Ease and comfort of pre-oxygenation with high-flow nasal oxygen cannulae vs. facemask: a randomised controlled trial.

The Difficult Airway Society recommends that all patients should be pre-oxygenated before the induction of general anaesthesia, but this may not always be easy or comfortable and anaesthesia may often be induced without full pre-oxygenation. We tested the hypothesis that high-flow nasal oxygen cannulae would be easier and more comfortable than facemasks for pre-oxygenation. We randomly allocated 199 patients undergoing elective surgery aged ≥ 10 years to pre-oxygenation using either high-flow nasal oxygen or facemask. Ease and comfort were assessed by anaesthetists and patients on 10-cm visual analogue scale and six-point smiley face scale, respectively. Secondary endpoints included end-tidal oxygen fraction after securing a definitive airway and time to secure an airway. A mean difference (95%CI) between groups in ratings of -0.76 (-1.25 to -0.27) cm for ease of use (p = 0.003) and -0.45 (-0.75 to -0.13) points for comfort (p = 0.006), both favoured high-flow nasal oxygen. A mean difference (95%CI) between groups in end-tidal oxygen fraction of 3.89% (2.41-5.37%) after securing a definitive airway also favoured high-flow nasal oxygen (p < 0.001). There was no significant difference between groups in the number of patients with hypoxaemia (Sp O2 < 90%) or severe hypoxaemia (Sp O2 < 85%) lasting ≥ 1 min or ≥ 2 min; in the proportion of patients with an end-tidal oxygen fraction < 87% in the first 5 min after tracheal intubation (52.2% vs. 58.9% in facemask and high-flow nasal oxygen groups, respectively; p = 0.31); or in time taken to secure an airway (11.6 vs. 12.2 min in facemask and high-flow nasal oxygen groups, respectively; p = 0.65). In conclusion, we found pre-oxygenation with high-flow nasal oxygen to be easier for anaesthetists and more comfortable for patients than pre-oxygenation with a facemask, with no clinically relevant differences in end-tidal oxygen fraction after securing a definitive airway or time to secure an airway. The differences in ease and comfort were modest.

Measurement of the sound intensity during suction of middle-ear fluid following myringotomy.

OBJECTIVE: To determine noise intensity during middle-ear aspiration in order to evaluate whether levels can be potentially harmful. METHODS: In this prospective, observational study, middle-ear effusion was aspirated following myringotomy using a suction instrument with a probe tube microphone. Sound pressure levels and duration were measured, and frequency domain analysis was performed. RESULTS: Forty-four ears were analysed, consisting of 20 with mucoid effusion, 11 with serous effusion and 13 with no effusion. Maximum peak sound intensity ranged from 84 to 157 dB. Half of the ears (50 per cent) were exposed to greater than 140 dB; of these, 82 per cent were exposed for longer than 0.2 ms (range, 0.05-14 ms). There was no significant difference in sound pressure level between ears with mucoid and serous effusion; however, ears with mucoid effusion required longer suction times (p < 0.0030). In addition, peak intensity was greater for ears with mucoid effusion versus those with serous or no effusion (p < 0.0001). CONCLUSION: Middle-ear aspiration during myringotomy caused noise levels within a potentially harmful range.

The population genetics and dynamics of the thalassemias.

The inherited disorders of hemoglobin, including the thalassemias, are by far the commonest monogenic diseases. Although several factors are responsible for their very high frequency, the major mechanism seems to be natural selection mediated by heterozygote protection against severe forms of malaria. Recent work has highlighted the complexity of the interplay among the different hemoglobin variants themselves and among different levels of malaria resistance, and is helping to explain the extraordinary heterogeneity in the distribution of the hemoglobin disorders even within short geographical distances. Some progress has also been made toward understanding the cellular and immune mechanisms that may underlie heterozygote protection against malaria in these conditions. In addition to providing valuable information about human evolutionary biology, work in this field has an increasingly important influence on the development of programs for the better management of the hemoglobin disorders, particularly in the poorer countries of the tropical world.

