Successful Treatment Without Using Dantrolene Sodium on a Child Occurring Malignant Hyperthermia During Induction of General Anesthesia: A Case Report.

Malignant hyperthermia (MH) is a fatal hyperthermia with a high mortality, which usually occurs during induction of general anesthesia. Dantrolene sodium is a wonder drug currently used for treating malignant hyperthermia. However, preparing, storing, and maintaining dantrolene sodium are crucially expensive, thus making it financially unsatisfactory and difficult for clinicians to acquire in time. Monitoring patients' condition closely and intervening promptly when early signs of malignant hyperthermia occur can effectively prevent the condition from worsening and win over time for the arrival of dantraline sodium. This article is to report a case in which we successfully rescued a child occurring malignant hyperthermia without using dantrolene sodium.

Access to Intrathecal Baclofen Treatment for Children with Cerebral Palsy in European Countries: An SCPE Survey Reveals Important Differences.

AIM: The aim is to study access to intrathecal baclofen (ITB) for children with cerebral palsy (CP) in Europe, as an indicator of access to advanced care. METHODS: Surveys were sent to CP registers, clinical networks, and pump manufacturers. Enquiries were made about ITB treatment in children born in 1990 to 2005 by sex, CP type, level of gross motor function classification system (GMFCS) and age at the start of treatment. Access to ITB was related to the country's gross domestic product (GDP) and % GDP spent on health. RESULTS: In 2011 population-based data from Sweden, Norway, England, Portugal, Slovenia, and Denmark showed that 114 (3.4%) of 3,398 children with CP were treated with ITB, varying from 0.4 to 4.7% between centers. The majority of the children were at GMFCS levels IV-V and had bilateral spastic CP. In Sweden, dyskinetic CP was the most commonly treated subtype. Boys were more often treated with ITB than girls (p = 0.014). ITB was reported to be available for children with CP in 25 of 43 countries. Access to ITB was associated with a higher GDP and %GDP spent on health (p < 0.01). Updated information from 2019 showed remaining differences between countries in ITB treatment and sex difference in treated children was maintained. CONCLUSION: There is a significant difference in access to ITB for children with CP across Europe. More boys than girls are treated. Access to ITB for children with CP is associated with GDP and percent of GDP spent on health in the country.

Association of Formulary Exclusions and Restrictions for Opioid Alternatives With Opioid Prescribing Among Medicare Beneficiaries.

Importance: Although there are many pharmacologic alternatives to opioids, it is unclear whether the structure of Medicare Part D formularies discourages use of the alternatives. Objectives: To quantify the coverage of opioid alternatives and prevalence of prior authorization, step therapy, quantity limits, and tier placement for these drugs, and test whether these formulary exclusions and restrictions are associated with increased opioid prescribing to older adults at the county level. Design, Setting, and Participants: County fixed-effect models were estimated using a panel of counties across the 50 US states and the District of Columbia over calendar years 2015 and 2016. Data analysis was conducted from July 1 to September 23, 2019. The sample included 2721 counties in 2015 and 2671 counties in 2016 with sufficient data on Medicare Part D formulary design and opioid prescribing. Main Outcomes and Measures: County-level opioid prescribing rate (number of opioid claims divided by the number of overall claims) and counts of excluded opioid alternatives and opioid alternatives with prior authorization, step therapy, quantity limits, and high-tier placements. Results: A total of 30 nonopioid analgesics were examined across 28 997 Medicare plans in 2015 and 30 390 plans in 2016. Medicare plans did not cover a mean of 7% of these drugs (interquartile range, 10%; lower to upper limit, 0%-23%). Among covered nonopioids, prior authorization and step therapy were uncommon, with fewer than 5% affected by prior authorization and 0% by step therapy. However, 13% of covered nonopioids had quantity limits (interquartile range, 10%; lower to upper limit, 0%-31%) and 22% were in high-cost tiers (interquartile range, 38%; lower to upper limit, 0%-50%). Increases in the number of nonopioids excluded on Medicare plans in a county were associated with increased opioid prescribing (effect size relative to mean, 2.2%-3.7%; P = .004). Conversely, increases in the number of opioids not covered on Medicare plans in a county was found to be associated with decreased opioid prescribing (effect size relative to mean, 0.8%-1.5%; P = .02). None of the utilization management strategies (prior authorization, step therapy, and quantity limits) examined or high-cost tier placements of nonopioids were associated with increased opioid prescribing. Conclusions and Relevance: Lack of Medicare coverage for pharmacologic alternatives to opioids may be associated with increased opioid prescribing.

