Rebounds of sevoflurane concentration during simulated trigger-free pediatric and adult anesthesia.

BACKGROUND: In trigger-free anesthesia a volatile anesthetic concentration of 5 parts per million (ppm) should not be exceeded. According to European Malignant Hyperthermia Group (EMHG) guideline, this may be achieved by removing the vapor, changing the anesthetic breathing circuit and renewing the soda lime canister followed by flushing with O2 or air for a workstation specific time. Reduction of the fresh gas flow (FGF) or stand-by modes are known to cause rebound effects. In this study, simulated trigger-free pediatric and adult ventilation was carried out on test lungs including ventilation maneuvers commonly used in clinical practice. The goal of this study was to evaluate whether rebounds of sevoflurane develop during trigger-free anesthesia. METHODS: A Dräger® Primus® was contaminated with decreasing concentrations of sevoflurane for 120 min. Then, the machine was prepared for trigger-free anesthesia according to EMHG guideline by changing recommended parts and flushing the breathing circuits using 10 or 18 l⋅min- 1 FGF. The machine was neither switched off after preparation nor was FGF reduced. Simulated trigger-free ventilation was performed with volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) including various ventilation maneuvers like pressure support ventilation (PSV), apnea, decreased lung compliance (DLC), recruitment maneuvers, prolonged expiration and manual ventilation (MV). A high-resolution ion mobility spectrometer with gas chromatographic pre-separation was used to measure sevoflurane in the ventilation gas mixture in a 20 s interval. RESULTS: Immediately after start of simulated anesthesia, there was an initial peak of 11-18 ppm sevoflurane in all experiments. The concentration dropped below 5 ppm after 2-3 min during adult and 4-18 min during pediatric ventilation. Other rebounds of sevoflurane > 5 ppm occurred after apnea, DLC and PSV. MV resulted in a decrease of sevoflurane < 5 ppm within 1 min. CONCLUSION: This study shows that after guideline-compliant preparation for trigger-free ventilation anesthetic machines may develop rebounds of sevoflurane > 5 ppm during typical maneuvers used in clinical practice. The changes in rate and direction of internal gas flow during different ventilation modes and maneuvers are possible explanations. Therefore, manufacturers should provide machine-specific washout protocols or emphasize the use of active charcoal filters (ACF) for trigger-free anesthesia.

Preparation of Dräger Atlan A350 and General Electric Healthcare Carestation 650 anesthesia workstations for malignant hyperthermia susceptible patients.

BACKGROUND: Patients at risk of malignant hyperthermia need trigger-free anesthesia. Therefore, anesthesia machines prepared for safe use in predisposed patients should be free of volatile anesthetics. The washout time depends on the composition of rubber and plastic in the anesthesia machine. Therefore, new anesthesia machines should be evaluated regarding the safe preparation for trigger-free anesthesia. This study investigates wash out procedures of volatile anesthetics for two new anesthetic workstations: Dräger Atlan A350 and General Electric Healthcare (GE) Carestation 650 and compare it with preparation using activated charcoal filters (ACF). METHODS: A Dräger Atlan and a Carestation 650 were contaminated with 4% sevoflurane for 90 min. The machines were decontaminated with method (M1): using ACF, method 2 (M2): a wash out method that included exchange of internal parts, breathing circuits and soda lime canister followed by ventilating a test lung using a preliminary protocol provided by Dräger or method 3 (M3): a universal wash out instruction of GE, method 4 (M4): M3 plus exchange of breathing system and bellows. Decontamination was followed by a simulated trigger-free ventilation. All experiments were repeated with 8% desflurane contaminated machines. Volatile anesthetics were detected with a closed gas loop high-resolution ion mobility spectrometer with gas chromatographic pre-separation attached to the bacterial filter of the breathing circuits. Primary outcome was time until < 5 ppm of volatile anesthetics and total preparation time. RESULTS: Time to < 5 ppm for the Atlan was 17 min (desflurane) and 50 min (sevoflurane), wash out continued for a total of 60 min according to protocol resulting in a total preparation time of 96-122 min. The Carestation needed 66 min (desflurane) and 24 min (sevoflurane) which could be abbreviated to 24 min (desflurane) if breathing system and bellows were changed. Total preparation time was 30-73 min. When using active charcoal filters time to < 5 ppm was 0 min for both machines, and total preparation time < 5 min. CONCLUSION: Both wash out protocols resulted in a significant reduction of trace gas concentrations. However, due to the complexity of the protocols and prolonged total preparation time, feasibility in clinical practice remains questionable. Especially when time is limited preparation of the anesthetic machines using ACF remain superior.

Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group.

Malignant hyperthermia is a potentially fatal condition, in which genetically predisposed individuals develop a hypermetabolic reaction to potent inhalation anaesthetics or succinylcholine. Because of the rarity of malignant hyperthermia and ethical limitations, there is no evidence from interventional trials to inform the optimal perioperative management of patients known or suspected with malignant hyperthermia who present for surgery. Furthermore, as the concentrations of residual volatile anaesthetics that might trigger a malignant hyperthermia crisis are unknown and manufacturers' instructions differ considerably, there are uncertainties about how individual anaesthetic machines or workstations need to be prepared to avoid inadvertent exposure of susceptible patients to trigger anaesthetic drugs. The present guidelines are intended to bundle the available knowledge about perioperative management of malignant hyperthermia-susceptible patients and the preparation of anaesthesia workstations. The latter aspect includes guidance on the use of activated charcoal filters. The guidelines were developed by members of the European Malignant Hyperthermia Group, and they are based on evaluation of the available literature and a formal consensus process. The most crucial recommendation is that malignant hyperthermia-susceptible patients should receive anaesthesia that is free of triggering agents. Providing that this can be achieved, other key recommendations include avoidance of prophylactic administration of dantrolene; that preoperative management, intraoperative monitoring, and care in the PACU are unaltered by malignant hyperthermia susceptibility; and that malignant hyperthermia patients may be anaesthetised in an outpatient setting.

Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines.

Faced with a malignant hyperthermia crisis, the immediate access to sufficient dantrolene is essential to achieve the best possible outcome for the patient. However, malignant hyperthermia crises are rare, and there may be administrative pressures to limit the amount of dantrolene stocked or, in some countries, not to stock dantrolene at all. There are no published guidelines to support anaesthetic departments in their effort to ensure availability of sufficient dantrolene for the management of malignant hyperthermia crises. After a literature review that confirmed a lack of clinical trials to inform this guideline, we undertook a formal consensus development process, in which 25 members of the European Malignant Hyperthermia Group participated. The consensus process used a modified web-based Delphi exercise, in which participants rated the appropriateness of statements that covered the dosing regimen for dantrolene in a malignant hyperthermia crisis, the types of facility that should stock dantrolene, and the amount of dantrolene that should be stocked. The resulting guidelines are based on available evidence and the opinions of international malignant hyperthermia experts representing a large group of malignant hyperthermia laboratories from around the world. Key recommendations include: the dosing regimen of dantrolene should be based on actual body weight, dantrolene should be available wherever volatile anaesthetics or succinylcholine are used, and 36 vials of dantrolene should be immediately available with a further 24 vials available within 1 h.

Preparation of anaesthesia workstation for trigger-free anaesthesia: An observational laboratory study.

BACKGROUND: Trigger-free anaesthesia is required for patients who are susceptible to malignant hyperthermia. Therefore, all trace of volatile anaesthetics should be removed from anaesthetic machines before induction of anaesthesia. Because the washout procedure is time consuming, activated charcoal filters have been introduced, but never tested under minimal flow conditions. OBJECTIVE: To investigate performance of activated charcoal filters during long duration (24 h) simulated ventilation. DESIGN: A bench study. SETTING: A Primus anaesthesia machine (Dräger) was contaminated with either 4% sevoflurane or 8% desflurane by ventilating a test lung for 90 min. The machine was briefly flushed according to manufacturer instructions, activated charcoal filters were inserted and a test lung was ventilated in a 24 h test. Trace gas concentrations were measured using a closed gas loop high-resolution ion mobility spectrometer with gas chromatographic preseparation. During the experiment reduced fresh gas flows were tested. At the end of each experiment the activated charcoal filters were removed and the machine was set to standby for 10 min to test for residual contamination within the circuit. The activated charcoal filters were reconnected into the circuit to test their ability to continue removing volatile anaesthetics (functional test) from the gas. Control experiments were conducted without activated charcoal filters. MAIN OUTCOME MEASURES: Absolute concentrations of desflurane and sevoflurane. RESULTS: The concentration of volatile anaesthetics dropped to less than 5 ppm (parts per million) following insertion of activated charcoal filters. In the desflurane experiments at least 1 l min FGF was needed to keep the concentration below an acceptable level (<5 ppm): 0.5 l min fresh gas flow was required in sevoflurane experiments. While activated charcoal filters in the sevoflurane tests passed the functional test after 24 h, activated charcoal filters in the desflurane tests failed. CONCLUSION: Activated charcoal filters meet the requirements for trigger-free low flow (1 l min) ventilation over 24 h. Minimal flow (0.5 l min) ventilation may be possible for sevoflurane contaminated machines.