NGF receptor TrkAd5: therapeutic agent and drug design target.

Biochemical studies have shown that domain 5 of the TrkA (tropomyosin receptor kinase A) receptor is involved in the binding of NGF (nerve growth factor). Crystallographic studies have confirmed this, demonstrating that one homodimer of NGF binds to two TrkAd5 molecules. TrkAd5 has been made recombinantly in Escherichia coli, purified and shown to bind NGF with picomolar affinity. We have used the co-ordinates of the crystal structure of the NGF-TrkAd5 complex to screen approximately two million compounds in silico for the identification of small molecule agonists/antagonists. Selected hits were shown to be active in an in vitro ligand-binding assay; structure-activity relationships are now being investigated. In addition, TrkAd5 has been shown to be efficacious in preclinical models of inflammatory pain and asthma by the sequestration of excess levels of endogenous NGF, and therefore represents a novel therapeutic agent.

Inhibition of intestinal transit by resuscitation-induced gut edema is reversed by L-NIL.

BACKGROUND: Post-resuscitation gut edema and associated gut dysfunction is a common and significant clinical problem that occurs after traumatic injury and shock. We have shown previously that gut edema without ischemia/reperfusion injury delays intestinal transit [1]. We hypothesized that gut edema increases expression of inducible nitric oxide synthase (iNOS) protein, and that selective iNOS inhibition using L-NIL reverses the delayed intestinal transit associated with gut edema. MATERIALS AND METHODS: One hour prior to laparotomy, rats were pretreated with 10 mg/kg body weight of intraperitoneal L-NIL or saline vehicle and underwent 80 ml/kg body weight of 0.9% saline + superior mesenteric venous pressure elevation (Edema) or sham surgery (Sham). A duodenal catheter was placed to allow injection of a fluorescent dye for the measurement of intestinal transit. At 6 h, the small bowel was divided and the mean geometric center (MGC) of fluorescent dye was measured to determine transit. Ileum was harvested for histological assessment of mucosal injury, evaluation of iNOS protein expression by Western blotting, and MPO activity. Tissue water was determined using the wet-to-dry weight ratio to assess gut edema. Data are expressed as mean +/- SEM, n = 3-6 and * = P <0.05 using ANOVA. RESULTS: Gut edema, expressed as increased wet-to-dry ratio, was associated with decreased intestinal transit and elevated iNOS protein expression. Pretreatment with l-NIL improved intestinal transit and decreased expression of iNOS protein without decreasing intestinal tissue water compared to edema animals. There was no difference in mucosal injury or MPO activity among groups. CONCLUSION: Gut edema delays intestinal transit via an iNOS-mediated mechanism.

Applications of free-electron lasers in the biological and material sciences.

Free-Electron Lasers (FELs) collectively operate from the terahertz through the ultraviolet range and via intracavity Compton backscattering into the X-ray and gamma-ray regimes. FELs are continuously tunable and can provide optical powers, pulse structures and polarizations that are not matched by conventional lasers. Representative research in the biological and biomedical sciences and condensed matter and material research are described to illustrate the breadth and impact of FEL applications. These include terahertz dynamics in materials far from equilibrium, infrared nonlinear vibrational spectroscopy to investigate dynamical processes in condensed-phase systems, infrared resonant-enhanced multiphoton ionization for gas-phase spectroscopy and spectrometry, infrared matrix-assisted laser-desorption-ionization and infrared matrix-assisted pulsed laser evaporation for analysis and processing of organic materials, human neurosurgery and ophthalmic surgery using a medical infrared FEL and ultraviolet photoemission electron microscopy for nanoscale characterization of materials and nanoscale phenomena. The ongoing development of ultraviolet and X-ray FELs are discussed in terms of future opportunities for applications research.

Perioperative monitoring of indocyanine green clearance and plasma disappearance rate in patients undergoing liver transplantation.