Retrospective Study of Patients with Hyperphenylalaninemia- Experience from a Tertiary Care Center in Pakistan.

OBJECTIVE: To assess the clinical and biochemical features as well as outcome of hyperphenylalaninemia patients. Methods: The descriptive retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data from January 2013 to February 2017 of plasma amino acid analysed at the Biochemical Genetic Laboratory of patients with phenylalanine levels >120 umol/L. Medical charts of patients registered with the Metabolic Clinics were reviewed, while outside referrals were contacted by telephone to collect data on a pre-structured questionnaire. Data was analysed using SPSS 21. RESULTS: Of the 18 patients, 13(72%) were males. Overall median age was 606 days (interquartile range: 761) and median phenylalanine levels were 1280 (interquartile range: 935) umol/L. Phenylalanine hydroxylase deficiency was present in 5(28%) patients while 3(16.6%) had defects in the metabolism or regeneration of tetrahydrobiopterin. The most common clinical features was intellectual deficit and seizures 14(78%) each, followed by lighter hair colour 10(55.5%) and hypotonia 11(61%). High treatment cost was the leading reason for cessation of therapy in 7(39%) followed by refusal by patient's family 5(28%). CONCLUSIONS: Most hyperphenylalaninemia cases were diagnosed late when intellectual disability had already developed.

Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

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.

Gender Differences in Use of Prolonged Nonoperative Therapies Before Index Lumbar Surgery.

OBJECTIVE: The purpose of the present study was to assess for gender-based differences in the usage and cost of maximal nonoperative therapy before spinal fusion surgery in patients with symptomatic lumbar stenosis or spondylolisthesis. METHODS: A large insurance database was queried for patients with symptomatic lumbar stenosis or spondylolisthesis undergoing index lumbar decompression and fusion procedures from 2007 to 2016. This database consists of 20.9 million covered lives and includes private or commercially insured and Medicare Advantage beneficiaries. Only patients continuously active within the Humana insurance system for ≥5 years before the index operation were eligible. Usage was characterized by the cost billed to the patient, prescriptions written, and number of units billed. RESULTS: A total of 4133 patients (58.5% women) underwent 1-, 2-, or 3-level posterior lumbar instrumented fusion. A significantly greater percentage of female patients used nonsteroidal anti-inflammatory drugs (P < 0.0001), lumbar epidural steroid injections (P = 0.0044), physical and/or occupational therapy (P < 0.0001), and muscle relaxants (P < 0.0001). The total direct cost associated with all maximal nonoperative therapy before index spinal fusion was $9,000,968, with men spending $3,451,479 ($2011.35 per patient) and women spending $5,549,489 ($2296.02 per patient). When considering the quantity of units billed, women used 61.5% of the medical therapy units disbursed despite constituting 58.5% of the cohort. When normalized by the number of pills billed per patient using therapy, female patients used more nonsteroidal anti-inflammatory drugs, opioids, and muscle relaxants. CONCLUSIONS: These results suggest that gender differences exist in the use of nonoperative therapies for symptomatic lumbar stenosis or spondylolisthesis before fusion surgery.

Tizanidina para o tratamento do espasmo muscular doloroso / Tizanidine for the treatment of painful muscle spasm

TECNOLOGIA: Tizanidina (Sirdalud®). INDICAÇÃO NA BULA: Espasmo muscular doloroso associado à distúrbios estáticos e funcionais da coluna (síndromes cervical e lombar) e após cirurgia, como por exemplo, de hérnia de disco intervertebral ou de osteoartrite do quadril. Também é indicado para a espasticidade decorrente de distúrbios neurológicos, tais como: esclerose múltipla, mielopatia crônica, doenças degenerativas da medula espinhal, acidentes cerebrovasculares e paralisia cerebral. PERGUNTA: Tizanidina é eficaz e segura para o tratamento do espasmo muscular doloroso? EVIDÊNCIAS: Foram incluídas duas revisões sistemáticas e um ensaio clínico randomizado. Uma revisão sistemática sugere que baclofeno e tizanidina têm eficácia semelhante em pacientes com espasticidade e que tizanidina está associada a maior frequencia de boca seca, enquanto baclofeno com maior fraqueza. Além disso, tizanidina foi eficaz em comparação com o placebo em pacientes com espasticidade (principalmente associada a esclerose múltipla, dor nas costas ou dor no pescoço). Outra revisão sistemática indicou que tizanidina não apresenta diferença na eficácia para baclofeno e diazepam. Em comparação com placebo, tizanidina reduziu o tônus muscular em até 34%. Os eventos adversos associados à tizanidina (que ocorreram em 60 a 88% dos pacientes) foram principalmente sonolência e boca seca, e com menor frequência, alteração nas enzimas hepáticas. O ensaio clínico randomizado demonstrou que tizanidina é eficaz contra placebo e possui eficácia comparável a tiocolchicósido no tratamento da dor lombar aguda associada a espasmos musculares. CONCLUSÕES: Com base em evidências derivadas de estudos de baixa qualidade, tizanidina demonstrou ser eficaz em comparação com o placebo e não apresenta diferença em termos de eficácia para outros comparadores ativos, como baclofeno e diazepam. O principal evento adverso associado ao medicamento foi boca seca. O medicamento não apresenta registro na EMA. Estudos mais robustos são necessários para confirmar a eficácia da tizanidina dentro da sua indicação clínica.(AU)

