of all variables and assumptions tested.
The results of this analysis suggest that stocking dantrolene for the treatment of MH in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States is cost-effective when compared with the estimated values of statistical life used by U.S. regulatory agencies.
... However, lethality rates between 1% and 12% have been reported in the literature. 3,21,31,32 Scenario simulations ...
Introduction:
Malignant hyperthermia (MH) is an acute syndrome triggered by certain anesthetic medications. Dantrolene is the only specific treatment for MH crises. Without treatment, lethality may be as high as 80%. In Colombia, it is not mandatory to keep dantrolene supplies in stock.
Objective:
To establish the cost-benefit ratio, from the perspective of healthcare institutions, of keeping dantrolene supplies in stock in the operating theater.
Methods:
Using a decision tree, a Monte Carlo simulation was run with 10,000 scenarios to determine the median annual cost of keeping full or partial stocks (36 or 12 vials x 20 mg, respectively) of dantrolene. For the option of not keeping supplies in stock, the cost threshold was calculated where the expected value of both alternatives of the decision tree is equalized. Indifference curves were constructed for complete and partial supplies.
Results:
The median annual cost was estimated at 6.6 million Colombian pesos (COP) for full dantrolene supplies, and at COP 2.2 million for partial supplies. The median economic consequence threshold for 1 death due to the unavailability of dantrolene was estimated at COP 18.5 million for full supplies, and at COP 57.0 million for partial supplies.
Conclusion:
If, as a result of the unavailability of dantrolene, the economic consequences of a death due to MH exceed the threshold of COP 57.0 or COP 18.5 million, the purchase of full or partial stocks, respectively, is justified.
... [18]. The discrepancy is likely due to the difference by the study populations as our analysis is restricted to obstetric patients and the prevalence of MH diagnosis in women is only about a third of the one in men [8,19]. ...
Abstract Background The cost-benefit of stocking dantrolene in maternity units for treating malignant hyperthermia (MH) has been recently questioned because of the low incidence of MH crisis in the general population and the low utilization of general anesthesia in obstetrics. However, no study has examined the prevalence of MH susceptibility in obstetrics. This study aimed to assess the prevalence of MH diagnosis and associated factors in obstetric patients. Methods Data for this study came from the National Inpatient Sample from 2003 to 2014, a 20% nationally representative sample of discharge records from community hospitals. A diagnosis of MH due to anesthesia was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was estimated according to the delivery mode and patient and hospital characteristics. Results During the 12-year study period, 47,178,322 delivery-related discharges [including 15,175,127 (32.2%) cesarean deliveries] were identified. Of them, 215 recorded a diagnosis of MH, yielding a prevalence of 0.46 per 100,000 [95% confidence interval (CI), 0.40 to 0.52]. The prevalence of MH diagnosis in cesarean deliveries was 0.81 per 100,000 (95% CI, 0.67 to 0.97), compared with 0.29 per 100,000 (95% CI, 0.23 to 0.35) in vaginal deliveries (P
... ASC, ambulatory surgical center; free, freestanding; Or, operating room. [67][68][69][70] relationship to Dantrolene. ...
What we already know about this topic:
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.
Methods:
The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.
Results:
Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.
Conclusions:
Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.
... The prevalence of MH in hospital discharges across the United States has been estimated to be approximately 1 per 100,000 [5,8,9]. Factors associated with elevated MH risk include male sex, young age, several myopathies and congenital anomalies [5,9,10]. MH susceptibility as diagnosed with a caffeine-halothane contracture has been documented in patients with heat stroke and exercise-induced rhabdomylosis [11][12][13][14]. ...
Study objective:
Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhalational anesthetics and the depolarizing neuromuscular blocking agent succinylcholine. Epidemiologic data on the geographic variation in MH prevalence is scant. The objective of this study is to examine the prevalence of recorded MH diagnosis in patients discharged from hospitals in four states in the United States.
Design:
Observational study.
Setting:
Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) for California (2011), Florida (2011), New York (2012) and Wisconsin (2012).
Patients:
A total of 164 hospital discharges that had a recorded diagnosis of MH using the International Classification of Disease, 9th Revision, Clinical Modification code 995.86.
Methods:
MH prevalence was assessed by patient demographic and clinical characteristics.
