Search

Purpose Anaemia is common in patients presenting with aneurysmal subarachnoid (aSAH) and intracerebral haemorrhage (ICH). In surgical patients, anaemia was identified as an idenpendent risk factor for postoperative mortality, prolonged hospital length of stay (LOS) and increased risk of red blood cell (RBC) transfusion. This multicentre cohort observation study describes the incidence and effects of preoperative anaemia in this critical patient collective for a 10-year period. Methods This multicentre observational study included adult in-hospital surgical patients diagnosed with aSAH or ICH of 21 German hospitals (discharged from 1 January 2010 to 30 September 2020). Descriptive, univariate and multivariate analyses were performed to investigate the incidence and association of preoperative anaemia with RBC transfusion, in-hospital mortality and postoperative complications in patients with aSAH and ICH. Results A total of n = 9081 patients were analysed (aSAH n = 5008; ICH n = 4073). Preoperative anaemia was present at 28.3% in aSAH and 40.9% in ICH. RBC transfusion rates were 29.9% in aSAH and 29.3% in ICH. Multivariate analysis revealed that preoperative anaemia is associated with a higher risk for RBC transfusion (OR = 3.25 in aSAH, OR = 4.16 in ICH, p < 0.001), for in-hospital mortality (OR = 1.48 in aSAH, OR = 1.53 in ICH, p < 0.001) and for several postoperative complications. Conclusions Preoperative anaemia is associated with increased RBC transfusion rates, in-hospital mortality and postoperative complications in patients with aSAH and ICH. Trial registration ClinicalTrials.gov, NCT02147795, https://clinicaltrials.gov/ct2/show/NCT02147795

Background Blood transfusions are common medical procedures and every age group requires detailed insights and treatment bundles. The aim of this study was to examine the association of anaemia, co-morbidities, complications, in-hospital mortality, and transfusion according to age groups to identify patient groups who are particularly at risk when undergoing surgery. Methods Data from 21 Hospitals of the Patient Blood Management Network Registry were analysed. Patients were divided into age subgroups. The incidence of preoperative anaemia, co-morbidities, surgical disciplines, hospital length of stay, complications, in-hospital mortality rate, and transfusions were analysed by descriptive and multivariate regression analysis. Results A total of 1 117 919 patients aged 18–108 years were included. With increasing age, the number of co-morbidities and incidence of preoperative anaemia increased. Complications, hospital length of stay, and in-hospital mortality increased with age and were higher in patients with preoperative anaemia. The mean number of transfused red blood cells (RBCs) peaked, whereas the transfusion rate increased continuously. Multivariate regression analysis showed that increasing age, co-morbidities, and preoperative anaemia were independent risk factors for complications, longer hospital length of stay, in-hospital mortality, and the need for RBC transfusion. Conclusion Increasing age, co-morbidities, and preoperative anaemia are independent risk factors for complications, longer hospital length of stay, in-hospital mortality, and the need for RBC transfusion. Anaemia diagnosis and treatment should be established in all patients.

Background: Critical Care Providers (CCPs) experience situations that challenge their ethics and professional standards and may entail moral distress (MD). Aim: To analyze MD perceived by CCPs in intensive care units (ICUs) or emergency departments (EDs) and further clarify whether CCPs who rely on spiritual resources differ in their perception of MD from those who do not utilize these resources. Methods: A cross-sectional anonymous survey was administered using a modified version of the German language version of the Moral Distress Scale (MDS) with 2 × 12 items to assess the frequency and the respective perceived burden of specific situations by applying a 5-point Likert scale. Explorative factor analysis was performed and the sub-constructs of the respective items regarding MD frequency and burden were identified. Job burden and professional satisfaction were measured using visual analogue scales (VAS) and a four-point Likert scale, respectively. The 15-item SpREUK questionnaire was applied to measure spiritual attitudes and behaviours and to differentiate between religious and spiritual persons. Data from 385 German-speaking CCPs were included (55% physicians, 45% nurses). Results: Conflict situations are similar for physicians and nurses although they are perceived as more burdensome by nurses. Among physicians, the MDS factor Looking away/Resignation scores highest for assistant physician residents, whereas distress caused by looking away is more often perceived by specialist physicians without a managerial position. Work satisfaction is inversely associated with MD and emotional exhaustion is positively associated with it. Participants’ spirituality is marginally associated with MD. The best predictors of both MD frequency and burden are emotional exhaustion with further influences of work satisfaction, being a nurse, and being a non-believer on the frequency of MD perception. Being a nurse, participants’ experience in ICU/ED, and being of the male gender are further predictors of MD burden. Conclusions: MD is experienced differently by different groups of CCPs depending on their place in the hierarchy of responsibility. As MD perception is best predicted by emotional exhaustion, these situations should be avoided. Although some CCPs may rely on spiritual resources, all need individual and team support to cope with MD.

Despite numerous studies on the regional cerebral oxygen saturation (rSOThe aim of the present study was therefore to identify possible patient-specific risk factors that enable prediction of CDE.Data were collected on 397 orthopedic patients undergoing shoulder surgery in the beach chair position. Routine anesthesia management and standard monitoring was used in all patients. Target value for the inspiratory oxygen concentration (FPatients with CDE (n = 238) were significantly more often classified as ASA 2 (p = 0.01) and RCRI 1 (p = 0.01), suffered more often from arterial hypertension (p = 0.01) and were older (median: 60 years compared to 55 years; p = 0.01) than patients without CDE (n = 159) in the beach chair position (Wilcoxon rank sum test). Arterial hypertension remained significant after removing the effect of age (p = 0.03) and RCRI classification (p = 0.04; two-way ANOVA multivariate analysis).On the basis of our study, patient-specific prognosis and risk factors for the occurrence of CDE, such as higher age, ASA 2 and RCRI 1 classification as well as pre-existing arterial hypertension could be determined. Arterial hypertension represents the main risk factor for the occurrence of CDE in the beach chair position. RCRI 1 classification or age, however, only has an effect on the occurrence of pathological rSOHINTERGRUND: Trotz zahlreicher Untersuchungen der zerebralen regionalen Sauerstoffsättigung (rSOZiel der vorliegenden Studie war es, neben einer Identifikation möglicher patientenspezifischer Risikofaktoren zum ersten Mal auch eine Gewichtung dieser durchzuführen.Insgesamt wurden 397 Patienten untersucht. Als CDE wurde eine Abnahme der rSOPatienten mit CDE (n = 238) waren signifikant häufiger als ASA 2 (p = 0,01) und RCRI 1 (p = 0,01) klassifiziert, litten häufiger unter einem arteriellen Hypertonus (p = 0,01) und waren älter (Median [Jahre]: 60 vs. 55; p = 0,01) als Patienten ohne CDE (n = 159) in Beach-chair-Position. Eine arterielle Hypertonie war jeweils nach Entfernen des Effekts des Alters (p = 0,03) und der RCRI-Klassifikation (p = 0,04) weiterhin signifikant.Höheres Alter, ASA 2, RCRI 1 und v. a. ein arterieller Hypertonus konnten als Risikofaktoren bestimmt werden, die es bereits präoperativ ermöglichen, Patienten zu identifizieren, die gegenüber dem intraoperativen Auftreten von CDE in Beach-chair-Position besonders gefährdet sind.

