Sheila Riazi

Effect of local anaesthetic volume (20 vs 5 ml) on the efficacy and respiratory consequences of ultrasound-guided interscalene brachial plexus block

BACKGROUND Interscalene brachial plexus block (ISBPB) is an effective nerve block for shoulder surgery. However, a 100% incidence of phrenic nerve palsy limits the application of ISBPB for patients with limited pulmonary reserve. We examined the incidence of phrenic nerve palsy with a low-volume ISBPB compared with a standard-volume technique both guided by ultrasound. METHODS Forty patients undergoing shoulder surgery were randomized to receive an ultrasound-guided ISBPB of either 5 or 20 ml ropivacaine 0.5%. General anaesthesia was standardized. Both groups were assessed for respiratory function by sonographic diaphragmatic assessment and spirometry before and after receiving ISBPB, and after surgery. Motor and sensory block, pain, sleep quality, and analgesic consumption were additional outcomes. Statistical comparison of continuous variables was analysed using one-way analysis of variance and Students t-test. Non-continuous variables were analysed using chi(2) tests. Statistical significance was assumed at P<0.05. RESULTS The incidence of diaphragmatic paralysis was significantly lower in the low-volume group compared with the standard-volume group (45% vs 100%). Reduction in forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow at 30 min after the block was also significantly less in the low-volume group. In addition, there was a significantly greater decrease in postoperative oxygen saturation in the standard-volume group (-5.85 vs -1.50, P=0.004) after surgery. There were no significant differences in pain scores, sleep quality, and total morphine consumption up to 24 h after surgery. CONCLUSIONS The use of low-volume ultrasound-guided ISBPB is associated with fewer respiratory and other complications with no change in postoperative analgesia compared with the standard-volume technique.

Connection between Elastin Haploinsufficiency and Increased Cell Proliferation in Patients with Supravalvular Aortic Stenosis and Williams-Beuren Syndrome

To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.

Determinants of complications with recombinant factor VIIa for refractory blood loss in cardiac surgery

PurposeRecombinant factor VIIa (rFVIIa) is being used for refractory, excessive blood loss (EBL) after cardiac surgery, but its safety for this indication is not known.MethodsThe unadjusted and risk-adjusted adverse event (AE) rates were compared between 114 consecutive cardiac surgical patients who received rFVIIa for refractory EBL and 541 concurrent patients who developed EBL but did not receive rFVIIa. Similarly, timing of rFVIIa therapy was assessed by dichotomizing rFVIIa patients based on median number of red blood cell (RBC) units received before therapy. The measured AE was a composite of death, stroke, renal failure, myocardial infarction, and major vein thrombosis. For risk adjustment, logistic regression models for this outcome were constructed using known predictors of AEs.ResultsThe median RBC units transfused before rFVIIa therapy was eight. The AE rates in the untreated, early (≤ 8 U), and late (> 8 U) treated patients were 24% (129/541), 30% (20/66), and 60% (29/48). The risk-adjustment model included total RBC units, pump time, weaning difficulty, gender, weight, and age. The unadjusted and adjusted AE odds ratios (OR) in the treatedvs untreated groups were 2.41 [confidence interval (CI) 1.58 -3.67;P < 0.0001 ] and 1.04 (CI 0.60 — 1.81 ;P = 0.9). In the rFVIIa group, the adjusted AE OR was lower in the early treated group (OR 0.41; CI 0.18 — 0.92;P = 0.03).ConclusionIn cardiac surgical patients with refractory hemorrhage, rFVIIa therapy is not associated with increased risk of AEs, and early treatment may be associated with better outcomes.RésuméObjectifLe facteur VIIa recombinant (rFVIIa) est utilisé pour traiter les pertes sanguines excessives (PSE) réfractaires après une opération cardiaque sans qu’on en connaisse l’innocuité.MéthodeLes taux d’événements indésirables (EI) non ajustés et ajustés en fonction des risques ont été comparés entre 114 patients consécutifs de cardiochirurgie ayant reçu le rFVIIa pour des PSE et 541 patients consécutifs qui ont eu des PSE mais pas de rFVIIa. De même, la programmation du traitement au rFVIIa a été étudiée par une division dichotomique des patients, recevant le rFVIIa, fondée sur le nombre médian d’unités de culots globulaires (CG) reçues avant le traitement. Les EI étaient la mort, l’accident vasculaire, l’insuffisance rénale, l’infarctus du myocarde et la thrombose veineuse majeure. Des modèles de régression logistique ont été construits pour ajuster le risque en utilisant les prédicteurs connus d’EI.RésultatsLa médiane des unités de CG transfusées avant le traitement au rFVIIa a été de huit. Les taux d’EI chez les patients non traités, traités tôt (≤ 8 U) et tard (> 8 U) ont été de 24 % (129/541), 30 % (20/66) et 60 % (29/48). Le modèle d’ajustement du risque comprenait le nombre total d’unités de CG, le temps de perfusion, les difficultés de sevrage, le sexe, le poids et l’âge. Les risques relatifs (RR) d’EI non ajustés et ajustés chez les patients traités vs non traités ont été de 2,41 [intervalle de confiance (IC) de 1,58 -3,67 ;P< 0,0001] et 1,04 (IC 0,60-1,81 ;P = 0,9). Dans le groupe rFVIIa, le RR d’EI ajusté a été plus bas chez les patients traités tôt (RR 0,41 ; IC 0,18 — 0,92 ; P = 0,03).ConclusionChez les patients de cardiochirurgie victimes d’hémorragie réfractaire, le traitement au rFVIIa n’est pas associé