Main results:
The prevalence of MH per 100,000 hospital discharges ranged from 1.23 (95% Confidence Interval [CI], 0.80-1.66) in New York to 1.91 (95% CI, 1.48-2.34) in California, and the prevalence of MH per 100,000 surgical discharges ranged from 1.47 (95% CI, 0.93-2.02) in New York to 2.86 (95% CI, 2.00-3.71) in Florida. The prevalence of MH in male patients was more than twice the prevalence in female patients. Of the 164 patients with MH diagnosis, 11% were dead on discharge.
Conclusions:
There exists a modest variation in the prevalence of recorded MH diagnosis in hospital discharges in California, Florida, New York and Wisconsin. Epidemiologic patterns of MH diagnosis in hospital discharges appear to be similar across the four states. Further research is needed to better understand the geographic variation and contributing factors of MH in different populations.
... Grosu et al. (6) reported using sevoflurane in a patient with Ullrich myopathy and concluded that halogenated agents can be safely used in patients with Ullrich's disease because the mutations of genes associated with malignant hyperthermia are not present in the disease. However, Li et al. (10) demonstrated that malignant hyperthermia is observed six times more in patients with musculoskeletal disorders on the basis of a large paediatric inpatient sample. We had chosen not to use sevoflurane and preferred TIVA as a safer method. ...
Here, we report anaesthesia management and the successful use of total intravenous anaesthesia and sugammadex in a patient with Ullrich’s disease. Propofol and remifentanyl infusion was used for anaesthesia. After the end of the surgery, when the train-of-four value was 0%, 4 mg kg−1 sugammadex was administered, and the patient was successfully extubated after 36 s. No adverse effects or safety concerns were observed. In conclusion, we suggest that the use of propofol infusion to avoid the use of inhalation anaesthetics and the use of sugammadex for the reversal of the effects of rocuronium is safe in patients with Ullrich’s disease.
... En un estudio que evaluó cuantitativamente la existencia de comorbilidades y el diagnóstico HM, se observó que cuando se comparaban con la población pediátrica en general, los niños con diagnóstico de HM tuvieron signifi cativamente comorbilidades del tipo: enfermedades del sistema musculoesquelético y tejido conectivo, enfermedades del sistema circulatorio y anomalías congénitas. El diagnóstico específi co que estuvo más fuertemente asociado a la HM fue la distrofi a muscular 30 . El niño descrito tenía un síndrome musculoesquelético que respaldaba los hallazgos del citado estudio. ...
La hipertermia maligna (HM) es un trastorno farmacogenético de la musculatura esquelética, caracterizado por un estado hipermetabólico después de la anestesia con la succinilcolina y/o agentes anestésicos volátiles. Varios síndromes neuromusculares están asociados con la susceptibilidad, sin embargo el síndrome de Moebius no se describe. El dantroleno es el fármaco de elección para el tratamiento. La recrudescencia puede ocurrir incluso en un 20% de los casos después del tratamiento del evento inicial.
... The availability of a special ICD code for MH has made it possible to conduct epidemiological research related to MH, including use of the code to evaluate MH prevalence, trends in MH occurrence, and coexisting diseases. [2][3][4] However, the validity of the findings from studies based on ICD-coded data has been a serious concern. ICD codes are prone to error at several different levels including but not limited to physician, coding, and sequencing errors. ...
Background:
In 1997, the International Classification of Diseases (ICD), 9th Revision Clinical Modification (ICD-9) coding system introduced the code for malignant hyperthermia (MH) (995.86). The aim of this study was to estimate the accuracy of coding for MH in hospital discharge records.
Methods:
An expert panel of anesthesiologists reviewed medical records for patients with a discharge diagnosis of MH based on ICD-9 or ICD-10 codes from January 1, 2006 to December 31, 2008 at six tertiary care medical centers in North America. All cases were categorized as possible, probable, or fulminant MH, history of MH (family or personal) or other.
Results:
A total of 47 medical records with MH diagnoses were reviewed; 68.1% had a documented surgical procedure and general anesthesia, and 23.4% (95% CI, 12.3-38.0%) had a possible, probable, or fulminant MH event. Dantrolene was given in 81% of the MH events. All patients judged to have an incident MH event survived to discharge. Family and personal history of MH accounted for 46.8% of cases. High fever without evidence of MH during admission accounted for 23.4%, and the reason for MH coding was unclear in 6.4% of cases.