Cost-effectiveness of Intrathecal Baclofen Therapy in severe refractory non-focal disabling spasticity: a Spanish hospital perspective.

BACKGROUND: Current knowledge about long-term economic consequences of Intrathecal Baclofen Therapy (ITB Therapy®) is incomplete. METHODS: A markov model was developed to estimate long-term clinical and economic outcomes with ITB Therapy® and conventional medical management of severe refractory non-focal disabling spasticity. Clinical and cost inputs were obtained through a non-interventional, prospective, observational study in a Spanish neurorehabilitation hospital. RESULTS: ITB Therapy® increased remaining lifetime costs by €35,605 and resulted in a gain of 1.06 quality-adjusted life-years (QALYs), thus showing an incremental cost-effectiveness ratio (ICER) of €33,619/QALY gained. In alternative scenarios, reflecting other clinical settings and management options, considerably lower ICER values were obtained. In particular, opportunities were identified to improve efficiency by setting clinically and economically sound targets for post-operation length of stay. CONCLUSION: In the Spanish setting, ITB Therapy® resulted in an ICER close to €30,000/QALY gained; potential ways to reduce costs and further enhance efficiency can be identified.

[Complex regional pain syndrome (CRPS) - difficulties in diagnostics, therapy and assessment]. / Das komplexe regionale Schmerzsyndrom (CRPS)- Schwierigkeiten in der Diagnostik, Therapie und Begutachtung.

CRPS is still widely unknown among physicians. However, surgeons and GPs should know the diagnostic criteria and the modern therapeutic approaches in order to start early therapy according to recent medical guidelines. Pain specialists and/ or neurologists should be involved because of their clinical and neuroanatomic knowledge. First-line therapy comprises neither extensive instrumental diagnostic procedures nor invasive treatments, which - in some cases - could even worsen the disease. The key point is a variety of specific physiotherapeutic techniques. The prognosis is not as poor as many physicians believe.

Incidence of difficult airway situations during prehospital airway management by emergency physicians--a retrospective analysis of 692 consecutive patients.

INTRODUCTION: In the prehospital setting, advanced airway management is challenging as it is frequently affected by facial trauma, pharyngeal obstruction or limited access to the patient and/or the patient's airway. Therefore, incidence of prehospital difficult airway management is likely to be higher compared to the in-hospital setting and success rates of advanced airway management range between 80 and 99%. METHODS: 3961 patients treated by an emergency physician in Zurich, Switzerland were included in this retrospective analysis in order to determine the incidence of a difficult airway along with potential circumstantial risk factors like gender, necessity of CPR, NACA score, GCS, use and type of muscle relaxant and use of hypnotic drugs. RESULTS: 692 patients underwent advanced prehospital airway management. Seven patients were excluded due to incomplete or incongruent documentation, resulting in 685 patients included in the statistical analysis. Difficult intubation was recorded in 22 patients, representing an incidence of a difficult airway of 3.2%. Of these 22 patients, 15 patients were intubated successfully, whereas seven patients (1%) had to be ventilated with a bag valve mask during the whole procedure. CONCLUSION: In this physician-led service one out of five prehospital patients requires airway management. Incidence of advanced prehospital difficult airway management is 3.2% and eventual success rate is 99%, if performed by trained emergency physicians. A total of 1% of all prehospital intubation attempts failed and alternative airway device was necessary.

