Exertional Heat Stroke and Rhabdomyolysis: A Medical Record Review and Patient Perspective on Management and Long-Term Symptoms.

INTRODUCTION: Exertional heat stroke (EHS) is a medical emergency, occurring when the body generates more heat than it can dissipate, and frequently associated with exertional rhabdomyolysis (ERM). In the present study we aimed to (I) identify clinical features and risk factors, (II) describe current prehospital management, (III) investigate long-term outcomes including the impact on mental health, and review the guidance received during restarting activities. We hope that our approach will improve individual and organizational heat illness preparedness, and improve follow-up care. METHODS: We performed a prospective online survey and retrospective medical record review among athletes and military personnel with an episode of EHS/ERM in the Netherlands between 2010 and 2020. We evaluated prehospital management, risk factors, clinical features and long-term outcomes at 6 and 12 months after the event, including mental health symptoms. Furthermore, we investigated what guidance participants received during follow-up, and assessed the patients' perspective on these outcomes. RESULTS: Sixty participants were included, 42 male (70%) and 18 female (30%), of which 47 presented with EHS (78%) and 13 with ERM (22%). Prehospital management was inconsistent and in the majority of participants not conducted according to available guidelines. Self-reported risk factors included not feeling well-acclimatized to environmental heat (55%) and peer pressure (28%). Self-reported long-term symptoms included muscle symptoms at rest (26%) or during exercise (28%), and neurological sequelae (11%). Validated questionnaires (CIS, HADS and SF-36) were indicative of severe fatigue (30%) or mood/anxiety disorders (11%). Moreover, 90% expressed a lack of follow-up care and that a more frequent and intensive follow-up would have been beneficial for their recovery process. CONCLUSION: Our findings indicate major inconsistencies in the management of patients with EHS/ERM, emphasizing the compelling need for implementing standardized protocols. Based on the results of long-term outcome measures, we recommend to counsel and evaluate every patient not only immediately after the event, but also in the long-term.

Perioperative Care for Patients with Neuromuscular Disorders in the Netherlands - A Questionnaire Study Among Anaesthesiologists, Neurologists and Clinical Geneticists.

BACKGROUND: Patients with neuromuscular disorders are at increased risk of suffering perioperative complications. Current knowledge concerning this topic is based on small retrospective studies and expert opinion. Therefore, an individualized multidisciplinary approach to perioperative anaesthesia planning is invaluable to anticipate difficulties and to optimize outcomes. OBJECTIVE: To evaluate current practice regarding preoperative counselling and perioperative care of neuromuscular patients, with the aim to facilitate standardization and improvement of perioperative care for neuromuscular patients. METHODS: A questionnaire-based cross-sectional, observational study was conducted between July, 1st 2020 and December, 31st, 2020 in Dutch anaesthesia, neurology and clinical genetics departments. Main outcome measures were 1.) frequency of consultation requests for neuromuscular patients prior to surgery, 2.) current practice, educational activities and departmental approach to this topic and 3.) preoperative counselling of neuromuscular patients. RESULTS: A total of 83 departments participated. Consultations for a neuromuscular patient scheduled for anaesthesia were requested from anaesthesia and neurology department only infrequently. Local guidelines concerning perioperative care of neuromuscular patients were available in 36.4% of the participating departments. Quality of specific training for residents and staff anaesthetists/neurologists covering perioperative care of neuromuscular patients was rated as 'very good' or 'good' by 42.9%. Neuromuscular patients scheduled for surgery were 'always' or 'often' discussed in multidisciplinary meetings involving anaesthesiologists and neurologists in 20.8% of the participating departments. CONCLUSION: Perioperative care for neuromuscular patients in the Netherlands is highly variable and might benefit from guidelines, education of health care professionals and multidisciplinary meetings between anaesthesiologists and neurologists on a regular basis.

The etiology of rhabdomyolysis: an interaction between genetic susceptibility and external triggers.

