Neuraxial block and postoperative epidural analgesia: effects on outcomes in the POISE-2 trial†.

BACKGROUND: We assessed associations between intraoperative neuraxial block and postoperative epidural analgesia, and a composite primary outcome of death or non-fatal myocardial infarction, at 30 days post-randomization in POISE-2 Trial subjects. METHODS: 10 010 high-risk noncardiac surgical patients were randomized aspirin or placebo and clonidine or placebo. Neuraxial block was defined as intraoperative spinal anaesthesia, or thoracic or lumbar epidural anaesthesia. Postoperative epidural analgesia was defined as postoperative epidural local anaesthetic and/or opioid administration. We used logistic regression with weighting using estimated propensity scores. RESULTS: Neuraxial block was not associated with the primary outcome [7.5% vs 6.5%; odds ratio (OR), 0.89; 95% CI (confidence interval), 0.73-1.08; P=0.24], death (1.0% vs 1.4%; OR, 0.84; 95% CI, 0.53-1.35; P=0.48), myocardial infarction (6.9% vs 5.5%; OR, 0.91; 95% CI, 0.74-1.12; P=0.36) or stroke (0.3% vs 0.4%; OR, 1.05; 95% CI, 0.44-2.49; P=0.91). Neuraxial block was associated with less clinically important hypotension (39% vs 46%; OR, 0.90; 95% CI, 0.81-1.00; P=0.04). Postoperative epidural analgesia was not associated with the primary outcome (11.8% vs 6.2%; OR, 1.48; 95% CI, 0.89-2.48; P=0.13), death (1.3% vs 0.8%; OR, 0.84; 95% CI, 0.35-1.99; P=0.68], myocardial infarction (11.0% vs 5.7%; OR, 1.53; 95% CI, 0.90-2.61; P=0.11], stroke (0.4% vs 0.4%; OR, 0.65; 95% CI, 0.18-2.32; P=0.50] or clinically important hypotension (63% vs 36%; OR, 1.40; 95% CI, 0.95-2.09; P=0.09). CONCLUSIONS: Neuraxial block and postoperative epidural analgesia were not associated with adverse cardiovascular outcomes among POISE-2 subjects.

Perioperative administration of fibrinogen does not increase adverse cardiac and thromboembolic events after cardiac surgery.

BACKGROUND: Although infusion of fibrinogen concentrate is increasingly used in bleeding patients after cardiac surgery, safety data are scarce. We aimed to evaluate the effect of perioperative administration of fibrinogen concentrate on postoperative morbidity and mortality in patients undergoing cardiac surgery. METHODS: During a 2 yr study period, 991 patients underwent cardiac surgery at a single university centre and were eligible for propensity score (PS) matching. We matched 190 patients with perioperative infusion of fibrinogen concentrate (median dose 2 g) with 190 controls without fibrinogen administration. After PS matching, crude outcome was analysed. Further, a multivariate logistic regression including additional risk factors for adverse outcome was performed. The primary endpoint was a composite of mortality and the occurrence of major cardiac and thromboembolic events within 1 yr. Secondary outcomes included mortality after 30 days and 1 yr and the composite of mortality and adverse events after 30 days. RESULTS: The administration of fibrinogen concentrate was not associated with an increased risk for mortality and thromboembolic or cardiac events within 1 yr after cardiac surgery [unadjusted hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.55-1.49; P=0.697]. When using multivariate logistic regression model, the HR for adverse outcome in patients with administration of fibrinogen concentrate was 0.57 (95% CI 0.25-1.17; P=0.101). Similarly, the administration of fibrinogen concentrate did not adversely affect the secondary outcomes when applying unadjusted and multivariate regression analyses. CONCLUSIONS: Our study strongly suggests that the administration of fibrinogen concentrates at low dose is not associated with thromboembolic complications or adverse outcomes after cardiac surgery.

Intra-operative assessment of pulmonary artery pressure by transoesophageal echocardiography.