A universal, mobile protection system for work close to patients suffering from acute infectious diseases with aerosol formation has been developed. It is considered useful by the main medical disciplines involved in the treatment of CoVid patients. In those times, disposable protection gear is scarce, and the robust, reusable protection system might be helpful for medical personnel to work more safely in vulnerable situations.

Approximately one in three patients has untreated preoperative anaemia, which in turn is associated with an increased need for transfusion of allogenic red blood cell concentrates (RBC) and complications in the context of a surgical intervention. Here, the prevalence of preoperative and postoperative anaemia as well as their effects on transfusion rate, hospital length of stay and hospital mortality in primary hip and knee arthroplasty has been analysed.From January 2012 to September 2018, 378,069 adult inpatients from 13 German hospitals were analysed on the basis of an anonymized registry. Of these, n = 10,017 patients had a hip and knee joint primary arthroplasty. The primary endpoint was the incidence of preoperative anaemia, which was analysed by the first available preoperative haemoglobin value according to the WHO definition. Secondary endpoints included in-hospital length of stay, number of patients with red blood cell concentrate transfusion, incidence of hospital-acquired anaemia, number of deceased patients, and postoperative complications.The preoperative anaemia rate was 14.8% for elective knee joint arthroplasty, 22.9% for elective hip joint arthroplasty and 45.0% for duo-prosthesis implantation. Preoperative anaemia led to a significantly higher transfusion rate (knee: 8.3 vs. 1.8%; hip: 34.5 vs. 8.1%; duo-prosthesis: 42.3 vs. 17.4%), an increased red blood cell concentrate consumption (knee: 256 ± 107 vs. 29 ± 5 RBC/1000 patients; hip: 929 ± 60 vs. 190 ± 16 RBC/1000 patients; duo-prosthesis: 1411 ± 98 vs. 453 ± 42 RBC/1000 patients). Pre-operative anaemia was associated with prolonged hospital stay (12.0 [10.0; 17.0] d vs. 11.0 [9.0; 13.0] d; p 0.001) and increased mortality (5.5% [4.6 - 6.5%] vs. 0.9% [0.7 - 1.2%]; Fisher p 0.001) compared to non-anaemic patients. In patients aged 80 years and older, the incidence of preoperative anaemia and thus the transfusion rate was almost twice as high as in patients under 80 years of age.Preoperative anaemia is common in knee and hip primary arthroplasty and was associated with a relevant increase in red blood cell concentrate consumption. In the context of patient blood management, a relevant potential arises, especially in elective orthopaedic surgery, to better prepare elective patients, to avoid unnecessary transfusions and thus to conserve the valuable resource blood.Präoperativ liegt bei etwa jedem 3. Patienten eine nicht therapierte Anämie vor, die wiederum im Kontext eines chirurgischen Eingriffs mit einem erhöhten Transfusionsbedarf von allogenen Erythrozytenkonzentraten (EK) sowie Komplikationen einhergeht. In der vorliegenden Arbeit soll die Prävalenz einer prä- und postoperativen Anämie und deren Einfluss auf den Transfusionsbedarf von EK, Krankenhausverweildauer sowie Krankenhaussterblichkeit in der primären Hüft- und Kniegelenkendoprothetik analysiert werden.Basierend auf einem anonymisierten Register wurden von Januar 2012 bis September 2018 378 069 erwachsene stationäre Patienten aus 13 deutschen Krankenhäusern analysiert, von denen n = 10 017 Patienten eine Hüft- und Kniegelenkprimärimplantation hatten. Der primäre Endpunkt war die Inzidenz einer präoperativen Anämie, die über den 1. präoperativ verfügbaren Hämoglobinwert entsprechend der WHO-Definition analysiert wurde. Zu den sekundären Endpunkten zählte die Krankenhausverweildauer, Anzahl Patienten mit EK-Transfusion, Inzidenz einer postoperativen krankenhauserworbenen Anämie, Anzahl verstorbener Patienten sowie verschiedene postoperative Komplikationen.Die präoperative Anämierate betrug bei elektiver Kniegelenkendoprothetik 14,8%, bei elektiver Hüftgelenkendoprothetik 22,9% und bei Duokopfprothesenimplantation sogar 45,0%. Eine präoperative Anämie führte zu einer signifikant höheren EK-Transfusionsrate (Kniegelenkprothese: 8,3 vs. 1,8%; Hüftgelenksprothese: 34,5 vs. 8,1%; Duokopfprothese: 42,3 vs. 17,4%) sowie einem erhöhten EK-Verbrauch (Kniegelenk: 256 ± 107 vs. 29 ± 5 EK/1000 Patienten; Hüftgelenk: 929 ± 60 vs. 190 ± 16 EK/1000 Patienten; Duokopfprothese: 1411 ± 98 vs. 453 ± 42). Im Gesamtkollektiv war eine präoperative Anämie gegenüber nicht anämischen Patienten mit einer verlängerten Krankenhausverweildauer (12,0 [10,0; 17,0] d vs. 11,0 [9,0; 13,0] d; p 0,001) sowie einer erhöhten Sterblichkeit assoziiert (5,5% [4,6 – 6,5%] vs. 0,9% [0,7% – 1,2%]; Fisher p 0,001). Bei Patienten mit einem Alter von 80 Jahren und höher war die Inzidenz einer präoperativen Anämie und damit die Transfusionsrate nahezu doppelt so hoch wie bei den unter 80-Jährigen.Eine präoperative Anämie kommt bei Knie- und Hüftgelenkprimärimplantation häufig vor und ist mit einem relevant erhöhten EK-Verbrauch assoziiert. Vor diesem Hintergrund könnte sich in der Zukunft vor allem in der elektiven orthopädischen Chirurgie ein relevantes Potenzial ergeben, im Sinne von Patient Blood Management die elektiven Patienten besser vorzubereiten, um unnötige Transfusionen zu vermeiden und so die wertvolle Ressource Blut zu schonen.

Due to increasing demands for computing power by upcoming applications, such as autonomous driving or Car2x, more and more multi-core processors finding their way into electronic control units of the automotive domain. This leads to a paradigm shift from sequential to parallel processing, which creates many challenges in the development of safety-critical embedded multi-core systems.