Conclusions:
Approximately one quarter of ICD-9 or ICD-10 coded MH diagnoses in hospital discharge records refer to incident MH episodes and an additional 47% to MH susceptibility (including personal history or family history). Information such as surgical procedure, anesthesia billing data, and dantrolene administration may aid in identifying incident MH cases among those with an ICD-9 or ICD-10 coded MH diagnosis in their hospital discharge records.
... Malignant hyperthermia is an uncommon inherited subclinical myopathy triggered by exposure to volatile anesthetic agents and succinylcholine that may occur anytime during a surgical procedure or the recovery phase. In children, the prevalence is noted to be 3/100 000 according to the kids' inpatient database for the years 2000, 2003, and 2006 [12]. The typical treatment algorithm entails immediate cessation of volatile agents, administration of dantrolene, initiation of cooling methods, and expedient closure of the surgical site. ...
Purpose of review:
This article reviews the pertinent perioperative, intraoperative, and short- and long-term postoperative risks associated with general anesthesia in children undergoing ocular surgery.
Recent findings:
Animal studies suggest an association between general anesthesia and neurodevelopmental delay; however, animal pharmacodynamics and pharmacokinetics do not directly correlate with human metrics. Retrospective human studies present conflicting data. Further, prospective studies in humans are underway, with projected results available within the next 3-5 years.
Summary:
All surgeons should be aware of current practices in pediatric anesthetic care, as well as the immediate- and long-term risks of general anesthesia. Ophthalmologists with pediatric patients should be aware of the potentially life-threatening conditions associated with general anesthesia. Additionally, the relative lifelong risks and benefits of general anesthetic exposure should be considered when recommending surgery, especially in light of the child's age, health status, and necessity of multiple anesthetic events.
... Several neuromuscular diseases are associated with increasing amounts of connective tissue, and an above average coincidence of clinical MH-suspicion and disorders of connective tissue as well as musculoskeletal disorders has been suggested [8,9]. Nonetheless, the current protocols do not address the content and properties of fascial tissue in the biopsy specimens. ...
Malignant hyperthermia is a dreaded complication of general anaesthesia. Predisposed individuals can be identified using the standardised caffeine/halothane in-vitro contracture test on a surgically dissected skeletal muscle specimen. Skeletal muscle is composed of muscle fibres and interwoven fascial components. Several malignant hyperthermia-associated neuromuscular diseases are associated with an altered connective tissue composition. We analysed adjacent fascial components of skeletal muscle histologically and physiologically. We investigated whether the fascial tissue is sensitive to electrical or pharmacological stimulation in a way similar to the in-vitro contracture test for diagnosing malignant hyperthermia. Using immunohistochemical staining, α-smooth muscle actin-positive cells (myofibroblasts) were detected in the epi-, endo- and perimysium of human fascial tissue. Force measurements on isolated fascial strips after pharmacological challenge with mepyramin revealed that myofascial tissue is actively regulated by myofibroblasts, thereby influencing the biomechanical properties of skeletal muscle. Absence of electrical reactivity and insensitivity to caffeine and halothane suggests that, reassuringly, the malignant hyperthermia diagnostic in-vitro contracture test is not influenced by the muscular fascial tissue.
Introducción:
El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos).
Caso clínico:
Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena.
Conclusiones:
El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.