BACKGROUND AND PURPOSE: Rhabdomyolysis is a medical emergency characterized by acute skeletal muscle breakdown with a sudden rise and subsequent fall of serum creatine kinase (CK) levels. Rhabdomyolysis events are provoked by exposure to external triggers, possibly in combination with an increased genetic susceptibility. We aimed to describe comprehensively the external triggers and potentially pathogenic genetic variants possibly implicated in increased rhabdomyolysis susceptibility. METHODS: We performed a retrospective single-center study, including a total of 1302 patients with an acute CK level exceeding 2000 IU/l. RESULTS: Anoxia was the most frequently reported trigger (40%). A subset of 193 patients were clinically suspected of an underlying genetic disorder (recurrent episodes, a positive family history, very high or persistently increased CK levels). In 72 of these patients, an unequivocal genetic defect was identified. A total of 22 genes with pathogenic variants were identified, including 52 different variants. Of those, 11 genes have been previously associated with rhabdomyolysis (ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, RYR1). Eleven genes are probably implicated in increased susceptibility (including AGL, CAPN3, CNBP, DMPK, MAGT1, ACADM, SCN4A, SGCA, SGCG, SMPD1, TANGO2). CONCLUSION: These findings suggest that the spectrum of genetic susceptibility for rhabdomyolysis has not yet been completely clarified. With the increasing availability of next-generation sequencing in a diagnostic setting, we expect that in more cases a genetic defect will be identified.

HyperCKemia and rhabdomyolysis in the neuroleptic malignant and serotonin syndromes: A literature review.

Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with other syndromes that have a clear genetic background, in particular RYR1-related malignant hyperthermia. Through a literature review, performed according to the PRISMA guidelines, we aimed to report the clinical features of both syndromes, and the results of genetic testing performed. 10 case series and 99 case reports were included, comprising 134 patients. A male predominance of 58% was found. The median age was 35 (range 4-84) years. Eight patients experienced recurrent episodes of rhabdomyolysis. Genetic analysis was performed in eleven patients (8%), revealing four RYR1 variants, three likely benign (p.Asp849Asn, p.Arg4645Gln, p.Arg4645Gln) and one variant of uncertain significance (p.Ala612Thr). This review underlines that a subset of patients with neuroleptic malignant syndrome and serotonin syndrome develop recurrent episodes of rhabdomyolysis. This recurrent pattern suggests a possible underlying (genetic) susceptibility. However, the genetic background of neuroleptic malignant syndrome and serotonin syndrome has only been investigated to a very limited degree so far. The increasing availability of next generation sequencing offers an opportunity to identify potentially associated genetic backgrounds, especially in patients with recurrent episodes or a positive family history.

[Multidisciplinary management of the pediatric sickle cell patient in 2019]. / Prise en charge multidisciplinaire du patient drépanocytaire pédiatrique en 2019.

Sickle cell disease is a common genetic disorder that affects haemoglobin. It is manifested by haemolytic anaemia and vaso-occlusive crisis. It can affect all organs and its evolution is unpredictable. The multidisciplinary management of pediatric patients who suffer from it is essential to adapt their treatment and optimize their evolution. One of the major challenges is to succeed the transition to adult medicine. New therapeutic perspectives are in development and look promising.

La drépanocytose est une maladie génétique fréquente qui affecte l'hémoglobine. Elle se manifeste par une anémie hémolytique et des phénomènes vaso-occlusifs. Elle peut toucher tous les organes et son évolution est imprévisible. La prise en charge multidisciplinaire des patients pédiatriques qui en souffrent est essentielle pour optimaliser leur évolution et adapter leur traitement. Un des défis majeurs est de réussir la transition vers la médecine adulte. De nouvelles perspectives thérapeutiques sont en développement.

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations.

OBJECTIVE: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases. METHODS: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible. RESULTS: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants. CONCLUSIONS: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Functional impairments, fatigue and quality of life in RYR1-related myopathies: A questionnaire study.

Mutations in RYR1 are a common genetic cause of non-dystrophic neuromuscular disorders. To obtain baseline data concerning the prevalence of fatigue, the psychological disease burden and quality of life associated with these common conditions, we performed a questionnaire study. Seventy-two patients were included in this study, 33 with a congenital myopathy and 39 with malignant hyperthermia or exertional rhabdomyolysis. Our results showed that patients with RYR1-related myopathies have more functional impairments and significant chronic fatigue compared to healthy controls, with almost half of patients being severely fatigued. Whilst fatigue, pain and associated physical and social difficulties were more pronounced in those with permanent phenotypes, individuals with intermittent phenotypes also scored higher in all relevant categories compared to healthy controls. These findings indicate that RYR1-related myopathies, despite being often considered relatively mild conditions, are nevertheless associated with severe fatigue and functional limitations, resulting in substantial loss of quality of life. Moreover, milder but in essence similar findings in patients with RYR1-related malignant hyperthermia and rhabdomyolysis suggest that those phenotypes are not truly episodic but in fact associated with a substantial permanent disease burden. These preliminary data should help to design more comprehensive quality of life studies to inform standards of care.

RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide spectrum of inherited myopathies presenting throughout life. Malignant hyperthermia susceptibility (MHS)-related RYR1 mutations have emerged as a common cause of exertional rhabdomyolysis, accounting for up to 30% of rhabdomyolysis episodes in otherwise healthy individuals. Common triggers are exercise and heat and, less frequently, viral infections, alcohol and drugs. Most subjects are normally strong and have no personal or family history of malignant hyperthermia. Heat intolerance and cold-induced muscle stiffness may be a feature. Recognition of this (probably not uncommon) rhabdomyolysis cause is vital for effective counselling, to identify potentially malignant hyperthermia-susceptible individuals and to adapt training regimes. Studies in various animal models provide insights regarding possible pathophysiological mechanisms and offer therapeutic perspectives.

European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility.

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings.

RYR1-related myopathies: a wide spectrum of phenotypes throughout life.

BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.

Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment.

BACKGROUND: This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR ≥80 ml min(-1)). METHODS: Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. RESULTS: The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. CONCLUSIONS: Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. CLINICAL TRIAL REGISTRATION: NCT00702715.

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Train-of-four ratio recovery often precedes twitch recovery when neuromuscular block is reversed by sugammadex.

BACKGROUND: Sugammadex reverses rocuronium-induced neuromuscular block (NMB). In all published studies investigating sugammadex, the primary outcome parameter was a train-of-four (TOF) ratio of 0.9. The recovery time of T1 was not described. This retrospective investigation describes the recovery of T1 vs. TOF ratio after the reversal of NMB with sugammadex. METHODS: Two studies were analyzed. In study A, a phase II dose-finding study, ASA I-II patients received an intravenous (IV) dose of rocuronium 1.2 mg/kg, followed by an IV dose of sugammadex (2.0, 4.0, 8.0, 12.0 or 16.0 mg/kg) or placebo (0.9% saline) after 5 min. In study B, a phase III trial comparing patients with renal failure and healthy controls, rocuronium 0.6 mg/kg was used to induce NMB; sugammadex 2.0 mg/kg was administered at reappearance of T2. Neuromuscular monitoring was performed by acceleromyography and TOF nerve stimulation. The primary efficacy variable was time from the administration of sugammadex to recovery of the TOF ratio to 0.9. Retrospectively, the time to recovery of T1 to 90% was calculated. RESULTS: After the reversal of rocuronium-induced NMB with an optimal dose of sugammadex [16 mg/kg (A) or 2 mg/kg (B)], the TOF ratio recovered to 0.9 significantly faster than T1 recovered to 90%. Clinical signs of residual paralysis were not observed. CONCLUSION: After the reversal of NMB by sugammadex, full recovery of the TOF ratio is possible when T1 is still depressed. The TOF ratio as the only measurement for the adequate reversal of NMB by sugammadex may not always be reliable. Further investigations for clinical implications are needed.

Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group.

Survival from a malignant hyperthermia (MH) crisis is highly dependent on early recognition and prompt action. MH crises are very rare and an increasing use of total i.v. anaesthesia is likely to make it even rarer, leading to the potential risk of reduced awareness of MH. In addition, dantrolene, the cornerstone of successful MH treatment, is unavailable in large areas around the world thereby increasing the risk of MH fatalities in these areas. The European Malignant Hyperthermia Group collected and reviewed all guidelines available from the various MH centres in order to provide a consensus document. The guidelines consist of two textboxes: Box 1 on recognizing MH and Box 2 on the treatment of an MH crisis.

Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study.