Can Ultrasound of the Tibial Nerve Detect Diabetic Peripheral Neuropathy?: A cross-sectional study

OBJECTIVE Peripheral nerve imaging by portable ultrasound (US) may serve as a noninvasive and lower-cost alternative to nerve conduction studies (NCS) for diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). We aimed to examine the association between the size of the posterior tibial nerve (PTN) and the presence and severity of DSP. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 98 consecutive diabetic patients classified by NCS as subjects with DSP or control subjects. Severity was determined using the Toronto Clinical Neuropathy Score. A masked expert sonographer measured the cross-sectional area (CSA) of the PTN at 1, 3, and 5 cm proximal to the medial malleolus. RESULTS Fifty-five patients had DSP. The mean CSA of the PTN in DSP compared with control subjects at distances of 1 (23.03 vs. 17.72 mm2; P = 0.004), 3 (22.59 vs. 17.69 mm2; P < 0.0001), and 5 cm (22.05 vs. 17.25 mm2; P = 0.0005) proximal to the medial malleolus was significantly larger. Although the area under the curve (AUC) for CSA measurements at all three anatomical levels was similar, the CSA measured at 3 cm above the medial malleolus had an optimal threshold value for identification of DSP (19.01 mm2) with a sensitivity of 0.69 and a specificity of 0.77 by AUC analysis. CONCLUSIONS This large study of diabetic patients confirms that the CSA of the PTN is larger in patients with DSP than in control subjects, and US is a promising point-of-care screening tool for DSP.

Malignant Hyperthermia in Canada: Characteristics of Index Anesthetics in 129 Malignant Hyperthermia Susceptible Probands