JUSTIFICATIVA E OBJETIVOS: A hipertermia maligna (HM) é uma desordem farmacogenética da musculatura esquelética, caracterizada por estado hipermetabólico após anestesia com succinilcolina e/ou agentes anestésicos voláteis. Várias síndromes neuromusculares estão associadas com susceptibilidade, no entanto a síndrome de Moebius não é descrita. O dantrolene é o fármaco de escolha para o tratamento. Recrudescência pode ocorrer em até 20% dos casos após o tratamento do evento inicial. RELATO DO CASO: Lactente, masculino, primeiro gemelar, sete meses, 6,5 kg. Portador da síndrome de Moebius. Internado para correção de pé torto congênito. Apresentou HM após exposição à sevoflurano e succinilcolina, prontamente revertida com dantrolene, sendo o fármaco mantido por 24 horas. Dez horas após a interrupção do dantrolene, houve recrudescência da HM, a qual não respondeu satisfatoriamente ao tratamento, evoluindo para óbito. DISCUSSÃO: Doenças musculoesqueléticas em crianças estão associadas a aumento de risco para desenvolvimento de MH, embora a síndrome de Moebius ainda não tenha sido descrita. O dantrolene é fármaco de eleição para o tratamento da síndrome, está indicada profilaxia durante as primeiras 24-48 horas do episódio inicial. Os principais fatores associados à recrudescência são: tipo muscular, longa latência após exposição anestésica e aumento da temperatura. A criança tinha apenas um fator de risco. Este caso nos remete à reflexão de que devemos estar atentos a crianças com doença musculoesquelético e que devemos manter o tratamento durante 48 horas.
Background
Malignant Hyperthermia (MH) is a potentially fatal metabolic disorder. Due to its rarity, limited evidence exists about risk factors, morbidity, and mortality especially in children.Methods
Using the Nationwide Inpatient Sample and the Kid's Inpatient Database (KID), admissions with the ICD-9 code for MH (995.86) were extracted for patients 0–17 years of age. Demographic characteristics were analyzed. Logistic regression was performed to identify patient and hospital characteristics associated with mortality. A subset of patients with a surgical ICD-9 code in the KID was studied to calculate the prevalence of MH in the dataset.ResultsA total of 310 pediatric admissions were seen in 13 nonoverlapping years of data. Patients had a mortality of 2.9%. Male sex was predominant (64.8%), and 40.5% of the admissions were treated at centers not identified as children's hospitals. The most common associated diagnosis was rhabdomyolysis, which was present in 26 cases. Regression with the outcome of mortality did not yield significant differences between demographic factors, age, sex race, or hospital type, pediatric vs nonpediatric. Within a surgical subset of 530 449 admissions, MH was coded in 55, giving a rate of 1.04 cases per 10 000 cases.Conclusions
This study is the first to combine two large databases to study MH in the pediatric population. The analysis provides an insight into the risk factors, comorbidities, mortality, and prevalence of MH in the United States population. Until more methodologically rigorous, large-scale studies are done, the use of databases will continue to be the optimal method to study rare diseases.
Background and objectives:
Malignant hyperthermia (MH) is a pharmacogenetic skeletal muscle disorder characterized by a hypermetabolic state after anesthesia with succinylcholine and/ or volatile anesthetics. Various neuromuscular syndromes are associated with susceptibility; however, Moebius syndrome has not been reported. Dantrolene is the drug of choice for treatment. Recurrence may occur in up to 20% of cases after the initial event treatment.
Case report:
Male infant, fi rst twin, 7 months old, weighing 6.5kg and presenting with Moebius syndrome was admitted for clubfoot repair. The patient had MH after exposure to sevoflurane and succinylcholine, which was readily reversed with dantrolene maintained for 24 hours. Ten hours after dantrolene discontinuation, there was recrudescence of MH that did not respond satisfactorily to treatment, and the patient died.
Discussion:
Musculoskeletal disorders in children are associated with increased risk of developing MH, although Moebius syndrome has not yet been reported. Dantrolene is the drug of choice for treating this syndrome; prophylaxis is indicated during the fi rst 24-48 hours of the episode onset. The main risk factors for recurrence are muscular type, long latency after anesthetic exposure, and increased temperature. The child had only one risk factor. This case leads us to reflect on how we must be attentive to children with musculoskeletal disease and maintain treatment for 48 hours.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of anesthesia. Recent advances dealing with epidemiology of MH and the safe anesthetic course of MH susceptible patients are shortly presented here with a special insight into the preparation of modern anesthesia workstations, which they will share in operating room.
Copyright © 2012. Published by Elsevier SAS.
The heterogeneous nature of neuromuscular disorders (NMDs) continues to promote slow but steady advances in diagnosis, classification, and treatment. This review focuses on the updates in the general management and treatment of NMDs, with emphasis on key updates in muscular dystrophy, myotonic dystrophy, mitochondrial myopathy, spinal muscular atrophy, and hereditary neuropathies.