BACKGROUND Extravascular lung water is a quantitative marker of the amount of fluid in the thoracic cavity besides the vasculature. Indexing to both predicted and actual body weight have been proposed to compare different individuals and provide a uniform range of normal. OBJECTIVE We explored extravascular lung water measured by single-indicator transpulmonary thermodilution in a large cohort of patients without cardiopulmonary instability, in order to evaluate current and alternative indexing methods. DESIGN Prospective, observational. SETTING Neurosurgical ICU in a tertiary referral academic teaching hospital. PATIENTS One hundred and one consecutive patients requiring elective brain tumor surgery and postoperative ICU surveillance. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Indexed to predicted body weight, females had a mean extravascular lung water of 9.1 (SD=3.1, range: 5-23) mL/kg and males of 8.0 (SD=2.0, range: 4-19) mL/kg (p

BACKGROUND Droperidol is a highly potent butyrophenone used for the therapy of postoperative nausea and vomiting. Its cardiac safety in cardiovascular-healthy patients and those with long QT (LQT) syndrome is a matter of debate. In this study, we investigated whether droperidol has subtype-specific effects in cellular and computational models of LQT syndrome. METHODS Left ventricular cardiac myocytes were isolated from adult guinea pig hearts. LQT1-like behavior was pharmacologically induced by chromanol 293B (10 micromol/L) and LQT2-like states by E4031 (10 micromol/L). Computational analysis was performed using the Luo-Rudy dynamic model. Data are given as mean + or - SEM. RESULTS In control myocytes, droperidol lengthened action potentials in a concentration-dependent manner with a maximal prolongation of 37% + or - 13% (n = 4) at a concentration of 0.6 micromol/L. In LQT1-like myocytes, droperidol (0.6 micromol/L) further prolonged action potentials by 31% + or - 6% (n = 6) but shortened action potentials of LQT2-like myocytes by 11% + or - 2% (n = 8). Computational modeling supported the concept that droperidol, in addition to the rapid component of the delayed K(+) current, blocks depolarizing targets, such as the L-type Ca(2+) current, the Na(+)-Ca(2+) exchanger, and the Na(+)-K(+) adenosine triphosphatase. CONCLUSIONS Droperidol has more detrimental effects on cardiac repolarization of LQT1-like than of LQT2-like myocytes suggesting subtype-specific cardiotoxic effects in patients with LQT syndrome. The subtype specificity of droperidol seems to be caused by a complex interaction of droperidol with several different molecular targets. This interaction deserves further investigation to establish the feasibility of a subtype-directed approach in the perioperative management of patients with LQT syndrome.

Background The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes. Methods Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique. Results Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 microM. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nM prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed. Conclusions Droperidol is a high-affinity blocker of HERG channels. Amino acid residues typically involved in high-affinity block mediate droperidol effects. Patch clamp results and computational modeling allow the hypothesis that interaction with calcium currents may explain why droperidol at antiemetic concentrations prolongs the action potential without inducing early afterdepolarizations.

Background Local anesthetics interact with human ether-a-go-go-related gene (HERG) channels via the aromatic amino acids Y652 and F656 in the S6 region. This study aimed to establish whether the residues T623, S624, and V625 residing deeper within the pore are also involved in HERG channel block by bupivacaine. In addition, the study aimed to further define the role of the aromatic residues Y652 and F656 in bupivacaine inhibition by mutating these residues to threonine. Methods Alanine and threonine mutants were generated by site-directed mutagenesis. Electrophysiologic and pharmacologic properties of wild-type and mutant HERG channels were established using two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing HERG channels. Results Tail currents at -120 mV through HERG wild-type channels were inhibited with an IC50 value of 132 +/- 22 microm (n = 33). Bupivacaine (300 microm) inhibited wild-type tail currents by 62 +/- 12% (n = 7). Inhibition of HERG tail currents by bupivacaine (300 microm) was reduced by all mutations (P < 0.001). The effect was largest for F656A (inhibition 5 +/- 2%, n = 6) in the lower S6 region and for T623A (inhibition 13 +/- 4%, n = 9) near the selectivity filter. Introducing threonine at positions 656 and 652 significantly reduced inhibition by bupivacaine compared with HERG wild type (P < 0.001). Conclusions The authors' results indicate that not only the aromatic residues Y652 and F656 but also residues residing deeper within the pore and close to the selectivity filter of HERG channels are involved in inhibition of HERG channels by the low-affinity blocker bupivacaine.

BACKGROUND Intoxication with local anesthetics may induce cardiac arrhythmias by interaction with ion channels. Ropivacaine has been introduced into clinical anesthesia as a safer alternative to bupivacaine, which is associated with a relatively high risk of cardiac arrhythmias. Diverging safety profiles may result from differences in the mode of interaction with cardiac Na(+) channels. We conducted this study to test this hypothesis and to provide experimental basis for the ongoing discussion regarding the cardiotoxic profiles of these local anesthetics. METHODS The influence of bupivacaine and ropivacaine on the electrophysiological properties of Na(+) channels was investigated in human embryonic kidney-293 cells stably transfected with SCN5A channels cloned from the human heart using the patch-clamp technique in the outside-out configuration. RESULTS Open-channel block of SCN5A channels was concentration dependent, with bupivacaine being approximately 4.5-fold more potent than ropivacaine (IC50 = 69.5 ± 8.2 μM vs IC50 = 322.2 ± 29.9 μM). Both drugs influenced the voltage dependency of channel activation and steady-state inactivation by shifting the membrane potential of half-maximal activation/inactivation toward somewhat more negative membrane potentials. In their inactivated state, SCN5A channels were slightly more sensitive toward bupivacaine than toward ropivacaine (IC50 = 2.18 ± 0.16 μM vs IC50 = 2.73 ± 0.27 μM). Blockade of inactivated channels developed in a concentration-dependent manner, with comparable time constants for both drugs, whereas recovery from block was approximately 2-fold faster for ropivacaine than for bupivacaine. CONCLUSIONS Human cardiac Na(+) channels show state-dependent inhibition by ropivacaine, and the mode of interaction is comparable to that of bupivacaine. Therefore, modest differences in cardiotoxicity between these local anesthetic drugs are compatible with subtle differences in their interaction with human cardiac Na(+) channels.

Hypothesis Lidocaine may lead to an alteration in the processing of hearing as observed during tinnitus by inhibiting voltage-gated potassium channels at clinically relevant concentrations. Background Recent molecular evidence suggests that the voltage-gated potassium channels Kv 3.1 and Kv 1.1 play an important functional role in the auditory system. Lidocaine is known to influence the auditory system and may thus exert pharmacological effects on these human potassium channels. Methods Patch-clamp recordings were performed on the pharmacologic action of lidocaine on Kv 3.1 channels natively expressed in SH-SY5Y cells and Kv 1.1 channels expressed in HEK 293 cells. Results Lidocaine reversibly inhibited Kv 3.1 and Kv 1.1 channels in a concentration-dependent manner. The half-maximal inhibitory concentration for conductance block was 607 micromol/L for Kv 3.1 (n=47) and 4,550 micromol/L for Kv 1.1 channels (n=56), respectively. The Hill coefficients were 0.9 and 0.8. Conductance block was voltage dependent for Kv 3.1 but not for Kv 1.1 channels. The midpoint of current activation of both channels was shifted to hyperpolarized potentials. At free plasma concentrations determined during suppression (0.5-1 mg/L; 1.75-3.5 micromol/L) or induction (>1-2 mg/L; >3.5-7 micromol/L) of tinnitus Kv 3.1 and K v1.1 channels would be suppressed by at most 1.5 to 2%. Conclusion Human Kv 3.1 and Kv 1.1 channels exhibited different sensitivities to the inhibitory action of lidocaine. The small effect at clinically relevant concentrations suggests that the physiologic roles of Kv 3.1 and Kv 1.1 channels in auditory neurons seem not to be impaired during the therapeutic or diagnostic application of lidocaine in the auditory system.