The clinical value of the estimation of systolic pulmonary artery pressure, based on Doppler assessment of peak tricuspid regurgitant velocity using transoesophageal echocardiography, is unclear. We studied 109 patients to evaluate the feasibility of obtaining adequate Doppler recordings, and compared Doppler estimates with values measured using a pulmonary artery catheter in a subset of 33 patients. Tricuspid regurgitation was evaluated at the mid-oesophageal level at 0-120° using Doppler echocardiography. A Doppler signal was defined as adequate if there was a ≤ 20° alignment and a full envelope. Doppler estimates of systolic pulmonary artery pressure within 10 mmHg and 15% of the value recorded with the pulmonary artery catheter were considered to be in sufficient agreement. Adequate Doppler signals were obtained in 64/109 (59%) patients before and 54/103 (52%) after surgery. Doppler estimates by transoesophageal echocardiography were within 10 mmHg and 15% of values recorded with the pulmonary artery catheter in 28/33 (75%) patients and 22/31 (55%) patients, respectively. In 7 (21%) patients, the echocardiographic Doppler measurement exceeded the measured systolic pulmonary artery pressure by more than 30%. Our study indicates that estimation of the systolic pulmonary artery pressure using transoesophageal Doppler echocardiography is not a reliable and clinically useful method in anaesthetised patients undergoing mechanical ventilation.

The influence of clinical risk factors on pre-operative B-type natriuretic peptide risk stratification of vascular surgical patients.

The role of the revised cardiac risk index in risk stratification has recently been challenged by studies reporting on the superior predictive ability of pre-operative B-type natriuretic peptides. We found that in 850 vascular surgical patients initially risk stratified using B-type natriuretic peptides, reclassification with the number of revised cardiac risk index risk factors worsened risk stratification (p < 0.05 for > 0, > 2, > 3 and > 4 risk factors, and p = 0.23 for > 1 risk factor). When evaluated with pre-operative B-type natriuretic peptides, none of the revised cardiac risk index risk factors were independent predictors of major adverse cardiac events in vascular patients. The only independent predictor was B-type natriuretic peptide stratification (OR 5.1, 95% CI 1.8-15 for the intermediate class, and OR 25, 95% CI 8.7-70 for the high-risk class). The clinical risk factors in the revised cardiac risk index cannot improve a risk stratification model based on B-type natriuretic peptides.

The influence of pre-admission hypoglycaemic therapy on cardiac morbidity and mortality in type 2 diabetic patients undergoing major non-cardiac surgery: a prospective observational study.

It remains unclear whether type 2 diabetics treated with either insulin or oral hypoglycaemic agents have the same incidence of cardiac morbidity and mortality after major non-cardiac surgery. We prospectively studied 360 type 2 diabetic patients undergoing major non-cardiac surgery of which 105 were treated with insulin only, 171 were treated with oral hypoglycaemics only and 84 were treated with a combination of insulin and oral hypoglycaemics. All-cause mortality after 30 days and after 12 months was highest in the insulin (10% and 26%) and lowest in the oral hypoglycaemics group (2% and 13%; p = 0.02 and 0.007, respectively). Insulin treatment was independently associated with increased mortality after 30 days (hazard ratio 3.93; 95% CI 1.22-12.64; p = 0.022) and 12 months (hazard ratio 2.03; 95% CI 1.16-3.58; p = 0.014) after multivariate adjustment for age, sex and the revised cardiac risk index (insulin treatment excluded). The increased mortality in insulin-treated diabetic patients may be due to a more progressive disease state in these patients rather than the treatment modality itself.

Remifentanil does not impair left ventricular systolic and diastolic function in young healthy patients.