Current research shows that improvements in morbidity and mortality in various NMDs may be possible. Key components include advances in identification and classification of individual NMDs; attention to anesthetic and surgical risks; aggressive pulmonary care; and implementations of a proactive, multidisciplinary, standard-of-care approach. Innovative molecular and pharmaceutical therapeutic options are being investigated in many of these disorders, but unfortunately no new intervention has borne out.
Important advances were made in the last year in the field of neuromuscular disease. However, because of their heterogeneous nature and rarity, diagnosis and treatment of these disorders either as a single disorder or as a group continue to be both a clinical and a research challenge. It is of utmost importance that clinicians and researchers be aware of these disorders to aid in identification and treatment.
At least 100 Ryanodine receptor type 1 (RYR1) mutations associated with malignant hyperthermia (MH) and central core disease (CCD) have been identified, but 2 RYR1 mutations accompanying multiminicore myopathy in an MH and/or CCD family have been reported only rarely.
Fifty-three members of a large MH family were investigated with clinical, histopathologic, RYR1 mutation, and haplotyping studies. Blood creatine kinase (CK) and myoglobin levels were also measured where possible.
Sequencing of the entire RYR1 coding region identified a double RYR1 mutation (R2435H and A4295V) in MH/CCD regions 2 and 3. Haplotyping analysis revealed that the two missense heterozygous mutations (c.7304G>A and c.12891C>T) were always present on a common haplotype allele, and were closely cosegregated with histological multiminicores and elevated serum CK. All the subjects with the double mutation showed elevated serum CK and myoglobin, and the obtained muscle biopsy samples showed multiminicore lesions, but only two family members presented a late-onset, slowly progressive myopathy.
We found multiminicore myopathy with clinical and histological variability in a large MH family with an unusual double RYR1 mutation, including a typical CCD-causing known mutant. These results suggest that multiminicore lesions are associated with the presence of more than two mutations in the RYR1 gene.
Malignant hyperthermia (MH) is rarely associated with specific myopathies or musculoskeletal abnormalities. Three clinical
investigations of MH associated with either non‐specific myopathies or congenital disorders in three separate families are
presented. Two of these cases also show evidence of exercise‐induced rhabdomyolysis. In each case MH susceptibility was confirmed
by in vitro contracture testing of quadriceps muscle. DNA sequence analysis of each kindred revealed the presence of a common novel mutation
that results in an arginine401–cysteine substitution in the skeletal muscle ryanodine receptor gene (RYR1). Haplotype analysis using chromosome 19q markers indicated that the three families are likely to be unrelated, providing
confirmation that the MH/central core disease region 1 of RYR1 is a mutation hot spot.
Br J Anaesth 2002; 88: 508–15
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation–contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility. Hum Mutat 15:410–417, 2000. © 2000 Wiley-Liss, Inc.
Magnetic resonance imaging (MRI) has become an important tool in diagnosing complex congenital muscular dystrophies (CMD) with brain abnormalities. Currently, there are two recognized types of CMDs with MRI brain abnormalities, firstly, laminin α2-chain-deficient CMD (MDC1A) with mutations in the LAMA2 gene, and secondly CMDs with hypoglycosylated α-dystroglycan which include Walker–Warburg syndrome (WWS), muscle–eye–brain disease (MEB), Fukuyama CMD (FCMD) and CMD types 1C and 1D (MDC1C and 1D). Brain MRI in MDC1A demonstrates abnormal white matter but rarely other brain abnormalities. In the latter group of CMDs, there is a whole spectrum of abnormalities involving both white and gray matter. The most severe MRI findings are in WWS. Patients with MEB, FCMD and MDC1C and lD also have gray and white matter abnormalities, which, in general, are less severe than those observed in WWS. There may be an overlap in these complex CMDs, both genotypically and in MRI findings.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation–contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility. Hum Mutat 15:410–417, 2000. © 2000 Wiley-Liss, Inc.