Background Human ether-a-go-go-related gene (HERG) potassium channels constitute a potential target involved in cardiotoxic side effects of amino-amide local anesthetics. The molecular interaction site of these low-affinity blockers with HERG channels is currently unknown. The aim of this study was to determine the effect of the mutations Y652A and F656A in the putative drug binding region of HERG on the inhibition by bupivacaine, ropivacaine, and mepivacaine. Methods The authors examined the inhibition of wild-type and mutant HERG channels, transiently expressed in Chinese hamster ovary cells by bupivacaine, ropivacaine, and mepivacaine. Whole cell patch clamp recordings were performed at room temperature. Results Inhibition of HERG wild-type and mutant channels by the different local anesthetics was concentration dependent, stereoselective, and reversible. The sensitivity decreased in the order bupivacaine > ropivacaine > mepivacaine for wild-type and mutant channels. The mutant channels were approximately 4-30 times less sensitive to the inhibitory action of the different local anesthetics than the wild-type channel. The concentration-response data were described by Hill functions (bupivacaine: wild-type IC50 = 22 +/- 2 microm, n = 38; Y652A IC50 = 95 +/- 5 microm, n = 31). The mutations resulted in a change of the stereoselectivity of HERG channel block by ropivacaine. The potency of the local anesthetics to inhibit wild-type and mutant channels correlated with the lipophilicity of the drug (r > 0.9). Conclusions These results indicate that local anesthetics specifically but not exclusively interact with the aromatic residues Y652 and F656 in S6 of HERG channels.

Background Inhibition of cardiac K channels by local anesthetic may contribute to QTc interval prolongation of the electrocardiogram and induction of ventricular arrhythmia. The transient outward current Ito has been identified as a toxicologically relevant target of bupivacaine. S(-)-ropivacaine has been developed as a safer alternative to bupivacaine. The effects of S(-)-ropivacaine on Ito have not been investigated. In human ventricular myocardium, Ito is formed by Kv4.3 and KChIP2.2 subunits. Therefore, the aim of this study was to establish the effects of S(-)-ropivacaine on human Kv4.3/KChIP2.2 channels. Methods Kv4.3/KChIP2.2 complementary DNA cloned from human heart was transiently transfected in Chinese hamster ovary cells. The pharmacologic effects of S(-)-ropivacaine were investigated with the patch clamp method. Results Ropivacaine inhibited Kv4.3/KChIP2.2 channels in a concentration-dependent, stereospecific, and reversible manner. The IC50 value of S(-)-ropivacaine for inhibition of the charge conducted by Kv4.3/KChIP2.2 channel was 117 +/- 21 microm (n = 30). The local anesthetic accelerated macroscopic current decline with an IC50 value of 77 +/- 11 microm (n = 30). It shifted the midpoint of channel activation into the depolarizing direction, and it slowed recovery from inactivation without altering steady state inactivation. Kv4.3 channels are more sensitive to the inhibitory effect than Kv4.3/KChIP2.2 channels. Conclusions : The results are consistent with the idea that ropivacaine, by blocking Kv4.3/KChIP2.2 from the open state, interferes with the gating modifying effects of KChIP2.2 on Kv4.3 channels. Inhibition of Kv4.3/KChIP2.2 channels by the local anesthetic may contribute to the deterioration of cardiac function during events of intoxication.

Background. Myocardial potassium channels are complexes formed by different subunits. The subunit composition may influence the cardiotoxic action of local anaesthetics. The effects of amide local anaesthetics on HERG channels co-expressed with the putative subunit MiRP1 have not been established. It is also unclear if the common polymorphism MiRP1T8A that predisposes individuals to drug-induced cardiac arrhythmia increases local-anaesthetic sensitivity of HERG/MiRP1 channels. This may suggest the presence of genetic risk factors for local-anaesthetic-induced cardiac arrhythmia. Methods. Whole-cell patch-clamp recordings and site-directed mutagenesis were combined to compare local anaesthetic sensitivities of cloned and mutated human potassium channel subunits. The ion channels were activated by a protocol that approximated ventricular action potentials. Results. The amide local anaesthetics bupivacaine, levobupivacaine and ropivacaine inhibited HERG channels at toxicologically relevant concentrations, with IC50 values of 20 (SEM 2) mM (n=29), 10 (1) m M( n=40) and 20 (2) m M( n=49), respectively. Hill coefficients were close to unity. There were no indications of qualitative differences in channel inhibition between the three anaesthetics. The putative subunit MiRP1 did not alter local anaesthetic sensitivity of HERG channels. The common single nucleotide polymorphism producing MiRP1T8A did not increase local anaesthetic sensitivity of HERG/MiRP1 channels. Conclusions. Amide local anaesthetics target HERG and HERG/MiRP1 channels with identical potency. The effects on these ion currents may significantly contribute to local-anaestheticinduced cardiac arrhythmia. MiRP1T8A does not seem to confer an increased risk of severe cardiac side-effects to carriers of this common polymorphism.

Biophysical properties of delayed rectifier K channels in the human neuroblastoma SH-SY5Y were established using patch clamp recordings. The whole cell K+ conductance activated at membrane potentials positive to -20 mV. The midpoint of current activation was 9.6 +/- 5.1 mV, the equivalent charge was 3.7 +/-.6. Whole-cell currents inactivated slightly with time constants of 700 ms and 5 s. The K+ currents were sensitive to micromolar concentrations of TEA and 4-aminopyridine. RT-PCR experiments amplified a cDNA fragment specific for human Kv3.1 channels. Activation gating parameters in outside-out patches were shifted by approximately 14 mV in the hyperpolarizing direction.