BACKGROUND: Sugammadex is a selective relaxant binding agent designed to encapsulate the neuromuscular blocking agent, rocuronium. The sugammadex-rocuronium complex is eliminated by the kidneys. This trial investigated the pharmacokinetics (PKs) of sugammadex and rocuronium in patients with renal failure and healthy controls. METHODS: Fifteen ASA class II-III renal patients [creatinine clearance (CL(CR)) <30 ml min(-1)] and 15 ASA I-II controls (CL(CR) > or =80 ml min(-1)) were included. After induction of anaesthesia, a single i.v. dose of rocuronium 0.6 mg kg(-1) was given, followed by a single i.v. dose of sugammadex 2.0 mg kg(-1) at reappearance of the second twitch of the train-of-four response. Plasma concentrations of rocuronium and sugammadex were estimated and PK variables determined using non-compartmental analyses. Percentages of sugammadex and rocuronium excreted in the urine were measured. RESULTS: PK data were obtained from 26 patients. Mean total plasma clearance (CL) of sugammadex was 5.5 ml min(-1) in renal patients and 95.2 ml min(-1) in controls (P<0.05). Rocuronium CL was 41.8 ml min(-1) in renal patients and 167 ml min(-1) in controls (P<0.05). The median amount of sugammadex and rocuronium excreted in the urine over 72 h in renal patients was 29% and 4%, respectively, and 73% and 42% over 24 h in controls. CONCLUSIONS: Large differences in the PKs of sugammadex and rocuronium between patients with renal failure and healthy controls were observed. The effect of renal impairment on the PK variables of rocuronium was less than with sugammadex. Urinary excretion of both drugs was reduced in renal patients.

Plain articaine or prilocaine for spinal anaesthesia in day-case knee arthroscopy: a double-blind randomized trial.

BACKGROUND: Both prilocaine and articaine are short-acting local anaesthetics suited for spinal anaesthesia for day-case knee arthroscopy. Articaine is thought to have a faster onset and shorter duration of action than prilocaine, although no comparative study has been published in the anaesthetic literature. METHODS: In this prospective randomized double-blind study, spinal anaesthesia was performed in 72 ASA I-II patients undergoing knee arthroscopy with 50 mg of either plain prilocaine or plain articaine. The primary outcome variable was duration of motor block. Secondary outcomes were onset of sensory and motor blocks, maximum spread of the sensory block, time to spontaneous voiding, and side-effects. RESULTS: Time to full motor function recovery was shorter after articaine than prilocaine [mean (SD) 140 (33) vs 184 (46) min, respectively, P<0.001]. Time to spontaneous voiding was shorter after articaine than prilocaine [mean (SD) 184 (39) vs 227 (45) min, respectively, P<0.001]. One patient in the articaine group reported mild transient neurological symptoms (TNS) limited to the first postoperative day, but there were no significant differences in adverse effects between the groups. CONCLUSIONS: Spinal anaesthesia with plain articaine 50 mg resulted in a faster recovery of motor function and earlier spontaneous voiding compared with plain prilocaine 50 mg. Surgical anaesthesia was not different. The incidence of TNS was low.

Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function.

BACKGROUND: Sugammadex, a modified gamma-cyclodextrin, is the first selective relaxant binding agent that specifically encapsulates the steroidal neuromuscular blocking agent, rocuronium. The action of rocuronium is prolonged in patients with renal failure. As sugammadex is primarily cleared renally, this phase III trial investigated the efficacy and safety of sugammadex for reversal of rocuronium-induced neuromuscular block (NMB) in patients with end-stage renal failure. METHODS: Thirty adult patients were studied: 15 renally impaired [creatinine clearance (CL(CR)) <30 ml min(-1)] and 15 controls (CL(CR)>80 ml min(-1)). Anaesthesia was induced and maintained using i.v. opiates and propofol. Neuromuscular monitoring was performed by acceleromyography and train-of-four (TOF) nerve stimulation. Rocuronium (0.6 mg kg(-1)) was given, followed by a single i.v. dose of sugammadex (2.0 mg kg(-1)) at reappearance of the second twitch of the TOF. The primary efficacy variable was time from administration of sugammadex to recovery of the TOF ratio to 0.9. Safety variables included clinical evidence of reoccurrence of NMB. RESULTS: After sugammadex administration, the mean (sd) time to recovery of the TOF ratio to 0.9 was 2.0 (0.72) min in renal patients and 1.65 (0.63) min in controls (NS). Recurrence of NMB was not observed in any patient. No sugammadex-related serious adverse events were reported. CONCLUSIONS: Sugammadex administered at reappearance of T(2) rapidly and effectively reverses NMB induced by rocuronium in renal failure and healthy patients. Sugammadex was well tolerated by all patients. Further safety studies on sugammadex in patients with severe renal impairment are warranted.