It has been suggested that exertional rhabdomyolysis (ER) and malignant hyperthermia (MH) are related syndromes. We hypothesize that patients with unexplained ER harbor mutations in the ryanodine receptor gene type 1 (RYR1), a primary gene implicated in MH, and therefore ER patients are at increased risk for MH. Although there are reported cases of MH in individuals of African descent, there are no data available on molecular characterization of these patients. We analyzed RYR1 in six, unrelated African American men with unexplained ER, who were subsequently diagnosed as MH susceptible (MHS) by the Caffeine Halothane Contracture Test. Three novel and two variants, previously reported in Caucasian MHS subjects, were found in five studied patients. The novel variants were highly conserved amino acids and were absent among 230 control subjects of various ethnic backgrounds. These results emphasize the importance of performing muscle contracture testing and RYR1 mutation screening in patients with unexplained ER. The MHS-associated variant Ala1352Gly was identified as a polymorphism predominant in individuals of African descent. Our data underscore the need for investigating RYR1 across different ethnic groups and will contribute to interpretation of genetic screening results of individuals at risk for MH.
In this article, we analyze myopathies with cores, for which an association to malignant hyperthermia (MH) has been suggested. We discuss the clinical features, the underlying genetic defects, subsequent effects on cellular calcium metabolism, and in vitro muscle responses to MH triggers. We describe in detail central core disease, multiminicore disease, and nemaline rod myopathy. We categorize the diseases according to the affected proteins and discuss the risk for MH, which is high or theoretically possible when the calcium-conducting proteins are affected.
Malignant hyperthermia (MH) is a pharmacogenetic syndrome that variably expresses itself on exposure to triggering agents. MH prevalence in the United States is not well documented. In this study, we assessed the prevalence of MH in New York State hospitals.
Using New York hospital discharge data for the years 2001 through 2005, we identified all patients with a diagnosis of MH due to anesthesia using International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was evaluated by demographic and clinical characteristics.
Of the 12,749,125 discharges from New York hospitals during the study period, 73 patients had a recorded diagnosis of MH due to anesthesia. Nearly three quarters of the MH patients were male and 71% were patients from emergency/urgent admissions. The estimated prevalence rate of MH was 0.96 (95% confidence interval [CI] 0.67-1.24) per 100,000 surgical discharges and 1.08 (95% CI 0.75-1.41) per 100,000 discharges in which there was any indication of exposure to anesthesia. The estimated prevalence of MH for males was 2.5 to 4.5 times the rate for females.
The prevalence of MH due to anesthesia in surgical patients treated in New York State hospitals is approximately 1 per 100,000. MH risk in males is significantly higher than in females.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle in which volatile anesthetics trigger a sustained increase in intramyoplasmic Ca(2+) via release from sarcoplasmic reticulum and, possibly, entry from the extracellular milieu that leads to hypermetabolism, muscle rigidity, rhabdomyolysis, and death. Myotonias are a class of myopathies that result from gene mutations in various channels involved in skeletal muscle excitation-contraction coupling and sarcolemmal excitability, and unusual DNA sequence repeats that result in the inability of many proteins, including skeletal muscle channels that affect excitability, to undergo proper splicing. The suggestion has often been made that myotonic patients have an increased risk of developing MH. In this article, we review the physiology of muscle excitability and excitation-contraction coupling, the pathophysiology of MH and the myotonias, and review the clinical literature upon which the claims of MH susceptibility are based. We conclude that patients with these myopathies have a risk of developing MH that is equivalent to that of the general population with one potential exception, hypokalemic periodic paralysis. Despite the fact that there are no clinical reports of MH developing in patients with hypokalemic periodic paralysis, for theoretical reasons we cannot be as certain in estimating their risk of developing MH, even though we believe it is low.
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.
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder with an estimated mortality of less than 5%. The purpose of this study was to evaluate the current incidence of MH and the predictors associated with in-hospital mortality in the United States.
The Nationwide Inpatient Sample, which is the largest all-payer inpatient database in the United States, was used to identify patients discharged with a diagnosis of MH during the years 2000-2005. The weighted exact Cochrane-Armitage test and multivariate logistic regression analyses were used to assess trends in the incidence and risk-adjusted mortality from MH, taking into account the complex survey design.