Resequencing array for gene variant detection in malignant hyperthermia and butyrylcholinestherase deficiency.

Malignant hyperthermia (MH) and butyrylcholinestherase (BCHE) deficiency are two relevant pharmacogenetic disorders in anesthetic practice linked with sequence variants, the former in the RyR1 and CACNA1S genes, the latter in the BCHE gene. Genotyping for known pathogenic variants in these genes is useful to help identify susceptible individuals, and others may exist but remain unknown, because full-length sequence of these genes is, in general, not investigated. To facilitate this task, we developed a resequencing DNA array, the perioperative patient safety (POPS) array, to be able to screen the entire coding sequences of the RyR1, CACNA1S and BCHE genes. MH-susceptible individuals (n = 121) identified with the in vitro contracture test, the standard diagnostic tool for MH susceptibility, were genotyped with the arrays. Compared with capillary sequencing, call rates with the arrays could achieve 100% at maximal sensitivity, although to reduce false positive rates, sensitivity was adjusted to 0.85, 0.87 and 0.66 for RyR1, CACNA1S and BCHE respectively, with overall base call specificity exceeding 99%. Detection of 29 predetermined RyR1 variants in 44 individuals was successful in 97% of the cases, among them all 16 variants of established diagnostic value. In a trial application of the arrays, 21 MH-susceptible subjects with no known RyR1 or CACNA1S variants were screened, resulting in the discovery of new variants, all confirmed by capillary sequencing. In conclusion, arrays offer an efficient high-throughput alternative for diagnostic genotyping of candidate genes affecting MH susceptibility, BCHE deficiency and other neuromuscular disorders, simultaneously enabling a comprehensive search for rare variants in these genes.

Skeletal muscle expression of the adhesion-GPCR CD97: CD97 deletion induces an abnormal structure of the sarcoplasmatic reticulum but does not impair skeletal muscle function.

CD97 is a widely expressed adhesion class G-protein-coupled receptor (aGPCR). Here, we investigated the presence of CD97 in normal and malignant human skeletal muscle as well as the ultrastructural and functional consequences of CD97 deficiency in mice. In normal human skeletal muscle, CD97 was expressed at the peripheral sarcolemma of all myofibers, as revealed by immunostaining of tissue sections and surface labeling of single myocytes using flow cytometry. In muscle cross-sections, an intracellular polygonal, honeycomb-like CD97-staining pattern, typical for molecules located in the T-tubule or sarcoplasmatic reticulum (SR), was additionally found. CD97 co-localized with SR Ca2+-ATPase (SERCA), a constituent of the longitudinal SR, but not with the receptors for dihydropyridine (DHPR) or ryanodine (RYR), located in the T-tubule and terminal SR, respectively. Intracellular expression of CD97 was higher in slow-twitch compared to most fast-twitch myofibers. In rhabdomyosarcomas, CD97 was strongly upregulated and in part more N-glycosylated compared to normal skeletal muscle. All tumors were strongly CD97-positive, independent of the underlying histological subtype, suggesting high sensitivity of CD97 for this tumor. Ultrastructural analysis of murine skeletal myofibers confirmed the location of CD97 in the SR. CD97 knock-out mice had a dilated SR, resulting in a partial increase in triad diameter yet not affecting the T-tubule, sarcomeric, and mitochondrial structure. Despite these obvious ultrastructural changes, intracellular Ca2+ release from single myofibers, force generation and fatigability of isolated soleus muscles, and wheel-running capacity of mice were not affected by the lack of CD97. We conclude that CD97 is located in the SR and at the peripheral sarcolemma of human and murine skeletal muscle, where its absence affects the structure of the SR without impairing skeletal muscle function.