Impact of vitamin D supplementation on health-care use in a 25-hydroxyvitamin D-tested population in France: a population-based descriptive cohort study.

OBJECTIVE: Chronic vitamin D deficiency has been associated in some patients with diffuse musculoskeletal pain. These unspecific symptoms may partly explain why vitamin D deficiency is often diagnosed late. Our aim was to analyse health-care claims after vitamin D supplementation in patients likely to have vitamin D deficiency. DESIGN: Ambulatory health-care claims were compared before and after a vitamin D supplementation prescribed following a 25-hydroxyvitamin D assay. SETTING: Health Insurance Fund (FHIF) database of the Rhône-Alpes area, France. SUBJECTS: Among patients reimbursed for a 25-hydroxyvitamin D assay between 1 December 2008 and 31 January 2009, those supplemented with vitamin D after the assay were matched on the date of assay to patients who did not receive vitamin D. RESULTS: Among the 3023 patients who had a 25-hydroxyvitamin D assay, 935 were consequently supplemented and matched to 935 patients not supplemented. Their median age was 50·0 and 49·5 years, respectively. Patients supplemented decreased their muscle relaxant consumption whereas no change was observed in the reference group, the difference between the two groups was significant (P=0·03). Second and third Pain Relief Ladder prescriptions decreased in both groups but not significantly differently between groups (P=0·58). There was a decrease in prescriptions of biological examination in both groups with no significant difference. CONCLUSIONS: Besides a decrease in muscle relaxant prescriptions in the supplemented group, it was difficult to assess the impact of vitamin D supplementation in patients likely to have vitamin D deficiency. Prospective cohort studies and randomized trials are needed to assess the efficiency of screening and supplementing vitamin D deficiency.

Clinical case reviews and poster sessions in multiple sclerosis spasticity: main outcomes and highlights.

BACKGROUND: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary : Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic 'priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.

Use of an active surveillance system by the FDA to observe patterns of quinine sulfate use and adverse hematologic outcomes in CMS Medicare data.

PURPOSE: In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes. METHODS: Medicare beneficiaries, aged 65 years and older, in 2006-2012, were included in incident quinine or comparator, diltiazem, cohorts if 183 days prior to dispensing, they were enrolled in Medicare, had no dispensing of quinine, diltiazem, ticlodipine, clopidogrel, and sulfonamide drugs, and had no diagnoses of thrombocytopenia, immune thrombocytopenic purpura (ITP), thrombotic microangiopathy (TMA), or hemolytic-uremic syndrome (HUS). Diagnoses of malaria or leg cramps were observed during 183 days prior to index dispensing. Outcomes of ITP, TMA, or HUS in inpatient or emergency room settings were then observed during drug use. RESULTS: Prevalent use of quinine decreased by 99%, from 419 675 to 6036 users during 2006-2012. Of 88 066 quinine users, 9 had diagnoses of malaria and 36 218 had leg cramps. Incidence rates (per 1000 person-years) for ITP were quinine 1.67 and diltiazem 0.40 [incidence rate ratio 4.2 (95% confidence interval 2.5, 6.5)], for TMA were quinine 0.23 and diltiazem 0.03 [incidence rate ratio 6.9 (95% confidence interval 1.3, 24.0)], and for HUS were quinine 0 and diltiazem 0.01. CONCLUSIONS: Use of quinine decreased substantially, although diagnoses of leg cramps persist. To our knowledge, this is the first demonstration of an association for quinine and ITP and TMA in claims data.

Multiple sclerosis spasticity daily management: retrospective data from Europe.

Multiple sclerosis (MS) is a distressing and debilitating disease, which often leads to a state of progressive deterioration for the individual. Spasticity is a common and disabling neurological feature with increasing presence and severity throughout the progression of MS. Management of this spasticity is a key component of day-to-day care for patients with MS. Data from recent epidemiological studies in Spain (the '6E' and '5E' studies) and Germany (the 'MOVE 1' study) confirm the frequent occurrence of spasticity symptoms in patients with MS. Despite the difficulties experienced by MS patients with spasticity, the condition is largely undertreated because current treatment options do not provide adequate control of MS spasticity. With worsening MS spasticity there is an increase in individual patient symptoms, worsening of quality of life and impairment of daily living. From a healthcare/societal perspective, MS spasticity has been shown to be associated with substantial costs. Many of these costs relate to the increased disability (and consequent need for rehabilitation and caregiver support) that are associated with moderate-to-severe spasticity. Consequently, newer drugs that can provide better symptomatic relief and may slow progression to more severe forms of disability will be a step forward in the level of care that we can provide for MS patients.

