Peter Nagele

Multicenter Randomized Comparison of the Efficacy and Safety of Xenon and Isoflurane in Patients Undergoing Elective Surgery

Background All general anesthetics used are known to have a negative inotropic side effect. Since xenon does not have a negative inotropic effect, it could be an interesting future general anesthetic. The aim of this clinical multicenter trial was to test the hypothesis of whether recovery after xenon anesthesia is faster compared with an accepted, standardized anesthetic regimen and that it is as effective and safe. Method A total of 224 patients in six centers were included in the protocol. They were randomly assigned to receive either xenon (60 ± 5%) in oxygen or isoflurane (end-tidal concentration, 0.5%) combined with nitrous oxide (60 ± 5%). Sufentanil (10 &mgr;g) was intravenously injected if indicated by defined criteria. Hemodynamic, respiratory, and recovery parameters, the amount of sufentanil, and side effects were assessed. Results The recovery parameters demonstrated a statistically significant faster recovery from xenon anesthesia when compared with isoflurane–nitrous oxide. The additional amount of sufentanil did not differ between both anesthesia regimens. Hemodynamics and respiratory parameters remained stable throughout administration of both anesthesia regimens, with advantages for the xenon group. Side effects occurred to the same extent with xenon in oxygen and isoflurane–nitrous oxide. Conclusion This first randomized controlled multicenter trial on the use of xenon as an inhalational anesthetic confirms, in a large group of patients, that xenon in oxygen provides effective and safe anesthesia, with the advantage of a more rapid recovery when compared with anesthesia using isoflurane–nitrous oxide.

Chest-compression-only versus standard cardiopulmonary resuscitation: a meta-analysis.

BACKGROUND In out-of-hospital cardiac arrest, dispatcher-assisted chest-compression-only bystander CPR might be superior to standard bystander CPR (chest compression plus rescue ventilation), but trial findings have not shown significantly improved outcomes. We aimed to establish the association of chest-compression-only CPR with survival in patients with out-of-hospital cardiac arrest. METHODS Medline and Embase were systematically reviewed for studies published between January, 1985, and August, 2010, in which chest-compression-only bystander CPR was compared with standard bystander CPR for adult patients with out-of-hospital cardiac arrest. In the primary meta-analysis, we included trials in which patients were randomly allocated to receive one of the two CPR techniques, according to dispatcher instructions; and in the secondary meta-analysis, we included observational cohort studies of chest-compression-only CPR. All studies had to supply survival data. The primary outcome was survival to hospital discharge. A fixed-effects model was used for both meta-analyses because of an absence of heterogeneity among the studies (I(2)=0%). FINDINGS In the primary meta-analysis, pooled data from three randomised trials showed that chest-compression-only CPR was associated with improved chance of survival compared with standard CPR (14% [211/1500] vs 12% [178/1531]; risk ratio 1·22, 95% CI 1·01-1·46). The absolute increase in survival was 2·4% (95% CI 0·1-4·9), and the number needed to treat was 41 (95% CI 20-1250). In the secondary meta-analysis of seven observational cohort studies, no difference was recorded between the two CPR techniques (8% [223/2731] vs 8% [863/11 152]; risk ratio 0·96, 95% CI 0·83-1·11). INTERPRETATION For adults with out-of-hospital cardiac arrest, instructions to bystanders from emergency medical services dispatch should focus on chest-compression-only CPR. FUNDING US National Institutes of Health and American Heart Association.

High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery

BACKGROUND Perioperative myocardial infarction (MI) is a serious complication after noncardiac surgery. We hypothesized that preoperative cardiac troponin T detected with a novel high-sensitivity (hs-cTnT) assay will identify patients at risk for acute MI and long-term mortality after major noncardiac surgery. METHODS This was a prospective cohort study within the VINO trial (n = 608). Patients had been diagnosed with or had multiple risk factors for coronary artery disease and underwent major noncardiac surgery. Cardiac troponin I (contemporary assay) and troponin T (high-sensitivity assay) and 12-lead electrocardiograms were obtained before and immediately after surgery and on postoperative days 1, 2, and 3. RESULTS At baseline before surgery, 599 patients (98.5%) had a detectable hs-cTnT concentration, and 247 (41%) were >14 ng/L (99th percentile). After surgery, 497 patients (82%) had a rise in hs-cTnT (median change in hs-cTnT +2.7 ng/L [interquartile range 0.7-6.8]). During the first 3 postoperative days, there were 9 patients (2.5%) with a preoperative hs-cTnT <14 ng/L with acute MI, compared with 21 patients (8.6%) with a preoperative hs-cTnT >14 ng/L (odds ratio 3.67, 95% CI 1.65-8.15). During long-term follow-up, 80 deaths occurred. The 3-year mortality rate was 11% in patients with a preoperative hs-cTnT concentration <14 ng/L compared with 25% in patients with a preoperative hs-cTnT >14 ng/L (adjusted hazard ratio 2.17, 95% CI 1.19-3.96). CONCLUSIONS In this cohort of high-risk patients, preoperative hs-cTnT concentrations were significantly associated with postoperative MI and long-term mortality after noncardiac surgery.