BACKGROUND: Experimental studies and investigations in patients with cardiac diseases suggest that opioids at clinical concentrations have no important direct effect on myocardial relaxation and contractility. In vivo data on the effect of remifentanil on myocardial function in humans are scarce. This study aimed to investigate the effects of remifentanil on left ventricular (LV) function in young healthy humans by transthoracic echocardiography (TTE). We hypothesized that remifentanil does not impair systolic, diastolic LV function, or both. METHODS: Twelve individuals (aged 18-48 yr) without any history or signs of cardiovascular disease and undergoing minor surgical procedures under general anaesthesia were studied. Echocardiographic examinations were performed in the spontaneously breathing subjects before (baseline) and during administration of remifentanil at a target effect-site concentration of 2 ng ml(-1) by target-controlled infusion. Analysis of systolic function focused on fractional area change (FAC). Analysis of diastolic function focused on peak early diastolic velocity of the mitral annulus (e') and on transmitral peak flow velocity (E). RESULTS: Remifentanil infusion at a target concentration of 2 ng ml(-1) did not affect heart rate or arterial pressure. There was no evidence of systolic or diastolic dysfunction during remifentanil infusion, as the echocardiographic measure of systolic function (FAC) was similar to baseline, and measures of diastolic function remained unchanged (e') or improved slightly (E). CONCLUSION: Continuous infusion of remifentanil in a clinically relevant concentration did not affect systolic and diastolic LV function in young healthy subjects during spontaneous breathing as indicated by TTE.

[Perioperative management of long-term medication]. / Langzeitmedikation und perioperatives Management.

Anesthesiologists and surgeons are increasingly faced with patients who are under long-term medication. Some of these drugs can interact with anaesthetics or anaesthesia and/or surgical interventions. As a result, patients may experience complications such as bleeding, ischemia, infection or severe circulatory reactions. On the other hand, perioperative discontinuation of medication is often more dangerous. The proportion of outpatient operations has increased dramatically in recent years and will probably continue to increase. Since the implementation of DRGs (pending in Switzerland, introduced in Germany for some time), the patient enters the hospital the day before operation. This means that the referring physician as well as anesthesiologists and surgeons at an early stage must deal with issues of perioperative pharmacotherapy. This review article is about the management of the major drug classes during the perioperative period. In addition to cardiac and centrally acting drugs and drugs that act on hemostasis and the endocrine system, special cases such as immunosuppressants and herbal remedies are mentioned.

Randomized clinical trial of moxonidine in patients undergoing major vascular surgery.

BACKGROUND: Myocardial ischaemia is the leading cause of perioperative morbidity and mortality after surgery in patients with coronary artery disease. The aim of this study was to evaluate the effects of moxonidine, a centrally acting sympatholytic agent, on perioperative myocardial ischaemia and 1-year mortality in patients undergoing major vascular surgery. METHODS: In this double-blind, placebo-controlled two-centre trial, 141 patients were randomly assigned to receive moxonidine or placebo on the morning before surgery and on the following 4 days. Levels of cardiac troponin I (cTnI) were analysed before surgery and on days 1, 2, 3 and 7 thereafter. Holter electrocardiograms were recorded for 48 h starting before the administration of the study drug. Patients were followed daily during admission and by telephone interview 12 months after surgery. RESULTS: The incidence of raised perioperative cTnI levels or alteration in the ST segment in the Holter electrocardiogram or both was 40 per cent in the moxonidine group and 37 per cent in the placebo group (P = 0.694). All-cause mortality rates within 12 months were 10 per cent in the moxonidine group and 11 per cent in the placebo group (P = 0.870). CONCLUSION: Small oral doses of moxonidine did not reduce the incidence of perioperative myocardial ischaemia and had no effect on mortality in patients undergoing vascular surgery. REGISTRATION NUMBER: NCT00244504 (http://www.clinicaltrials.gov).

No holds barred sport fighting: a 10 year review of mixed martial arts competition.