From 2000 to 2005, the number of cases of MH increased from 372 to 521 per year. The occurrence of MH increased from 10.2 to 13.3 patients per million hospital discharges (P = 0.001). Mortality rates from MH ranged from 6.5% in 2005 to 16.9% in 2001 (P < 0.0001). The median age of patients with MH was 39 (interquartile range, 23-54 yr). Only 17.8% of the patients were children, who had lower mortality than adults (0.7% vs. 14.1%, P < 0.0001). Logistic regression analyses revealed that risk-adjusted in-hospital mortality was associated with increasing age, female sex, comorbidity burden, source of admission to hospital, and geographic region of the United States.
The incidence of MH in the United States has increased in recent years. The in-hospital mortality from MH remains elevated and higher than previously reported. The results of this study should enable the identification of areas requiring increased focus in MH-related education.
Malignant hyperthermia (MH) was first recognized in Australia in 1960. Malignant hyperthermia is a pharmacogenetic disease triggered by the depolarizing muscle relaxant suxamethonium and all the anesthetic vapors, although some are more potent triggers than others. Malignant hyperthermia has always been recognized as a skeletal muscle disease, involving the excitation-contraction (E-C) coupling mechanism, the means by which nervous activity is transferred to skeletal muscle activity at the neuromuscular junction. E-C coupling is a complex dynamic process in which Ca2+ plays a crucial role. Deep membrane projections (the T-tubules) into the sarcoplasm ensure rapid and even distribution of the impulse. Recent studies using skinned muscle fibers from MH-susceptible patients suggests that reduced Mg2+ concentrations may influence the effect of halothane on Ca2+ release and so have a clinical role in the development of an MH reaction. Malignant hyperthermia-susceptible patients only manifest when exposed to trigger agents, so appear outwardly normal and therefore cannot be identified preoperatively unless there is a personal/family history of anesthetic problems suggestive of MH. The clinical presentation of a MH crisis can be very variable and no one sign is unique to MH, making clinical diagnosis sometimes difficult. MH can develop insidiously over several hours, especially when small concentrations of a vapor are used during artificial ventilation, or it can develop into a dramatic full-blown life-threatening event within half an hour. With current monitoring standards it is apparent that the increase in temperature after which it is named is a comparatively late sign of MH.
Information was collected on 89 patients who responded to general anaesthetics with malignant hyperthermia. The syndrome occurred at the rate of about one in 14,000 anaesthetics among a hospital population of children. The patient mortality was 64 per cent. The finding that males were somewhat more commonly affected than were females does not contradict previous observations of dominant inheritance of the syndrome. About one-third of patients had relatives who were also affected with malignant hyperthermia, although a few patients had had previous uneventful general anaesthetics. The racial origin was varied. A pre-existing muscle or musculoskeletal disease was present more frequently than expected in patients who manifested rigidity.
Clinical manifestations followed the administration of a muscle relaxant or a potent inhalational agent, usually halothane. Fever was invariably present within the first one to two hours of the induction. Skeletal muscle rigidity occurred in more than two-thirds of cases. The use of anticholinergic drugs given preoperatively appeared to increase the incidence of rigidity. The use of non-depolarizing relaxants in vain attempts to overcome the rigidity has certainly not improved the chances of survival. The higher the absolute maximum temperature and the longer the duration of anaesthesia, the greater was the mortality rate.
It is possible that the cases with and without rigidity represent slightly different disorders. In cases characterized by rigidity there were often tachypnoea, tachycardia, arrhythmias, acute heart failure, late neurological deterioration, hypoxia, respiratory and metabolic acidoses, hyperkalaemia, hypocalcaemia, elevated serum enzymes, impaired blood coagulation, haemo- and myoglobinuria, oliguria, and muscle biopsy abnormalities.
Treatment included a wide variety of therapeutic measures. No particular agent could be credited with having improved the survival rate. So far, the most effective treatment was early detection and early cessation of anaesthesia.
Individuals from a large North American population were screened for the presence of the mutation in the alpha1 subunit of the voltage-dependent calcium channel (CACNA1S) that has recently been associated with malignant hyperthermia (MH). This Arg1086His mutation was screened for in 154 MH normal (MHN) individuals and 112 MH susceptible (MHS) individuals, who were diagnosed by the North American protocol of the in vitro contracture test. PCR and restriction enzyme analysis was used to test for the mutation. The Arg1086His mutation in the CACNA1S was not found in any of the MHN individuals. In contrast, two related individuals (grandfather and grandson, father and son of the MH proband) among the MHS group exhibited this mutation. However, a third MHS individual in the same family (granddaughter, cousin of the grandson) did not exhibit this mutation. These results indicate that this mutation may be associated with MH in this family. Genetic alterations in the CACNA1S associated with MH are present in approximately 1% of this North American MHS population.