BACKGROUND:Between 1992 and 2011, 373 Canadian individuals with adverse anesthetic reaction were referred to the Malignant Hyperthermia Unit in Toronto, Ontario, Canada for malignant hyperthermia (MH) diagnostic testing. We analyzed the epidemiologic characteristics of the index adverse anesthetics for those probands who were confirmed to be MH susceptible. METHODS:One hundred twenty-nine proband survivors of adverse anesthetic reactions, whose MH susceptible status was confirmed by caffeine-halothane contracture testing were selected. Individuals were excluded if the index anesthetic record was not available for review. Data regarding demographics, clinical signs, laboratory findings, treatment, and complications were retrospectively compiled and analyzed. A Fisher exact test and &khgr;2 test were applied to compare categorical variables. The Wilcoxon rank-sum test was applied with continuous variables. RESULTS:Young males (61.2%) dominated among selected patients. Seventeen of 129 (13.2%) patients had prior unremarkable anesthesia. Anesthetic triggers were volatile-only (n = 58), succinylcholine-only (n = 20), or both volatile and succinylcholine (n = 51). Eight (6.2%) cases occurred in the postanesthetic care unit. There were no reactions after discharge from the postanesthetic care unit. The most frequent clinical signs were hyperthermia (66.7%), sinus tachycardia (62.0%), and hypercarbia (51.9%). Complications occurred in 20.1% of patients, the most common complication being renal dysfunction. When 20 or more minutes between the first adverse sign and dantrolene treatment elapsed, complication rates increased to ≥30%. CONCLUSIONS:This is the first Canadian study in 3 decades to report nationwide data on MH epidemiology. Features that differ from earlier reports include a 15.5% incidence of reactions triggered by succinylcholine alone and lower complication rates. In agreement with previously published studies, we confirmed in this independent dataset that increased complication rates were associated with an increased time interval between the first adverse clinical sign and dantrolene treatment. This underscores the need for early diagnosis and rapid dantrolene access and administration in anesthetizing locations using either succinylcholine or volatile anesthetic drugs.

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

PurposeTo 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 findingsAn 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 CO2. 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.ConclusionThe 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.RésuméObjectifSignaler l’identification d’une nouvelle mutation du gène CACNA1S, qui code la sous-unité alpha 1 (Cav1.1) du canal calcique voltage-dépendant de type L des cellules musculaires squelettiques chez une patiente souffrant d’hyperthermie maligne.Éléments cliniquesUne femme de 34 ans généralement en santé a développé une hyperthermie maligne (HM) fulminante alors qu’elle se trouvait sous anesthésie au sévoflurane pendant une néphrectomie laparoscopique pour don d’organe. Le premier signe s’est manifesté sous la forme d’une augmentation du CO2 télé-expiratoire. Un diagnostic présumé d’hyperthermie maligne a été effectué de manière précoce, et des méthodes de réanimation, y compris des traitements de soutien et des traitements spécifiques, ont été adoptées avec succès. La patiente a refusé la biopsie musculaire ouverte pour le test de contracture à la caféine-halothane (CHCT); par conséquent, seules les analyses moléculaires génétiques ont été effectuées. Le séquençage de l’ensemble du transcrit du récepteur de ryanodine de type 1 n’a révélé aucune mutation associée à la HM. Cependant, une nouvelle mutation homozygote, p.Arg1086Ser, a été identifiée dans le gène CACNA1S, qui code la sous-unité alpha 1 du canal calcique de type L des cellules musculaires squelettiques (Cav1.1). Une mutation du gène CACNA1S, p.Arg1086His, impliquant le même résidu Arg1086 qui a muté chez notre patiente, a précédemment été signalée en association avec la HM chez trois familles indépendantes.ConclusionLa mutation p.Arg1086Ser homozygote de CACNA1S, le gène qui code la sous-unité alpha 1 du canal calcique voltage-dépendant des cellules musculaires squelettiques, est une nouvelle mutation associée à l’hyperthermie maligne.

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

PurposeMalignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population.MethodsIn this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families.ResultsEighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations.ConclusionsThe distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing.RésuméObjectifL’hyperthermie maligne (HM) est une maladie pharmacogénétique héréditaire dominante autosomique qui se manifeste lors de l’exposition des personnes susceptibles à des anesthésiques halogénés ou à la succinylcholine. Étant donné que l’HM est principalement associée aux mutations au niveau du gène des récepteurs de ryanodine de type 1 (RYR1), l’objectif de cette étude était de déterminer la distribution et la fréquence des mutations RyR1 causant une HM chez la population canadienne susceptible à l’HM (SHM).MéthodeDans cette étude, nous avons examiné une cohorte représentative de 36 personnes canadiennes SHM sans liens familiaux pour identifier les mutations RYR1 en séquençant des transcrits complets de RYR1 et des régions choisies de transcrits de CACNA1S. Nous avons ensuite analysé la corrélation entre les résultats de l’étude de la contractilité de la cellule musculaire en présence de caféine et d’halothane (test CHCT) et les génotypes RYR1 au sein des familles d’HM.RésultatsQuatre-vingt-six pour cent (31 sur 36) des patients ont manifesté au moins une mutation RyR1, dont cinq sans liens familiaux étaient porteurs de la double variante. Quinze des 27 mutations identifiées sur le RYR1 étaient nouvelles. Huit mutations nouvelles, y compris des acides aminés bien conservés, ont été anticipées comme étant causales. Deux des mutations se sont co-ségrégées avec le phénotype SHM dans deux vastes familles indépendantes (au total 79 personnes). Quatorze pour cent des personnes SHM (cinq sur les 36) n’étaient porteuses ni des mutations de RYR1 ni de mutations connues de CACNA1S.ConclusionLa distribution et la fréquence de mutations de RyR1 causatives de HM dans la population canadienne SHM sont semblables à celles de populations européennes SHM. Les nouvelles mutations décrites dans cette étude s’ajouteront au fonds mondial de mutations associées à la HM dans le gène RYR1, ce qui contribuera à augmenter la valeur du dépistage diagnostique génétique de l’HM.