Superficial cervical plexus neuropathy after interscalene brachial plexus block affects about 8% of patients postoperatively. One of the nerves involved in superficial cervical plexus neuropathy is the great auricular nerve. We report success in identification of the great auricular nerve with ultra

Die Benchmarking-Studie OP-Personaleinsatzplanung (OP-PEP) referenziert auf den Prozess der Einsatzplanung fur Operationen und das Zusammenspiel der Berufsgruppen OP-Management, OP-Pflege, Anasthesie-Pflege, Arztlicher Dienst Anasthesie, die unterstutzenden Dienstleister Reinigung, Ver- und Entsorgung, Zentralsterilisationsversorgung, sowie die Arzte der operierenden Fachabteilungen. Der Personaleinsatzplanungsprozess wird aus Sicht eines Prozess-Benchmarkings, im Sinne eines Vergleiches von Produktivitat und Kosten der Einsatzplanung der „Hauptdienstleister“ OP-Pflege, Anasthesiepflege, Arztlicher Dienst Anasthesie und OP-Management, betrachtet. Die zweite Perspektive behandelt die Werte zur Zufriedenheit der einzelnen „Kunden“ im Personeinsatzplanungsprozess. Die dritte Perspektive zeigt die Auswirkungen der Planungsaktivitaten der Berufsgruppen auf den OP-Plan. Zusammenfassend werden die einzelnen Benchmarking-Perspektiven gegenubergestellt und ein Leitfaden fur die Betrachtung aus ganzheitlicher, wertschopfungsorientierter Sicht fur die Kliniken aufgezeigt. Neben den Handlungsempfehlungen der einzelnen Perspektiven werden mogliche Zusammenhange aus wertschopfungsorientierter Sicht analysiert und Potentiale bei der Personaleinsatzplanung gegeben.

Background Recent evidence shows that inhibition of human Kv3 channels by intravenous anesthetics occurs at clinical concentrations. The effects of volatile anesthetics on these human ion channels are unknown. This study was designed to establish whether minimum alveolar concentrations (MAC) of halothane, enflurane, isoflurane, and desflurane exhibit effects on Kv3 channeLs. To obtain an indication whether these findings may be specific to Kv3 channels, the effects of enflurane and isoflurane on human Kv1.1 channels were also investigated. Methods Kv3 channels natively expressed in SH-SY5Y cells and Kv1.1 channels expressed in HEK293 cells were measured with the whole cell patch clamp technique by standard protocols. Concentrations of volatile anesthetics were determined by gas chromatography. Results Halothane, enflurane, isoflurane, and desflurane reversibly inhibited Kv3 channels in a concentration-dependent manner. Concentrations at half-maximal effect (IC50 values) ranged between 1,800 and 4,600 microM. Hill coefficients were between 1.7 and 2.5. IC50 values for inhibition of Kv1.1 channels were 2,800 and 5,200 microM, and Hill coefficients were 3.9 and 5.6 for enflurane and isoflurane, respectively. Conclusion Volatile anesthetics inhibit human Kv3 channels at clinical concentrations. At 1-3 MAC, inhibition would account on average for 2-12%. Inhibition would be highest with enflurane (between 3% and 22%) and lowest with isoflurane (between 0.2% and 3%). Kv1.1 channels would only be inhibited by enflurane at clinical concentrations (2% at 2 MAC and 8% at 3 MAC). Whether the degree of K channel inhibition by volatile anesthetics may contribute to their clinical action needs further study.

Objective: It is a matter of dispute whether etomidate exhibits an epileptogenic action. It is also disputed whether frequently observed myocloni induced by etomidate are related to seizure-like activity in the EEG. The clinical effects of anaesthetic agents reflect their molecular action. A possible epileptogenic action of etomidate should, therefore, result from action on a molecular target that has yet to be identified. Suppression of Kv 1.1 channels may be associated with epilepsy in men. Inhibition of Kv 1.1 channels by etomidate at clinically relevant concentrations would, thus, argue in favour of an epileptogenic action of etomidate. Methods: Patchclamp recordings of the pharmacological action of etomidate on cloned and functionally expressed human Kv 1.1 channels. Results: Etomidate inhibits human Kv 1.1 channels in a concentration-dependent and reversible manner. The IC 50 -value is 400 μM, the Hill-coefficient is 2. The ratio of free clinical plasma concentrations and the IC 50 -value is 0.006. At plasma concentrations determined in a clinical setting Kv 1.1 channels would be suppressed by less than 0.01%. Conclusion: The small effect of etomidate on human Kv 1.1 channels at these concentrations questions an epileptogenic action of etomidate caused by inhibition of Kv 1.1 channels.

Background Surprising clinical evidence suggests a block of sympathetic transmission by ketamine. The action of ketamine on nicotinic acetylcholine receptors (nAChRs) in human ganglions is unknown. Because ganglionic transmission depends on nAChRs, such information may help to clarify whether ketamine impairs ganglionic transmission in men. Because racemic ketamine as well as S(+)-ketamine are used clinically, the authors investigated stereospecific effects on human ganglionic nAChRs. Stereospecific psychomimetic effects have been attributed to voltage-dependent Kv channel inhibition; therefore the effects on nAChRs were compared with those on Kv channels present in the same cells. Methods Whole-cell currents through nAChRs and K channels were measured in SH-SY5Y cells with the patch-clamp technique by application of acetylcholine (1 mm, nAChRs) or by a step depolarization from a holding potential of -80 mV to +40 mV (K channels). Electrolyte conditions were identical for both currents. Results Racemic ketamine and the isomers inhibited nAChRs and K channels in a concentration-dependent and reversible manner. Racemic ketamine inhibited nAChRs and K channels, with the anesthetic concentration inducing the half-maximal effect being 1.4 and 300 micrometer, respectively. Only inhibition of the nAChRs was stereoselective. The half-maximal concentrations were 0.8 and 3.6 micrometer for S(+)- and R(-)-ketamine. The K channels were 350 and 70 times less sensitive to the effects of S(+)- and R(-)-ketamine. Conclusion Ketamine at concentrations found during clinical anesthesia exerts stereospecific effects on human ganglionic nAChRs but not on voltage-dependent K channels. Our results support the view that ketamine impairs sympathetic ganglionic transmission. Nonspecific effects on voltage-dependent K channels may underlie psychomimetic side effects.

Muskelrelaxanzien sind der haufigste Ausloser allergischer Reaktionen in der Anasthesie. Es wird uber den Fall einer lebensbedrohlichen anaphylaktischen Reaktion bei Narkoseeinleitung berichtet, bei der sich als Erstsymptom der Anaphylaxie ein schwerer Bronchospasmus fand. Eine Beatmung war zeitweilig nahezu unmoglich. Angesichts der Schwere der Reaktion waren eine multimodale antiallergische Therapie und eine hoch dosierte Katecholamintherapie erforderlich. Als Ausloser der anaphylaktischen Reaktion konnte das Muskelrelaxans Rocuronium mithilfe des Intrakutantests identifiziert werden.