OBJECTIVE: To identify the most salient medical issues that may be associated with mixed martial arts competition by determining the types and proportions of match stoppages. METHODS: Publicly available video footage of 1284 men competing in 642 consecutive televised matches from November 1993 to November 2003 was reviewed to determine the reasons for which matches were stopped. Matches were sanctioned by either a United States or Japan based mixed martial arts organisation. RESULTS: Of the 642 matches, 182 (28.3+/-3.4%) were stopped because of head impact, 106 (16.5+/-2.9%) because of musculoskeletal stress, 91 (14.1+/-2.7%) because of neck choke, 83 (12.9+/-2.6%) because of miscellaneous trauma, 173 (27.0+/-3.4%) because of expiration of match time, and seven (1.0+/-0.8%) because of disqualification, where the values in parentheses are percentages+/-95% confidence interval. CONCLUSIONS: Blunt force to the head resulted in the highest proportion of match stoppages. Further research is warranted to delineate the morbidity associated with participation in mixed martial arts.

High density binding of proteins and peptides to poly(D,L-lactide) grafted with polyacrylic acid.

The use of graft polymers for the functionalisation of biomaterial surfaces is already widespread. We investigated the adsorptive and covalent binding of a variety of proteins and peptides to poly(D,L-lactide) grafted with polyacrylic acid. Covalent attachment was achieved through coupling of amino groups of the protein/peptide to the carboxyl groups of the graft polymer by using a water-soluble carbodiimide and N-hydroxysuccinimide. Binding densities were determined by automated amino acid analysis after acid hydrolysis of both the poly(D,L-lactide) and the adsorbed and covalently bound proteins. Experiments in the absence and presence of the coupling reagents allow to discriminate between adsorptive and covalent binding. Although the adsorptivc binding is quite substantial in absolute terms, the amount of adsorbed protein is relatively low as compared to the total amount of bound protein. Total binding densities of 20-30 microg/cm2 can easily be achieved. Depending on the concentration and on the properties of the proteins and peptides, between 5% and 80% of the totally bound protein may be physically adsorbed. Densities expressed in molecules/10 nm2 vary from 0.5 molecule fibronectin to 2,000 laminin-peptide molecules: their binding densities clearly correlate with their respective molecular masses. Obviously, the binding densities are governed by their individual three-dimensional space requirements rather than the density of the available carboxyl groups. From the number of carboxyl groups/10 nm2 (18,000-30,000 COOH/10 nm2) the average length of the acrylic acid graft polymer molecules was estimated. Based on the assumption that about 10 copolymer chains can be accommodated on 10 nm2, the average length of the polymer chains, which corresponds to the thickness of the graft phase, is estimated to be 0.5-1 microm. The organisation of the proteins and peptides within the polyacrylic acid phase was further investigated by experiments in which a protein (BSA) and a peptide (Val-Lys) were allowed to react in either a singular, a consecutive or a simultaneous way. Together with XPS and IR-ATR surface characterisation experiments a three-dimensional picture of the arrangement of the immobilised proteins and peptides within the graft polymer phase emerges.

New insights into the thermostability of bacterial ferredoxins: high-resolution crystal structure of the seven-iron ferredoxin from Thermus thermophilus.

The crystal structure of the seven-iron ferredoxin from Thermus thermophilus (FdTt) has been determined at 1.64 A resolution, allowing us to unveil the common mechanisms of thermostabilization within "bacterial-type" ferredoxins. FdTt and other homologous thermophilic seven-iron ferredoxins are smaller than their mesophilic counterparts. Thermostabilizing features are optimized in a minimal structural and functional unit, with an extensive cross-linking of secondary structure elements mediated by improved polar and hydrophobic interactions. Most of the potentially stabilizing features are focused on the vicinity of the functional [3Fe-4S] cluster. The structural [4Fe-4S] cluster is shielded in thermophilic FdTt by an increased number of polar interactions involving the two N-terminal residues. Comparisons with the hyperthermostable ferredoxin from Thermotoga maritima reveal that (1) a reduction in the number of non-glycine residues in strained conformations, (2) improved polar interactions within the common iron-sulfur cluster binding (betaalphabeta)2 motif, and (3) an optimized charge distribution at the protein surface, constitute a common strategy for increasing the thermal stability of these ferredoxins.

Multiple deletions of mtDNA remove the light strand origin of replication.

