Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.

Dexamethasone as an adjuvant for peripheral nerve blockade: a randomised, triple-blinded crossover study in volunteers.

BACKGROUND: The efficacy of dexamethasone in extending the duration of local anaesthetic block is uncertain. In a randomised controlled triple blind crossover study in volunteers, we tested the hypothesis that neither i.v. nor perineurally administered dexamethasone prolongs the sensory block achieved with ropivacaine. METHODS: Ultrasound-guided ulnar nerve blocks (ropivacaine 0.75% wt/vol, 3 ml, with saline 1 ml with or without dexamethasone 4 mg) were performed on three occasions in 24 male volunteers along with an i.v. injection of saline 1 ml with or without dexamethasone 4 mg. The combinations of saline and dexamethasone were as follows: control group, perineural and i.v. saline; perineural group, perineural dexamethasone and i.v. saline; i.v. group, perineural saline and i.v. dexamethasone. Sensory block was measured using a VAS in response to pinprick testing. The duration of sensory block was the primary outcome and time to onset of sensory block the secondary outcome. RESULTS: All 24 subjects completed the trial. The median [inter-quartile range (IQR)] duration of sensory block was 6.87 (5.85-7.62) h in the control group, 7.37 (5.78-7.93) h in the perineural group and 7.37 (6.10-7.97) h in the i.v. group (P=0.61). There was also no significant difference in block onset time between the three groups. CONCLUSION: Dexamethasone 4 mg has no clinically relevant effect on the duration of sensory block provided by ropivacaine applied to the ulnar nerve. CLINICAL TRIAL REGISTRATION: DRKS, 00014604; EudraCT, 2018-001221-98.

Comparative epidemiology of suspected perioperative hypersensitivity reactions.

Suspected perioperative hypersensitivity reactions are rare but contribute significantly to the morbidity and mortality of surgical procedures. Recent publications have highlighted the differences between countries concerning the respective risk of different drugs, and changes in patterns of causal agents and the emergence of new allergens. This review summarises recent information on the epidemiology of perioperative hypersensitivity reactions, with specific consideration of differences between geographic areas for the most frequently involved offending agents.

Regional anesthesia for shoulder surgery.

Regional anesthesia should be the preferred technique for analgesia in shoulder surgery, which is a frequent procedure in the daily practice of anesthesiologists. The use of ultrasound guidance enables the visualization of the relevant nerve structures and the adjacent anatomical details. Low volumes of local anesthetics reduce the incidence of inadvertent blockade of the phrenic nerve with subsequent respiratory impairment. The additional administration of dexmedetomidine to local anesthetics prolonges the duration of analgesia with a minimal increased incidence of haemodynamic side effects. An optimal workflow is associated with economical advantages due to an improved use of operation rooms. Attention have to be paid regarding intraoperative hypotension, cerebral hypoperfusion and complications due to positioning.