Cost effectiveness of oromucosal cannabis-based medicine (Sativex®) for spasticity in multiple sclerosis.

BACKGROUND: Spasticity is common in patients with multiple sclerosis (MS) and is a major contributor to disability. Sativex®, an oromucosal spray containing cannabis-based medicinal products, has been found to be effective in reducing spasticity symptoms. OBJECTIVE: Our objective was to estimate the cost effectiveness of Sativex® plus oral anti-spasticity medicines compared with the current standard treatment for moderate or severe spasticity in MS in the UK. METHODS: A Markov model was used to assess the costs and benefits of Sativex® plus oral anti-spasticity medicines or current standard treatment based on their effects on the quality of life of patients. The main outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per additional QALY gained over 5 years of treatment. One-way, multi-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the findings. RESULTS: In the base case, Sativex® plus oral anti-spasticity medicines resulted in incremental costs of £7600 and a QALY gain of 0.15 per person over 5 years (ICER = £49 300 per QALY).[year 2009 data for costs]. Findings were sensitive to the costs of Sativex® (price and dose) and differences in utilities between responders and non-responders. CONCLUSIONS: Using a willingness-to-pay threshold of £30 000 per QALY, Sativex® appears unlikely to be considered cost effective by UK funders of healthcare for spasticity in MS. This is unfortunate, since it appears that Sativex® use is likely to benefit some patients in the management of this common consequence of MS.

[A system of prescriptions without drug approval: example of baclofen]. / Un dispositif de prescriptions hors-AMM : exemple du baclofène.

Baclofen is an anti-spastic drug that acts as an agonist of GABA-B receptors. It also seems to decrease the appetence for alcohol (anti-craving effect), although this effect has not been certified by Authorities for drug approval in France (AMM). However, baclofen receives a great deal of demand by patients hoping to reduce their alcohol consumption. Nonetheless, the lack of AMM and the high doses of baclofen supposed to exert an anti-craving effect often discourage practitioners from prescribing this drug in current medical practice. Therefore, it is preferable for a drug like baclofen to be prescribed under specific regulations. As such, certain criteria similar to those required in clinical trials are necessary to protect patients as well as the prescribing doctors. The criteria that are proposed here are: the use of drugs without AMM approval as a last resort (all other treatments must have failed), the collegiate decision for the drug prescription, good knowledge of the potency of the drug as well as good record keeping of patients and proper supervision. The departments of addiction, pharmacology and pharmacovigilance of the University Hospital of Lille, France present here a medical process named "multidisciplinary consultations for resort treatments of addictions" (CAMTEA). This process is designed to meet all the above mentioned criteria and to allow the use of baclofen as an anti-craving drug in safest conditions. If this proves to be successful with baclofen, it is possible to extend the use of CAMTEA to other drugs without AMM approval in addictologic pathologies.

A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene.

PURPOSE: To report the identification of a novel mutation in the CACNA1S gene that encodes the alpha-1-subunit (Cav1.1) of the voltage-gated skeletal muscle L-type calcium channel in a patient with malignant hyperthermia. CLINICAL FINDINGS: An otherwise healthy 34-yr-old female developed fulminant malignant hyperthermia (MH) under sevoflurane anesthesia during laparoscopic donor nephrectomy. The first sign was an increase in end-tidal CO(2). Malignant hyperthermia was suspected early, and resuscitative measures, including supportive and specific treatment, were successfully implemented. The patient rejected the open muscle biopsy for the Caffeine-Halothane Contracture Test (CHCT); therefore, only molecular genetic testing was performed. Sequencing of the entire ryanodine receptor type 1 transcript did not reveal any MH causative mutations. However, a novel homozygous mutation, p.Arg1086Ser, was identified in the CACNA1S gene that encoded for the alpha-1-subunit of the skeletal muscle L-type calcium channel (Cav1.1). A CACNA1S mutation, p.Arg1086His, involving the same Arg1086 residue that is mutated in our patient has previously been reported in association with MH in three independent families. CONCLUSION: The homozygous p.Arg1086Ser mutation of CACNA1S, the gene that encodes the alpha-1-subunit of the voltage-gated skeletal muscle L-type calcium channel, is a novel mutation associated with malignant hyperthermia.

Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006.

BACKGROUND: We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. METHODS: Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. RESULTS: Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. CONCLUSION: Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.