Idiopathic inflammatory myopathies are progressive, debilitating muscle diseases. The pathogenesis of these disorders is multifactorial and appears to include mutations of the mitochondrial genome, which are usually indicated by morphological changes of mitochondria. The vast majority of all mitochondrial DNA deletions found are located between the origins of replication in the "major region" between nt5760-nt190. Using long distance PCR and sequencing techniques, we detected deletions which were unusually large (ca. 10500-12800 bp) and show uncommon 5'-breakpoints between nt800 and nt3326. Unlike most other deletions, their breakpoints are far upstream of the "major region." The atypical location of these deletions suggests a different pathomechanism. The impact of the mitochondrial DNA deletions in the pathogenetic cascade remains uncertain.

Novel cluster of tRNALeu(UUR) mutations in a sporadic case of infantile myopathy restricted to muscle tissue.

In a previous study we reported on a case with severe infantile, mitochondrial myopathy caused by somatic mutation [12]. In the present study we give evidence for asymmetric tissue distribution of the mutations. Mitochondrial DNA (mtDNA) analysis showed a cluster of nearly homoplasmic point mutations in the tRNA gene for leucine (UUR) (A3259 G, A3261 G, A3266 G, A3268 G). The mutation is abundant in muscle, but is not found in blood cells. This cluster of mutations is sporadic, because the search for mutant molecules in the blood of the healthy mother and maternal grandmother did not show these alterations.

Structure and mechanism of the aberrant ba(3)-cytochrome c oxidase from thermus thermophilus.

Cytochrome c oxidase is a respiratory enzyme catalysing the energy-conserving reduction of molecular oxygen to water. The crystal structure of the ba(3)-cytochrome c oxidase from Thermus thermophilus has been determined to 2.4 A resolution using multiple anomalous dispersion (MAD) phasing and led to the discovery of a novel subunit IIa. A structure-based sequence alignment of this phylogenetically very distant oxidase with the other structurally known cytochrome oxidases leads to the identification of sequence motifs and residues that seem to be indispensable for the function of the haem copper oxidases, e.g. a new electron transfer pathway leading directly from Cu(A) to Cu(B). Specific features of the ba(3)-oxidase include an extended oxygen input channel, which leads directly to the active site, the presence of only one oxygen atom (O(2-), OH(-) or H(2)O) as bridging ligand at the active site and the mainly hydrophobic character of the interactions that stabilize the electron transfer complex between this oxidase and its substrate cytochrome c. New aspects of the proton pumping mechanism could be identified.

Primary structure of a novel subunit in ba3-cytochrome oxidase from Thermus thermophilus.

The bax-type cytochrome c oxidase from Thermus thermophilus is known as a two subunit enzyme. Deduced from the crystal structure of this enzyme, we discovered the presence of an additional transmembrane helix "subunit IIa" spanning the membrane. The hydrophobic N-terminally blocked protein was isolated in high yield using high-performance liquid chromatography. Its complete amino acid sequence was determined by a combination of automated Edman degradation of both the deformylated and the cyanogen bromide cleaved protein and automated C-terminal sequencing of the native protein. The molecular mass of 3,794 Da as determined by MALDI-MS and by ESI requires the N-terminal methionine to be formylated and is in good agreement with the value calculated from the formylmethionine containing sequence (3,766.5 Da + 28 Da = 3,794.5 Da). This subunit consits of 34 residues forming one helix across the membrane (Lys5-Ala34), which corresponds in space to the first transmembrane helix of subunit II of the cytochrome c oxidases from Paracoccus denitrificans and bovine heart, however, with opposite polarity. It is 35% identical to subunit IV of the ba3-cytochrome oxidase from Natronobacterium pharaonis. The open reading frame encoding this new subunit IIa (cbaD) is located upstream of cbaB in the same operon as the genes for subunit I (cbaA) and subunit II (cbaB).

The heme-copper oxidases of Thermus thermophilus catalyze the reduction of nitric oxide: evolutionary implications.