BACKGROUND: The effects of the local anesthetic bupivacaine on cardiac action potentials (APs) are mainly attributed to inhibition of cardiac Na(+) channels. The relevance of its ability to also induce high-affinity blockade of human ether-a-gogo-related gene (hERG) channels is unclear. We investigated whether this interaction may functionally become more significant in cellular and computational models of long (L)QT syndromes. METHODS: Left ventricular cardiomyocytes were isolated from adult guinea pig hearts, and bupivacaine-induced effects on APs were investigated using the patch-clamp technique. LQT-like states were pharmacologically induced by either blocking I(Ks) (LQT1-like, 10 μmol/L chromanol 293B), or I(Kr) (LQT2-like, 10 μmol/L E4031). Computational analysis of bupivacaine's effects was based on the Luo-Rudy dynamic model. RESULTS: Bupivacaine induced dose-dependent AP shortening in control myocytes. However, in the presence of 1 to 30 μmol/L bupivacaine, a high variability in AP duration with AP prolongations of up to 40% was observed. This destabilizing effect on AP duration was significantly increased in LQT1-like but not in LQT2-like myocytes. Similarly, the incidence of AP prolongations in the presence of 3 μmol/L bupivacaine was significantly increased from 6% in control myocytes to 24% in LQT1-like but not in LQT2-like myocytes. Computational modeling supported the concept that this bupivacaine-induced AP instability and the AP prolongations in the control and LQT1-like myocytes were caused by inhibition of hERG channels. CONCLUSIONS: This study provides evidence that bupivacaine induces inhibition of hERG channels, which is functionally silent under normal conditions but will become more relevant in LQT1-like states in which repolarization relies to a larger degree on hERG channels. Interactions with ion channels other than cardiac Na(+) channels may, therefore, determine the net cardiac effects of bupivacaine when the normal balance of ionic currents is altered.

BACKGROUND: Interscalene brachial plexus block (ISB) using the modified lateral approach provides a well-established method of anesthesia and analgesia for patients undergoing shoulder surgery. Considering the neural anatomy at the site of injection, the superficial cervical plexus may be at risk of injury. We evaluated the incidence and characteristics of superficial cervical plexus neuropathy. METHODS: During a 1-yr period, 273 consecutive patients requiring single-injection ISB for shoulder or proximal arm surgery were studied. Patients were examined for symptoms compatible with superficial cervical plexus injury before surgery, 24 h postoperatively, and contacted by telephone 31 days after surgery. Symptomatic patients received an additional phone call 6 mo after surgery. RESULTS: Twenty-four hours after shoulder surgery, 21 patients (7.7%) showed symptoms consistent with superficial cervical plexus neuropathy. Symptoms consisted of hypesthesia in 1–4 cutaneous branches of the cervical plexus. Five patients (1.8%) reported symptoms that lasted for >31 days. All symptoms had entirely resolved after 6 mo. CONCLUSIONS: Superficial cervical plexus neuropathy is not uncommon after ISB using the modified lateral approach and the possibility should be discussed with patients preprocedurally.

Background This study's aim was to investigate the interaction of amino-amide local anesthetics with human Kv1.1 potassium channels. These channels were chosen because of their proven physiologic role. By using a homolog series of local anesthetics with different lengths of the N-substituent, it was intended to elucidate the role of lipophilic interactions with Kv1.1. The use of stereoisomers allowed testing of the role of polar drug actions. Methods Human Kv1.1 channels were measured with the patch clamp technique. Concentration-response data were described by Hill functions. Gating changes were described by Boltzmann functions. Results Inhibition of Kv1.1 channels by dextrobupivacaine, bupivacaine, levobupivacaine, dextroropivacaine, levoropivacaine, and mepivacaine was concentration dependent, reversible, stereoselective, voltage dependent, and frequency independent. The IC(50) values were (mean +/- SEM) 41 +/- 3 microm (n = 20), 56 +/- 3 microm (n = 26), 76 +/- 8 microm (n = 24), 135 +/- 29 microm (n = 23), 313 +/- 32 microm (n = 25), and 1,451 +/- 351 microm (n = 23), respectively. The midpoint of current activation was shifted into the hyperpolarizing direction. The inhibitory potency as well as the potency to induce gating changes correlated with the number of CH(2) groups in the side chain of the drugs (r > 0.9, P < 0.05). Conclusions Kv1.1 channels constitute an important biophysical model for elucidating molecular mechanisms underlying local anesthetic drug effects. Inhibition likely results from an open state-dependent blocking mechanism. Interaction of local anesthetics with the ion channel protein is determined by lipophilic drug properties.

The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes.Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique.Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 microM. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nM prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed.Droperidol is a high-affinity blocker of HERG channels. Amino acid residues typically involved in high-affinity block mediate droperidol effects. Patch clamp results and computational modeling allow the hypothesis that interaction with calcium currents may explain why droperidol at antiemetic concentrations prolongs the action potential without inducing early afterdepolarizations.

Background Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a position corresponding to the local anesthetic binding site in HERG, may render drug insensitive KCNQ1 channels into a toxicologically relevant target of these pharmacologic agents. This may suggest that LQTS constitutes not only a nonspecific but also a specific pharmacogenetic risk factor for anesthesia. Methods The authors examined electrophysiologic and pharmacologic properties of wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, and mepivacaine were investigated using two-electrode voltage clamp and whole cell patch clamp recordings. Results The mutation A344V induced voltage-dependent inactivation in homomeric KCNQ1 channels and shifted the voltage dependence of KCNQ1/KCNE1 channel activation by +30 mV. The mutation furthermore increased the sensitivity of KCNQ1/KCNE1 channels for bupivacaine 22-fold (KCNQ1wt/KCNE1: IC50 = 2,431 +/- 582 microM, n = 20; KCNQ1A344V/KCNE1: IC50 = 110 +/- 9 microM, n = 24). Pharmacologic effects of the mutant channels were dominant when mutant and wild-type channels were coexpressed. Simulation of cardiac action potentials with the Luo-Rudy model yielded a prolongation of the cardiac action potential duration and induction of early afterdepolarizations by the mutation A344V that were aggravated by local anesthetic intoxication. Conclusions The results indicate that certain forms of the LQTS may constitute a specific pharmacogenetic risk factor for regional anesthesia.