High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: A prospective cohort study☆

OBJECTIVES To determine the proportion of noncardiac surgery patients exceeding the published 99th percentile or change criteria with the high sensitivity Troponin T (hs-TnT) assay. DESIGN AND METHODS We measured hs-TnT preoperatively and postoperatively on days 1, 2 and 3 in 325 adults. RESULTS Postoperatively 45% (95% CI: 39-50%) of patients had hs-TnT≥14ng/L and 22% (95% CI:17-26%) had an elevation (≥14ng/L) and change (>85%) in hs-TnT. CONCLUSION Further research is needed to inform the optimal hs-TnT threshold and change in this setting.

Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial

BACKGROUND N-methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD. METHODS In this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment. RESULTS Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%-45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, -4.8 points, 95% confidence interval [CI], -1.8 to -7.8 points, p = .002; at 24 hours, -5.5 points, 95% CI, -2.5 to -8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45-35.79; OR for remission, 3.0, 95% CI, .31-28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity. CONCLUSIONS This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.

A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics.

Metoprolol, a commonly prescribed β‐blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta‐analysis of pharmacokinetic studies that administered a single oral dose of immediate‐release metoprolol were performed. Pooled analysis (n = 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration–time curve, elimination half‐life, and apparent oral clearance that were 2.3‐, 4.9‐, 2.3‐, and 5.9‐fold between extensive and poor metabolizers, respectively, and 5.3‐, 13‐, 2.6‐, and 15‐fold between ultrarapid and poor metabolizers (all P < 0.001), respectively. Enantiomer‐specific analysis revealed genotype‐dependent enantio‐selective metabolism, with nearly 40% greater R‐ than S‐metoprolol metabolism in ultrarapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer‐specific metabolism of metoprolol.

Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Homocysteine Concentrations after Nitrous Oxide Anesthesia

Background:Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (677C>T, 1298A>C) cause elevated plasma homocysteine concentrations and have been linked to fatal outcomes after nitrous oxide anesthesia. This study tested the hypothesis that patients with common MTHFR 677C>T or 1298A>C mutations develop higher plasma homocysteine concentrations after nitrous oxide anesthesia than wild-type patients. Methods:In this prospective, observational cohort study with blinded, mendelian randomization, the authors included 140 healthy patients undergoing elective surgery. All patients received 66% nitrous oxide for at least 2 h. The main outcome variable, plasma total homocysteine, and folate, vitamin B12, and holotranscobalamin II were measured before, during, and after surgery. After completion of the study, all patients were tested for their MTHFR 677C>T or 1298A>C genotype. Results:Patients with a homozygous MTHFR 677C>T or 1298A>C mutation (n = 25) developed higher plasma homocysteine concentrations (median [interquartile range], 14.9 [10.0–26.4] &mgr;m) than wild-type or heterozygous patients (9.3 [7.5–15.5] &mgr;m; n = 115). The change in homocysteine after nitrous oxide anesthesia was tripled in homozygous patients compared with wild-type (5.6 &mgr;m [+60%] vs. 1.8 &mgr;m [+22%]). Only homozygous patients reached average homocysteine levels considered abnormal (> 15 &mgr;m). Plasma 5-methyl-tetrahydrofolate concentrations increased uniformly by 20% after nitrous oxide anesthesia, indicating the inactivation of methionine synthase and subsequent folate trapping. Holotranscobalamin II concentrations remained unchanged, indicating no effect of nitrous oxide on vitamin B12 plasma concentrations. Conclusions:This study shows that patients with a homozygous MTHFR 677C>T or 1298A>C mutation are at a higher risk of developing abnormal plasma homocysteine concentrations after nitrous oxide anesthesia.

Xenon Acts by Inhibition of Non–N -methyl-d-aspartate Receptor–mediated Glutamatergic Neurotransmission in Caenorhabditis elegans