We show that the heme-copper terminal oxidases of Thermus thermophilus (called ba(3) and caa(3)) are able to catalyze the reduction of nitric oxide (NO) to nitrous oxide (N(2)O) under reducing anaerobic conditions. The rate of NO consumption and N(2)O production were found to be linearly dependent on enzyme concentration, and activity was abolished by enzyme denaturation. Thus, contrary to the eukaryotic enzyme, both T. thermophilus oxidases display a NO reductase activity (3.0 +/- 0.7 mol NO/mol ba(3) x min and 32 +/- 8 mol NO/mol caa(3) x min at [NO] approximately 50 microM and 20 degrees C) that, though considerably lower than that of bona fide NO reductases (300-4,500 mol NO/mol enzyme x min), is definitely significant. We also show that for ba(3) oxidase, NO reduction is associated to oxidation of cytochrome b at a rate compatible with turnover, suggesting a mechanism consistent with the stoichiometry of the overall reaction. We propose that the NO reductase activity of T. thermophilus oxidases may depend on a peculiar Cu(B)(+) coordination, which may be revealed by the forthcoming three-dimensional structure. These findings support the hypothesis of a common phylogeny of aerobic respiration and bacterial denitrification, which was proposed on the basis of structural similarities between the Pseudomonas stutzeri NO reductase and the cbb(3) terminal oxidases. Our findings represent functional evidence in support of this hypothesis.

The active site structure of ba3 oxidase from Thermus thermophilus studied by resonance raman spectroscopy.

The ba3 cytochrome oxidase from Thermus thermophilus was studied by resonance Raman spectroscopy. The component spectra of both heme groups were determined by using different excitation wavelengths. In the ferric state the heme a3 group reveals resonance Raman marker bands characteristic for two high spin species with the heme iron in an in-plane and an out-of-plane configuration that reflects a coordination equilibrium. This equilibrium obviously results from protonation of one of the axial ligands that is ascribed to a hydroxide. Coordination by its protonated form, a water molecule, may be too weak to keep the heme iron in the porphyrin plane. The corresponding Fe-OH2 stretching mode was attributed to a weak H/D-sensitive band at 464 cm(-1). The coordination equilibrium not only depends on the pH but is also affected by the buffer, the salt concentration, and the binding of the natural redox partner cytochrome c552. These changes of the coordination equilibrium are attributed to the perturbation of the hydrogen bonding network at the catalytic center that is connected to the protein surface via a relay of hydrogen bonds. Environmental changes at the catalytic site are sensitively reflected by the formyl stretching of heme a3. The unique structural properties of the ba3 oxidase may be related to the unusual proton pump efficiency and heme a3 redox potential.

Time-resolved generation of a membrane potential by ba3 cytochrome c oxidase from Thermus thermophilus. Evidence for reduction-induced opening of the binuclear center.

ba3-type cytochrome c oxidase purified from the thermophilic bacterium Thermus thermophilus has been reconstituted in phospholipid vesicles and laser flash-induced generation of a membrane potential by the enzyme has been studied in a microsecond/ms time scale with Ru(II)-tris-bipyridyl complex (RuBpy) as a photoreductant. Flash-induced single electron reduction of the aerobically oxidized ba3 by RuBpy results in two phases of membrane potential generation by the enzyme with tau values of about 20 and 300 microseconds at pH 8 and 23 degrees C. Spectrophotometric experiments show that oxidized ba3 reacts very poorly with hydrogen peroxide or any of the other exogenous heme iron ligands studied like cyanide, sulfide and azide. At the same time, photoreduction of the enzyme by RuBpy triggers the electrogenic reaction with H2O2 with a second order rate constant of approximately 2 x 10(3) M-1 s-1. The data indicate that single electron reduction of ba3 oxidase opens the binuclear center of the enzyme for exogenous ligands. The fractional contribution of the protonic electrogenic phases induced by peroxide in cytochrome ba3 is much less than in bovine oxidase, pointing to a possibility of a different electrogenic mechanism of the ba3 oxidase as compared to the oxidases of the aa3-type.