Background The transient outward current Ito is an important repolarizing K current in human ventricular myocardium mediated by Kv4.3 and KChIP2.2 subunits. Inhibition of Ito by amino-amide local anesthetics may be involved in severe cardiotoxic side effects. This study elucidates the molecular mechanisms of bupivacaine interaction with complexes formed by Kv4.3 and KChIP2.2 as well as the modulatory effect of KChIP2.2. For this purpose, the pharmacologic effects of bupivacaine on Kv4.3wt/KChIP2.2 channels and on the pore mutant Kv4.3V401I were investigated. Methods Kv4.3/KChIP2.2 cDNA was transiently expressed in Chinese hamster ovary cells. Site-directed mutagenesis and patch clamp experiments were performed to analyze the effects of bupivacaine on wild-type and mutant channels. Results Inhibition of Kv4.3wt/KChIP2.2 channels by bupivacaine was concentration-dependent and reversible. The IC50s for inhibition of the charge conducted by Kv4.3wt/KChIP2.2 channels by bupivacaine and levobupivacaine were 55 +/- 8 and 50 +/- 5 microm, respectively. The local anesthetic accelerated macroscopic current decline of Kv4.3wt/KChIP2.2 and slowed recovery from inactivation without altering steady state inactivation. KChIP2.2 altered the response of Kv4.3wt channels to bupivacaine and bupivacaine modulated KChIP2.2 effects on Kv4.3wt channels. The pore mutation V401I slowed macroscopic current decline of Kv4.3 channels and recovery from inactivation, and it diminished modulation of gating by KChIP2.2. Bupivacaine inhibition of Kv4.3V401I resembled Kv4.3wt and was not changed by coexpression of KChIP2.2. Conclusions These results indicate that bupivacaine blocks Kv4.3/KChIP2.2 channels from the open state. They furthermore give structural evidence that amino-amide local anesthetics interfere with the effects of KChIP2.2 on Kv4.3 by an indirect mechanism.

Human ether-a-go-go-related gene (HERG) potassium channels constitute a potential target involved in cardiotoxic side effects of amino-amide local anesthetics. The molecular interaction site of these low-affinity blockers with HERG channels is currently unknown. The aim of this study was to determine the effect of the mutations Y652A and F656A in the putative drug binding region of HERG on the inhibition by bupivacaine, ropivacaine, and mepivacaine.The authors examined the inhibition of wild-type and mutant HERG channels, transiently expressed in Chinese hamster ovary cells by bupivacaine, ropivacaine, and mepivacaine. Whole cell patch clamp recordings were performed at room temperature.Inhibition of HERG wild-type and mutant channels by the different local anesthetics was concentration dependent, stereoselective, and reversible. The sensitivity decreased in the order bupivacaineropivacainemepivacaine for wild-type and mutant channels. The mutant channels were approximately 4-30 times less sensitive to the inhibitory action of the different local anesthetics than the wild-type channel. The concentration-response data were described by Hill functions (bupivacaine: wild-type IC50 = 22 +/- 2 microm, n = 38; Y652A IC50 = 95 +/- 5 microm, n = 31). The mutations resulted in a change of the stereoselectivity of HERG channel block by ropivacaine. The potency of the local anesthetics to inhibit wild-type and mutant channels correlated with the lipophilicity of the drug (r0.9).These results indicate that local anesthetics specifically but not exclusively interact with the aromatic residues Y652 and F656 in S6 of HERG channels.

Sudden infant death syndrome (SIDS) is a frequent cause of death among infants. The etiology of SIDS is unknown and several theories, including fatal ventricular arrhythmias, have been suggested. We performed an epidemiological and genetic investigation of SIDS victims to estimate the presence of inherited long QT syndrome (LQTS) as a contributor for SIDS. Forty-one consecutively collected and unrelated SIDS cases were characterized by clinical and epidemiological criteria. We performed a comprehensive gene mutation screening with single-strand conformation polymorphism analysis and sequencing techniques of the most relevant LQTS genes to assess mutation frequencies. In vitro characterization of identified mutants was subsequently performed by heterologous expression experiments in Chinese hamster ovary cells and in Xenopus laevis oocytes. A positive family history for LQTS was suspected by mild prolonged Q-T interval in family members in 2 of the 41 SIDS cases (5%). In neither case, a family history of sudden cardiac death was present nor a mutation could be identified after thorough investigation. In another SIDS case, a heterozygous missense mutation (H105L) was identified in the N-terminal region of the KCNQ1 (LQTS 1) gene. Despite absence of this mutation in the general population and a high conservational degree of the residue H105 during evolution, electrophysiological investigations failed to show a significant difference between wild-type and KCNQ1(H105L)/minK-mediated I(Ks) currents. Our data suggest that a molecular diagnosis of SIDS related to LQTS genes is rare and that, even when an ion channel mutation is identified, this should be regarded with caution unless a pathophysiological relationship between SIDS and the electrophysiological characterization of the mutated ion channel has been demonstrated.

Background Inhibition of KCNQ2/Q3 channels may cause convulsion in humans. The interaction of bupivacaine with these channels is unknown. The anticonvulsant retigabine activates KCNQ2/Q3 channels and may reverse inhibitory actions of bupivacaine. Potassium channel stimulation may thus constitute a novel approach to treat local anesthetic-induced seizures. The aim of this study was to characterize bupivacaine effects on KCNQ2/Q3 channels and to investigate whether retigabine reverses the effects of the local anesthetic. Methods KCNQ2/Q3 channels were transiently expressed in Chinese hamster ovary cells. The effects of bupivacaine and retigabine were studied with the patch-clamp technique. Results Bupivacaine inhibited KCNQ2/Q3 channels in a concentration-dependent and reversible manner. The concentration-response curve was described by a Hill equation (IC50 = 173 +/- 7 microm, Hill coefficient = 1.4 +/- 0.1, mean +/- SEM, n = 37). The inhibitory effect did not differ between bupivacaine and levobupivacaine (42 +/- 4%, n = 7, versus 42 +/- 5%, n = 10; P > 0.05). Ropivacaine was four times less potent than bupivacaine. The inhibition of KCNQ2/Q3 channels by bupivacaine resulted in a significant and reversible depolarization of the membrane potential. Retigabine (300 nm-10 microm) reversed the inhibitory action of bupivacaine on KCNQ2/Q3 channels as well as the depolarization of the membrane potential. Conclusions The anticonvulsant retigabine at nanomolar concentrations reverses the inhibitory effect of micromolar concentrations of bupivacaine. Our results allow the hypothesis that activation of KCNQ2/Q3 channels by retigabine may offer a novel therapeutic approach for the treatment of bupivacaine-induced seizures.

The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.

The effects of the antiarrhythmic drug propafenone at Kv2.1 channels were studied with wild-type and mutated channels expressed in Xenopus laevis oocytes. Propafenone decreased the Kv2.1 currents in a time- and voltage-dependent manner (decrease of the time constants of current rise, increase of block with the duration of voltage steps starting from a block of less than 19%, increase of block with the amplitude of depolarization yielding a fractional electrical distance delta of 0.11 to 0.16). Block of Kv2.1 appeared with application to the intracellular, but not the extracellular, side of membrane patches. In mutagenesis experiments, all parts of the Kv2.1 channel were successively exchanged with those of the Kv1.2 channel, which is much more sensitive to propafenone. The intracellular amino and carboxyl terminus and the intracellular linker S4-S5 reduced the blocking effect of propafenone, whereas the linker S5-S6, as well as the segment S6 of the Kv1.2 channel, abolished it to the value of the Kv1.2 channel. In the linker S5-S6, this effect could be narrowed down to two groups of amino acids (groups 372 to 374 and 383 to 384), which also affected the sensitivity to tetraethylammonium. In segment S6, several amino acids in the intracellularly directed part of the helix significantly reduced propafenone sensitivity. The results suggest that propafenone blocks the Kv2.1 channel in the open state from the intracellular side by entering the inner vestibule of the channel. These results are consistent with a direct interaction of propafenone with the lower part of the pore helix and/or residues of segment S6.