The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle.

A novel category of diseases of striated muscle is proposed, the couplonopathies, as those that affect components of the couplon and thereby alter its operation. Couplons are the functional units of intracellular calcium release in excitation–contraction coupling. They comprise dihydropyridine receptors, ryanodine receptors (Ca2+ release channels), and a growing list of ancillary proteins whose alteration may lead to disease. Within a generally similar plan, the couplons of skeletal and cardiac muscle show, in a few places, marked structural divergence associated with critical differences in the mechanisms whereby they fulfill their signaling role. Most important among these are the presence of a mechanical or allosteric communication between voltage sensors and Ca2+ release channels, exclusive to the skeletal couplon, and the smaller capacity of the Ca stores in cardiac muscle, which results in greater swings of store concentration during physiological function. Consideration of these structural and functional differences affords insights into the pathogenesis of several couplonopathies. The exclusive mechanical connection of the skeletal couplon explains differences in pathogenesis between malignant hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia (CPVT), conditions most commonly caused by mutations in homologous regions of the skeletal and cardiac Ca2+ release channels. Based on mechanistic considerations applicable to both couplons, we identify the plasmalemma as a site of secondary modifications, typically an increase in store-operated calcium entry, that are relevant in MH pathogenesis. Similar considerations help explain the different consequences that mutations in triadin and calsequestrin have in these two tissues. As more information is gathered on the composition of cardiac and skeletal couplons, this comparative and mechanistic approach to couplonopathies should be useful to understand pathogenesis, clarify diagnosis, and propose tissue-specific drug development.

CASQ1 gene is an unlikely candidate for malignant hyperthermia susceptibility in the North American population.

Background:Malignant hyperthermia (MH, MIM# 145600) is a complex pharmacogenetic disorder that is manifested in predisposed individuals as a potentially lethal reaction to volatile anesthetics and depolarizing muscle relaxants. Studies of CASQ1-null mice have shown that CASQ1, encoding calsequestrin 1, the major Ca2+ binding protein in the lumen of the sarcoplasmic reticulum, is a candidate gene for MH in mice. The aim of this study was to establish whether the CASQ1 gene is associated with MH in the North American population. Methods:The entire coding region of CASQ1 in 75 unrelated patients diagnosed by caffeine-halothane contracture test as MH susceptible (MHS) was analyzed by DNA sequencing. Subsequently, three groups of unrelated individuals (130 MHS, 100 MH negative, and 192 normal controls) were genotyped for a variant that was identified by sequencing. Levels of CASQ1 expression in the muscle from unrelated MHS and MH negative individuals were estimated by Western blotting. Results:Screening of the entire coding sequence of the CASQ1 gene in 75 MHS patients revealed a single variant c.260T > C (p.Met87Thr) in exon 1. This variant is unlikely to be pathogenic, because its allele frequency in the MHS group was not significantly different from that of controls. There was also no difference in calsequestrin 1 protein levels between muscle samples from MHS and controls, including those carrying the p.Met87Thr variant. Conclusions:This study revealed a low level of protein coding sequence variability within the human CASQ1 gene, indicating that CASQ1 is not a major MHS locus in the North American population.

Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.