INTRODUCTION: Indocyanine green (ICG) elimination tests have been repeatedly suggested as an early predictor of graft function in patients with liver transplantation. Conventionally, ICG clearance (ClICG) is measured by a series of blood samples with subsequent laboratory analysis. More recently bedside techniques have become available to measure ICG concentrations in vivo and in addition to ClICG, the plasma disappearance rate of ICG (PDRICG) is increasingly being used. The aim of this study was to assess and to compare the normal time courses of ClICG and PDRICG in liver transplant recipients. METHODS: ClICG and PDRICG were measured perioperatively and at various times up to 24 h after liver transplantation. The bedside transpulmonary indicator dilution technique with an arterial fiberoptic-thermistor catheter was used to assess the ICG concentration time curve together with total circulating blood volume (Vd circ). RESULTS: Similar patterns of the time courses of ClICG and PDRICG with a fast recovery of ICG elimination in the early reperfusion period were observed. Compared to healthy subjects, ClICG was supranormal and PDRICG was slightly subnormal. In this study, Vd circ was increased at baseline and remained increased during surgery. CONCLUSIONS: PDRICG and ClICG are well suited to monitor onset and maintenance of graft function in patients undergoing liver transplantation. The PDRICG values measured tend to be relatively lower than ClICG because of an increased blood volume in these patients. By knowing these differences it is justified to monitor liver function in a very simple manner with PDRICG.

Determinants of hospital length of stay after thoracoabdominal aortic aneurysm repair.

PURPOSE: Extended hospital length of stay (LOS) and consequent high costs are associated with thoracic and thoracoabdominal aortic aneurysm (TAAA) surgery. In this study, we examined factors that may influence LOS after TAAA repair. METHODS: Five hundred forty thoracic and TAAA repairs were performed by one surgeon between 1990 and 1999. The data were analyzed with multiple linear regression with appropriate logarithmic transformation. The predictor variables included patient demographics, disease extent, severity indicators, intraoperative factors, and postoperative complications. RESULTS: The median LOS was 15 days. Postoperative creatinine level of greater than 2.9 was the most important predictor of LOS, followed by spinal cord deficit, age, and pulmonary complication (all statistically significant with P <.05). A second model constrained to preoperative risk factors showed both age and complete diaphragmatic division to be associated with increased LOS. Preservation of the diaphragm led to reduced LOS by an average of 4 days. The adjunct cerebrospinal fluid drainage and distal aortic perfusion was associated with a decrease in LOS, although it did not reach statistical significance. CONCLUSION: Renal failure, spinal cord deficit, and pulmonary complication were the major determinants of LOS in patients for TAAA repair. This study shows that the preservation of diaphragmatic function and the use of the adjunct distal aortic perfusion and cerebrospinal fluid drainage may reduce hospital LOS.

Myocardial fluid balance.

Fluid accumulation in the cardiac interstitium or myocardial edema is a common manifestation of many clinical states. Specifically, cardiac surgery includes various interventions and pathophysiological conditions that cause or worsen myocardial edema including cardiopulmonary bypass and cardioplegic arrest. Myocardial edema should be a concern for clinicians as it has been demonstrated to produce cardiac dysfunction. This article will briefly discuss the factors governing myocardial fluid balance and review the evidence of myocardial edema in various pathological conditions. In particular, myocardial microvascular, interstitial, and lymphatic interactions relevant to the field of cardiac surgery will be emphasized.

Effect of sialyl Lewis(x) selectin blockade on myocardial protection during cardioplegic arrest and reperfusion.

PURPOSE: Selectins play a crucial role in the neutrophil-mediated myocardial injury associated with ischemia/reperfusion. We investigated the effect of selectin inhibition on neutrophil-endothelial cell adhesion, myocardial water content, and left ventricular (LV) recovery after cardiopulmonary bypass (CPB) and cardioplegia. METHODS: Dogs were subjected to CPB and 60 minutes of hypothermic cardioplegia. A selectin inhibitor (SI) (25 mg/kg) was given five minutes prior to CPB and as a continuous infusion (5 mg/kg/h) throughout CPB (n = 6). Saline-treated controls (n = 6) received identical volumes. Preload recruitable stroke work (PRSW) was calculated by sonomicrometry and micromanometry. Myocardial water content was determined by microgravimetry. Myeloperoxidase (MPO) activity was measured to quantify polymorphonuclear neutrophil (PMN) infiltration. RESULTS: SI did not attenuate PRSW as well as post-CPB MPO tissue activity. While we found no difference in myocardial water gain between groups 120 minutes post-CPB, there was better edema resolution with SI. CONCLUSIONS: Selectin antagonism does not reduce CPB-associated myocardial injury, and contractile recovery is not enhanced.