Propofol versus flunitrazepam for inducing and maintaining sleep in postoperative ICU patients.

CONTEXT: Sleep deprivation is a common problem on intensive care units (ICUs) influencing not only cognition, but also cellular functions. An appropriate sleep-wake cycle should therefore be maintained to improve patients' outcome. Multiple disruptive factors on ICUs necessitate the administration of sedating and sleep-promoting drugs for patients who are not analgo-sedated. AIMS: The objective of the present study was to evaluate sleep quantity and sleep quality in ICU patients receiving either propofol or flunitrazepam. SETTINGS AND DESIGN: Monocentric, randomized, double-blinded trial. MATERIALS AND METHODS: A total of 66 ICU patients were enrolled in the study (flunitrazepam n = 32, propofol n = 34). Propofol was injected continuously (2 mg/kg/h), flunitrazepam as a bolus dose (0.015 mg/kg). Differences between groups were evaluated using a standardized sleep diary and the bispectral index (BIS). STATISTICAL ANALYSIS USED: Group comparisons were performed by Mann-Whitney U-Test. P < 0.05 was considered to be statistically significant. RESULTS: Sleep quality and the frequency of awakenings were significantly better in the propofol group (Pg). In the same group lower BIS values were recorded (median BIS propofol 74.05, flunitrazepam 78.7 [P = 0.016]). BIS values had to be classified predominantly to slow-wave sleep under propofol and light sleep after administration of flunitrazepam. Sleep quality improved in the Pg with decreasing frequency of awakenings and in the flunitrazepam group with increasing sleep duration. CONCLUSIONS: Continuous low-dose injection of propofol for promoting and maintaining night sleep in ICU patients who are not analgo-sedated was superior to flunitrazepam regarding sleep quality and sleep structure.

Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study.

BACKGROUND: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. METHODS: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. RESULTS: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. CONCLUSIONS: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.

Individual receptor profiling as a novel tool to support diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC).

PURPOSE: Dysregulation of neurotransmitter receptors may contribute to bladder overactivity (OAB) symptoms. To address the question whether specific receptor expression patterns are associated with bladder pain syndrome/interstitial cystitis (BPS/IC), we examined the expression of muscarinic, purinergic and histamine receptors in the detrusor. METHODS: Detrusor receptor expression was investigated in bladder biopsies of female BPS/IC patients (n = 44; age 60.64 ± 13.78, mean ± SD) and carcinoma patients (n = 11; age 58.91 ± 12.72) undergoing cystectomy. Protein expression of muscarinic (M2, M3), purinergic (P2X1-3) and histamine receptors (H1, H2) was analysed by confocal immunofluorescence, and gene expression was quantified by real-time polymerase chain reaction (qPCR). RESULTS: M2, P2X1, P2X2 and H1 receptor immunoreactivity (-IR) was significantly enhanced in BPS/IC compared to the control group, while there was no difference for M3-, P2X3- and H2-IR. We calculated a score, which separated BPS/IC from control patients with an AUC of 89.46%, showing 84.09% sensitivity and 90.91% specificity. Patients had a 9.25 times enhanced calculated risk for BPS/IC. In addition, two patient subgroups (M2 > M3 and M3 > M2) were observed, which differed in associated purinergic and histamine receptor expression. CONCLUSIONS: M2, P2X1, P2X2 and H1 were significantly upregulated in BPS/IC patients, and H2 was occasionally highly overexpressed. There was no significant correlation between receptor protein and gene expression, implying posttranslational mechanisms being responsible for the altered receptor expressions. On the basis of individual receptor profiles, upregulated receptors could be targeted by monotherapy or combination therapy with already approved receptor inhibitors, thereby promoting tailored therapy for patients suffering from BPS/IC-like symptoms.

A mathematical model to improve on phenotyping for molecular genetic research in malignant hyperthermia.