Hypokalemic periodic paralysis is in most cases related to mutations within the dihydropyridine receptor gene. Susceptibility to malignant hyperthermia has been linked to a different part of the same gene, but is more frequently caused by mutations within the ryanodine receptor gene. We report the association of the two disorders in a patient for whom the most frequent mutations for hypokalemic periodic paralysis were not found. This suggests further genetic heterogeneity of this condition, the interest of this case residing in the known coupling between dihydropyridine and ryanodine receptors.
Hypokalemic periodic paralysis (HypoPP) and malignant hyperthermia (MH) are autosomal-dominant genetically heterogeneous ion channelopathies. MH has been described in patients with HypoPP, suggesting a potential link between these disorders. However, a common genetic determinant has not been described. With the aim of corroborating this association, four candidate genes were screened in two independent HypoPP patients, one of whom was also diagnosed as MH-susceptible and the other as MH-normal by the in vitro contracture test (IVCT). An A>G change at nucleotide 7025 was detected in the RYR1 gene in the HypoPP/MH-susceptible patient. Detection of the same mutation in three independent MH families suggested that 7025A>G represents a novel MH-susceptibility allele and that MH and HypoPP occurred independently in the case presented. Conclusive evidence in support of the hypothesis that MH and HypoPP are allelic was therefore not obtained.
Malignant hyperthermia (MH) is a life-threatening and frequently fatal disorder triggered by commonly used anesthetics. MH susceptibility is a genetically determined predisposition to the development of MH. Mutations in the ryanodine receptor type 1 (RYR1) gene are the major cause of MH susceptibility. The authors sought to develop a reliable genetic screening strategy based on efficient and relatively inexpensive mutation-detection procedures.
A cohort (n = 30) of North American MH patients and MH-susceptible individuals was studied. RNA and DNA extracted from muscle tissue or blood lymphocytes were used for analysis. The entire RYR1 coding region was amplified in 57 overlapping fragments and subjected to denaturing high-performance liquid chromatography analysis followed by direct nucleotide sequencing to characterize RYR1 alterations.
Nine previously reported and nine unknown RYR1 mutations were identified in 21 of 30 studied patients (70%). Some of the new mutations were located outside of known mutational "hot spots," suggesting that RYR1 contains previously unknown mutation-prone areas requiring analysis. The North American MH/MH-susceptible population is characterized by a high RYR1 allelic heterogeneity.
Denaturing high-performance liquid chromatography analysis of RNA samples extracted from the biopsied skeletal muscle followed by DNA sequencing is a highly efficient methodology for RYR1 mutation detection. This approach allows increasing the rate of mutation detection to 70% and identifying mutations in the entire RYR1 coding region.
Malignant hyperthermia (MH) is a dominantly inherited pharmacogenetic condition that manifests as a life-threatening hypermetabolic reaction when a susceptible individual is exposed to common volatile anesthetics and depolarizing muscle relaxants. Although MH appears to be genetically heterogeneous, RYR1 is the main candidate for MH susceptibility. However, since molecular analysis is generally limited to exons where mutations are more frequently detected, these are routinely found only in 30-50% of susceptible subjects. In this study the entire RYR1 coding region was analyzed in a cohort of 50 Italian MH susceptible (MHS) subjects. Thirty-one mutations, 16 of which were novel, were found in 43 individuals with a mutation detection rate of 86%, the highest reported for RYR1 in MH so far. These data provide clear evidence that mutations in the RYR1 gene are the predominant cause of MH.
The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype-phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions.
AHRQ Guide to Patient Safety Indicators (Appendices A & B)
- Healthcare Agency
- Quality Research
Agency for Healthcare Research and Quality. AHRQ Guide to Patient Safety Indicators (Appendices A & B). Available at:
http://www.qualityindicators.ahrq.gov/
archives/psi/psi_technical_specs_v32.pdf.
Published March 2003. Updated March 10,
2008. Accessed December 8, 2010.