Determination of optimal peat type to potentially capture copper and cadmium from solution.

The focus of this study was to determine the optimum type of peat for application as a medium to capture dissolved metals from aqueous solution. Seventeen media were examined, including eleven Irish peat samples from various locations and stages in processing, a Northern Ireland lignite, peat and lignite chars, a commercial-grade bone char, and two commercial-grade granular activated carbons. Considerable variation in sorption capacity was found with a ratio of 20:1 between the best-performing (bone char) and the poorest-performing (peat char) samples. Among the 14 varieties of peat, the best-performing sample outperformed the commonly investigated sphagnum moss by a ratio of 4:1. A correlation has been established between cation exchange capacity, the presence of adsorbed calcium, and the uptake capacity of different peats. This correlation will be a valuable tool in choosing peat type for filter media for metals removal applications.

Identification and structure of the nerve growth factor binding site on TrkA.

Nerve growth factor (NGF) is involved in the development and maintenance of the nervous system and has been implicated as a possible therapeutic target molecule in a number of neurodegenerative diseases, especially Alzheimer's disease. NGF binds with high affinity to the extracellular region of a tyrosine kinase receptor, TrkA, which comprises three leucine-rich motifs (LRMs), flanked by two cysteine-rich clusters, followed by two immunoglobulin-like (Ig-like) domains. We have expressed the second Ig-like domain as a recombinant protein in E. coli and demonstrate that NGF binds to this domain with similar affinity to the native receptor. This domain (TrkAIg(2)) has the ability to sequester NGF in vitro, preventing NGF-induced neurite outgrowth, and in vivo, inhibiting NGF-induced plasma extravasation. We also present the three-dimensional structure of the TrkAIg(2) domain in a new crystal form, refined to 2.0 A resolution.

Activity and mRNA abundance of Delta-5 and Delta-6 fatty acid desaturases in two human cell lines.

We analyzed fatty acid biosynthesis in Chang and ZR-75-1 cells. Both cell lines could desaturate and further elongate substrates for Delta-5 desaturase. ZR-75-1 but not Chang cells showed Delta-6 desaturation of 18:2n-6, 18:3n-3, 24:4n-6 and 24:5n-3. In both cell lines, the mRNA abundance can be related to Delta-5 or Delta-6 fatty acid desaturase activities. These results suggest that desaturase genes could have, at least in part, independent control mechanisms and that Delta-6 desaturase impairment is not specific to any particular step of the fatty acid metabolic pathways, which may diminish the rationale for the existence of at least two distinct enzymes.

Recombinant human nerve growth factor for clinical trials: protein expression, purification, stability and characterisation of binding to infusion pumps.

Nerve growth factor (NGF) has been suggested to be of therapeutic benefit to patients with Alzheimer's disease. One of the early changes in this disease is a loss of cholinergic function within the brain, and NGF is able to rescue cholinergic neurons both in vitro and in vivo. We describe the production of recombinant human beta-NGF (rhNGF), using baculovirus infection of insect cells; its purification, formulation and subsequent stability for use in clinical trials. Tests were also carried out to monitor release of protein from infusion pumps and catheters for intracerebroventricular administration (icv). Initial problems with non-specific binding were overcome using a blocking formula.

Esmolol and cardiopulmonary bypass during reperfusion reduce myocardial infarct size in dogs.