BACKGROUND: The in-vitro contracture test is the standard test to diagnose malignant hyperthermia (MH) susceptibility. Maximum sensitivity is important for patient safety. For scientific purposes, the reduced specificity of contracture testing is a major drawback, and precise phenotyping is of utmost importance. Our study aimed to improve phenotyping for MH susceptibility to more accurately select patients for molecular genetic research in MH, thus, improving the probability to detect novel MH associated variants. METHODS: Patients who underwent contracture and molecular genetic testing were selected from the database of two MH investigation centres (Basel and Leipzig). The area under the curve of halothane and caffeine contracture tests was calculated and a logistic regression model was applied to determine the odds of carrying a MH associated genetic variant. This model was subsequently applied to patients without familial MH related genetic variant. RESULTS: Validation of the logistic regression model showed 98% concordance with molecular genetic results. Among patients with unclear in-vitro contracture test diagnosis (MH equivocal), half of the mutation carriers were classified as positive by the model, whereas 86% of those without familial mutation were classified as negative. Excluding the MH equivocal group, the model showed sensitivity of 0.99 (95% confidence interval: 0.95-0.99) and specificity 0.98 (95% confidence interval: 0.94-0.99), respectively, to identify genetically positive MH individuals. CONCLUSION: Our model is a valuable tool to select patients from MH families for further molecular genetic research. This preselection increases the probability of successful molecular genetic research and is important when available resources are limited.

[Fulminant MH crisis during the ninth general anaesthesia]. / Kasuistik: Fulminante Maligne Hyperthermie - Untypischer Verlauf während der 9. Allgemeinanästhesie.

Malignant hyperthermia (MH) is a rare, often life-threatening complication of general anaesthesia. The timely diagnosis of an MH crisis in onset, as a prerequisite for successful therapy, can be difficult for the anaesthetist because of the few and non-specific early symptoms. This is even more so in patients in whom anaesthesia with MH trigger substances has already been performed in the past without any particular complications so leading to a false sense of security with regard to MH sensitivity. The case presented is a healthy young man with a congenital cleft lip, jaw and palette who developed a fulminant MH crisis during his ninth general anaesthesia. Post-operative research into the course of the previous anaesthesias revealed signs of MH crises which however proceeded abortively and were therefore unnoticed. In the case presented, the diagnosis was additionally complicated by the untypical course of the early symptoms. Tachycardia which in 80 % of cases is described as the first symptom of an MH crisis in onset, was at first completely absent and was only moderately pronounced in the full clinical picture of MH. On the other hand, a steady increase in body temperature, a cardinal symptom which usually appears later, was registered early. The suspected diagnosis of MH was then finally confirmed in the fourth hour after start of anaesthesia on the basis of the repeatedly increased end expiratory CO(2) levels. These could not otherwise be explained although several respiratory corrections were performed. Despite immediate MH specific therapy, the crisis developed in the following hour into the full clinical picture: maximum temperature of 41.4 degrees C, end expiratory CO(2) 100mm Hg, consumptive coagulopathy, acute renal failure and shock (systolic blood pressure < 50mm Hg, heart rate 115/minute). After 2 hours of specific intensive therapy, the patient was finally stabilized and transfer to the intensive care unit was possible. 24 hours after the event, the patient was could be extubated without any complications and 2 days later, he was transferred to the normal ward. The intra-operative diagnosis of MH was confirmed 3 days later by means of genetic analysis. Two mutations of the RYR1 gene were identified.

Iatrogenic tracheobronchial ruptures - treatment and outcomes.

In the present paper we discuss the indication and follow-up of 42 patients with iatrogenic tracheobrochial ruptures. Thirty-five patients were treated by operation and 7 patients were treated conservatively. In the operated patients, four developed an insufficiency of the tracheal closure and the rupture related mortality was 2.8%. A significant effect on suture dehiscence was seen for mediastinitis (P<0.005) prior to operation, prior resection of the esophagus (P<0.001), and a long delay between injury and diagnosis (P=0.004). In the conservatively treated group the rupture related mortality was 29%. In conclusion to our results we suggest a surgical procedure whenever a tracheobronchial rupture is diagnosed and the patient's constitution allows the surgical procedure or anesthesia.