Background Information on molecular targets that may be involved in the neurotoxicity of bupivacaine is limited. Suppression of Kv3 channels has been demonstrated to result in abnormal patterns in the electroencephalogram and in seizures. Inhibition of Kv3 channels by bupivacaine may consequently contribute to its neuroexcitatory side‐effects. Data on the effects of bupivacaine on these potassium channels are lacking. We therefore characterized the effects of bupivacaine on human Kv3 channels natively expressed in SH‐SY5Y cells. Methods Kv3 channels natively expressed in human SH‐SY5Y cells were studied using a standard whole‐cell patch‐clamp protocol. Results Bupivacaine reversibly inhibited Kv3 channels in a concentration‐dependent manner. The half‐maximal inhibitory concentration (IC50) for conductance block was 57 µM and the Hill coefficient was close to unity. Bupivacaine accelerated macroscopic current decline by inducing inactivation‐like behaviour. The midpoint of current activation was shifted to depolarized potentials in a concentration‐dependent and reversible manner by a maximum of 26 mV. The IC50 was 47 µM and the Hill coefficient was 2.4. The free arterial plasma concentrations of bupivacaine that have been estimated to occur during convulsions in man would inhibit the Kv3 channels by at least 40% and would shift the midpoint of current activation by a minimum of 9 mV. Conclusions Both inhibition of potassium channels and a depolarizing shift of their activation midpoint would increase neuronal excitability. The effects of bupivacaine on human Kv3 channels are thus compatible with a contributory role of Kv channel alteration in bupivacaine‐induced neuronal excitation. Br J Anaesth 2002; 88: 864–6

Long-QT syndrome (LQTS) may cause syncope and sudden death due to cardiac tachyarrhythmia. Chromosome 7-linked LQTS (LQT2) has been correlated with mutations in the human ether-a-go-go-related gene (HERG). HERG forms voltage-gated K channels that may be associated with Mink-related peptide 1 (MiRP1), an auxiliary beta-subunit. The channels mediate currents that resemble native I(Kr). Mutations in the KCNE2 gene encoding MiRP1 may also cause LQTS. In this study, the frequency of mutations in KCNE2 of 150 unrelated LQTS patients without known genotype and of 100 controls was analyzed using single-strand conformation polymorphism analysis and direct sequencing. We identified a novel missense mutation, V65 M, in the KCNE2 gene of a 17-year-old female with syncope and LQTS. Expression studies in Chinese hamster ovary cells revealed that mutant and wild-type MiRP1 co-localized with HERG subunits and formed functional channels. However, mutant HERG/MiRP1(V65M) channels mediated currents with an accelerated inactivation time course compared with wild-type channels. The accelerated inactivation time course of HERG/MiRP1(V65M) channels may decrease I(Kr) current density of myocardial cells, thereby impairing the ability of myocytes to repolarize in response to sudden membrane depolarizations such as extrasystoles.

A 29-year-old man was admitted to the ICU after emergency laparotomy for portal-mesenteric vein thrombosis. Under continuous intravenous heparin therapy the portal-mesenteric shunt occluded on the first postoperative day. After thrombectomy the heparin dose was increased, and the patient remained free of symptoms (partial thromboplastin time 53 s). Two days later abdominal distension developed concomitantly with ventilatory distress due to a large retroperitoneal hematoma. The patient was mechanically ventilated and underwent the third consecutive laparotomy for the hematoma removal on the fifth day. During the surgical procedure the abdomen was packed with towels to stop multiple bleeding sites. The heparin dose was reduced, aiming for a partial thromboplastin time of 30–35 s. Initial coagulation tests revealed increased levels of anticardiolipin immunoglobulin G. After removal of the surgical towels the patient was successfully weaned from mechanical ventilation and discharged from the ICU. Two weeks later genomic testing revealed that he also had a G20210A mutation of the prothrombin gene. Both, increased levels of anticardiolipin immunoglobulin G and the G20210A mutation of the prothrombin gene predispose to thrombosis. Increased levels of anticardiolipin immunoglobulin G may also cause bleeding. Long-term anticoagulation therapy was started with a vitamin K antagonist, and 2 months later a follow-up showed that the patient had no further symptoms of portal-mesenteric vein thrombosis or bleeding. This case illustrates that the convergence of multiple risk factors, including genetic defects, must be considered in patients suffering from thrombosis in unusual sites

Background Neuronal voltage-dependent potassium (K) currents are crucial for various cellular functions, such as the integration of temporal information in the central nervous system. Data for the effects of intravenous anesthetics on human neuronal K currents are limited. It was the authors' aim to evaluate the concentration-related effects of three opioids (fentanyl, alfentanil, sufentanil) and seven nonopioids (thiopental, pentobarbital, methohexital, propofol, ketamine, midazolam, droperidol) used in clinical anesthesia on neuronal voltage-dependent K currents of human origin. Method K currents were measured in SH-SY5Y cells using the whole cell patch-clamp technique. Currents were elicited by step depolarization from a holding potential of -80 to -50 mV through +90 mV, and their steady state amplitudes were determined. Results All drugs inhibited the K currents in a concentration-dependent and reversible manner. Because time dependence of inhibition differed among the drugs, effects were measured after 54-64 ms of the test pulse. The IC50 values (concentration of half-maximal inhibition) for current suppression ranged from 7 microM for sufentanil to 2 mM for pentobarbital. Suppression of the K currents by the opioids occurred at 10-fold lower IC50 values (concentration of half-maximal inhibition) than that by the barbiturates. As estimated from the concentration-response curves, K-current suppression at clinical concentrations would be less than 0.1% for the opioids and approximately 3% for the other drugs. Conclusions Effects of intravenous anesthetics on voltage-dependent K currents occur at clinical concentrations. The IC50 values for current inhibition of the nonopioid anesthetics correlated with these concentrations (r = 0.95). The results suggest that anesthetic drug action on voltage-dependent K currents may contribute to clinical effects or side effects of intravenous anesthetics.

We demonstrate for the first time that the extracellular potassium concentration influences the inhibition of human neuronal delayed rectifier potassium currents by general anesthetics. This observation suggests a modulatory role for extracellular potassium ions in the action of some general anesthetic agents.

Extravascular lung water (EVLW) is a marker for the severity of acute lung injury. To allow assessment of normal and pathologic states, traditionally EVLW data are either indexed to real or predicted body weight. Surprisingly and despite widespread use, this has so far not been validated in a larger cohort of subjects without cardiopulmonary compromise. The aim of the study was to prospectively evaluate a different ways of indexing EVLW data.