BACKGROUND: Infarct size can be reduced by beta-blockade in acute myocardial ischemia. However it is unknown whether myocardial salvage is still effective when beta-blockade is limited to reperfusion. METHODS: After initiation of cardiopulmonary bypass, 20 dogs were submitted to 2 hours of regional left ventricular ischemia, followed by 2 hours of reperfusion. In 11 dogs beta-blockade was started with the onset of reperfusion (esmolol group). The remaining dogs received no treatment (control, n = 9). Infarct size was determined by tetrazolium chloride staining. Myocardial water content (MWC) and ultrastructural damage (electronmicroscopy) were determined from transmural biopsies. RESULTS: Infarct size was significantly smaller in the esmolol group compared with control (49% versus 68%, p < 0.05). After 2 hours ischemia there was no difference in MWC between groups, whereas after 2 hours reperfusion MWC of ischemic myocardium was significantly lower in the esmolol group than in the control (p < 0.05). Ultrastructural changes were typical for ischemia-reperfusion injury in both groups. CONCLUSIONS: Beta-blockade may be cardioprotective during reperfusion through various mechanisms and may enhance myocardial salvage, even when treatment is initiated as late as with the onset of reperfusion.

Systematic root cause analysis of adverse drug events in a tertiary referral hospital.

BACKGROUND: Adverse drug events (ADEs) occur frequently, and serious ADEs are associated with mortality or prolonged morbidity. As many ADEs are preventable, identification and modification of systems and processes that permit ADEs has the potential to reduce the rate of ADEs. METHODS: Root cause analysis was systematically employed in a blame-free fashion to investigate the patterns of serious ADEs that occurred during a 29-month period at Hermann Hospital (Houston), and process improvements were implemented on the basis of these findings. The consistently nonpunitive responses to the results of the initial and subsequent root cause analyses was gradually seen, accepted, and ultimately embraced by the hospital staff. RESULTS: The most commonly identified root causes were environmental factors (for example, increased census, increased acuity, change of shift) and staffing issues (for example, personnel new to a unit). Policy changes that led to increased use of forcing or constraining functions (for example, removal of concentrated intravenous potassium solutions from floor stocks) and better personnel support (for example, early awareness and response to localized increases in census and acuity) were particularly effective. Although limited by our lack of active surveillance and not necessarily directly due to the process changes that we implemented, the rate of voluntarily reported serious ADEs/100,000 patient days decreased during this time from 7.2 to 4.0, a decline of 45% (p < 0.001). CONCLUSION: Systematic application of root cause analysis followed by implementation of process changes that target the underlying cause(s) of each event can be successfully implemented in a large hospital.

Effects of selectin-sialyl Lewis blockade on mesenteric microvascular permeability associated with cardiopulmonary bypass.

OBJECTIVES: Cardiopulmonary bypass is associated with an inflammatory response that is associated with a neutrophil-mediated microvascular barrier injury. We studied the effects of blocking neutrophil-endothelial tethering on microvascular permeability and edema formation during cardiopulmonary bypass. Using a selectin antagonist that prevents interactions with their ligands, we hypothesized that there would be less neutrophil infiltration into the tissue and a reduction in microvascular permeability and edema formation. METHODS: A canine mesenteric lymphatic fistula was created to measure Starling forces and to determine microvascular permeability. Normothermic, atrial-femoral cardiopulmonary bypass was initiated (70-90 mL. kg(-1). min(-1)). Intestinal tissue water was determined with microgravimetry. Ileal tissue myeloperoxidase was measured as an index of neutrophil tissue infiltration. One experimental group received the selectin antagonist TBC 1269 before the initiation of bypass, and the control group received saline solution. RESULTS: There was a modest increase in microvascular permeability in both groups, as evidenced by significantly increased transvascular protein clearance and a trend toward a decrease in reflection coefficient. There were no differences in the experimental group compared with the control group. Ileal tissue myeloperoxidase levels were lower in the experimental group than in the control group. CONCLUSIONS: The selectin antagonist TBC 1269 reduces neutrophil infiltration into the ileum without altering ileal microvascular permeability or edema associated with cardiopulmonary bypass.