Background:Electrophysiologic experiments in rodents have found that nitrous oxide and xenon inhibit N-methyl-d-aspartate (NMDA)–type glutamate receptors. These findings led to the hypothesis that xenon and nitrous oxide along with ketamine form a class of anesthetics with the identical mechanism, NMDA receptor antagonism. Here, the authors ask in Caenorhabditis elegans whether xenon, like nitrous oxide, acts by a NMDA receptor–mediated mechanism. Methods:Xenon:oxygen mixtures were delivered into sealed chambers until the desired concentration was achieved. The effects of xenon on various behaviors were measured on wild-type and mutant C. elegans strains. Results:With an EC50 of 15–20 vol% depending on behavioral endpoint, xenon altered C. elegans locomotion in a manner indistinguishable from that of mutants in glutamatergic transmission. Xenon reduced the frequency and duration of backward locomotion without altering its speed or other behaviors tested. Mutation of glr-1, encoding a non-NMDA glutamate receptor subunit, abolished the behavioral effects of xenon; however, mutation of nmr-1, which encodes the pore-forming subunit of an NMDA glutamate receptor previously shown to be required for nitrous oxide action, did not significantly alter xenon response. Transformation of the glr-1 mutant with the wild-type glr-1 gene partially restored xenon sensitivity, confirming that glr-1 was necessary for the full action of xenon. Conclusions:Xenon acts in C. elegans to alter locomotion through a mechanism requiring the non-NMDA glutamate receptor encoded by glr-1. Unlike for the action of nitrous oxide in C. elegans, the NMDA receptor encoded by nmr-1 is not essential for sensitivity to xenon.

Postoperative QT Interval Prolongation in Patients Undergoing Noncardiac Surgery under General Anesthesia

Background: Abnormal cardiac repolarization, indicated by a prolongation of the QT interval, increases the risk for torsades de pointes, a potentially life-threatening arrhythmia. Many perioperatively administered drugs and conditions prolong the QT interval. Despite several reports of perioperative torsades de pointes, systematic evidence regarding perioperative QT interval prolongation is limited. Methods: Serial postoperative 12-lead electrocardiograms were obtained from 469 adult patients undergoing major noncardiac surgery under general anesthesia. Heart rate corrected QT-interval duration (Fridericia formula) was the primary outcome. All perioperatively administered drugs were recorded. Emphasis was placed on absolute QTc prolongation greater than 500 ms and relative increases of 30 and 60 ms. Results: At the end of surgery, 80% of the patients (345 of 429) experienced a significant QTc interval prolongation (&Dgr;QTc 23 ± 26 ms (mean and SD), 95% CI 20–25 ms, P less than 0.001). Approximately 51% (219 of 429) had a QTc greater than 440 ms, and 4% (16 of 429) a QTc greater than 500 ms. In 39% (166 of 429), the &Dgr;QTc was greater than 30 ms, in 8% (34 of 429) >60 ms, and in greater than 0.5% (2 of 429) >100 ms. No changes in &Dgr;QTc occurred at subsequent time points. One patient developed torsades de pointes with a &Dgr;QTc: 29 ms (0.4% incidence rate). Several drugs had a large effect on &Dgr;QTc: isoflurane, methadone, ketorolac, cefoxitin, zosyn, unasyn, epinephrine, ephedrine, and calcium. Postoperative body temperature had a weak negative correlation with &Dgr;QTc (r = −0.15, P = 0.02); serum magnesium, potassium, and calcium concentrations were not correlated. Conclusion: Postoperative QT-interval prolongation is common. Several perioperatively administered drugs are associated with a substantial QT-interval prolongation. The exact cause and its clinical relevance are, however, unclear. Nevertheless, an association between postoperative QT prolongation and risk for torsades de pointes is likely.

Volatile Anesthetics Bind Rat Synaptic Snare Proteins

Background: Volatile general anesthetics (VAs) have a number of synaptic actions, one of which is to inhibit excitatory neurotransmitter release; however, no presynaptic VA binding proteins have been identified. Genetic data in Caenorhabditis elegans have led to the hypothesis that a protein that interacts with the presynaptic protein syntaxin 1A is a VA target. Motivated by this hypothesis, the authors measured the ability of syntaxin 1A and proteins that interact with syntaxin to bind to halothane and isoflurane. Methods: Recombinant rat syntaxin 1A, SNAP-25B, VAMP2, and the ternary SNARE complex that they form were tested. Binding of VAs to these proteins was detected by 19F-nuclear magnetic resonance relaxation measurements. Structural alterations in the proteins were examined by circular dichroism and ability to form complexes. Results: Volatile anesthetics did not bind to VAMP2. At concentrations in the clinical range, VAs did bind to SNAP-25B; however, binding was detected only in preparations containing SNAP-25B homomultimers. VAs also bound at clinical concentrations to both syntaxin and the SNARE complex. Addition of an N-terminal His6 tag to syntaxin abolished its ability to bind VAs despite normal secondary structure and ability to form SNARE complexes; thrombin cleavage of the tag restored VA binding. Thus, the VA binding site(s) has structural requirements and is not simply any α-helical bundle. VAs at supraclinical concentrations produced an increase in helicity of the SNARE complex; otherwise, VA binding produced no gross alteration in the stability or secondary structure of the SNARE complex. Conclusion: SNARE proteins are potential synaptic targets of volatile anesthetics.