High stretch induces endothelial dysfunction accompanied by oxidative stress and actin remodeling in human saphenous vein endothelial cells.

The rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin's nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.

Professor Ross Holland: The Special Committee Investigating Deaths Under Anaesthesia (SCIDUA) and his other contributions to anaesthesia.

As a young anaesthetic trainee in 1959 Ross Holland persuaded the Minister of Health in NSW, Australia, to establish SCIDUA, which by law required compulsory reporting for all deaths occurring during anaesthesia or up to 24 hours after cessation of the anaesthetic. The committee was multidisciplinary and, most importantly, had statutory privilege so that no discussions or findings were able to be subpoenaed for other legal investigations or case law. Holland was the foundation secretary of SCIDUA and later Chair. Apart from three years in the 1980s when there were political issues with legal privilege, the committee has met monthly and still meets. Holland was a major figure in antipodean anaesthesia, setting up in 1978 the clinical department at Westmead Hospital Sydney, then in 1987 becoming the foundation Professor to the Department of Anaesthesiology at the University of Hong Kong, and in 1990 foundation Professor and Chair, Department of Anaesthesia and Intensive Care at the University of Newcastle, NSW. Holland had strong historical interests and was responsible for founding the Society for the Preservation of Artefacts of Surgery and Medicine (SPASM) and its associated museum. He also served an important term as Dean of the Faculty of Anaesthetists, Royal Australasian College of Surgeons prior to that Faculty becoming independent as the Australian and New Zealand College of Anaesthetists (ANZCA). Professor Holland received many accolades for these activities during his life, which are noted. It is fitting to recognise his seminal contributions to patient safety over more than 50 years.

Genesis of the College of Intensive Care Medicine of Australia and New Zealand.

In 2009 the College of Intensive Care Medicine (CICM) of Australia and New Zealand was inaugurated in Melbourne, Australia. This College now regulates the education, training and accreditation for specialist intensivists for Australia and New Zealand. CICM origins started in 1975 with the formation of the Section of Intensive Care of the Faculty of Anaesthetists, Royal Australasian College of Surgeons (RACS), which moved through intermediary stages as the Faculty of Intensive Care, Australian and New Zealand College of Anaesthetists (ANZCA) when that College was formed from the former Faculty of Anaesthetists RACS, and then the Joint Faculty of Intensive Care Medicine (ANZCA and the Royal Australasian College of Physicians [RACP]), until becoming completely independent as CICM in 2010. There was a period of about 40-50 years evolution from the first formations of intensive care units in Australia and New Zealand, and discussions by the personnel staffing those units amongst themselves and with Members of the Board of the Faculty of Anaesthetists RACS, to the formation of the Section of Intensive Care, then through two intermediary Faculties of Intensive Care Medicine, to the final independent formation of the College of Intensive Care Medicine of Australia and New Zealand in 2010.

A high-throughput mechanofluidic screening platform for investigating tumor cell adhesion during metastasis.

The metastatic spread of cancer is a major barrier to effective and curative therapies for cancer. During metastasis, tumor cells intravasate into the vascular system, survive in the shear forces and immunological environment of the circulation, and then extravasate into secondary tumor sites. Biophysical forces are potent regulators of cancer biology and are key in many of the steps of metastasis. In particular, the adhesion of circulating cells is highly dependent upon competing forces between cell adhesion receptors and the shear stresses due to fluid flow. Conventional in vitro assays for drug development and the mechanistic study of metastasis are often carried out in the absence of fluidic forces and, consequently, are poorly representative of the true biology of metastasis. Here, we present a novel high-throughput approach to studying cell adhesion under flow that uses a multi-well, mechanofluidic flow system to interrogate adhesion of cancer cell to endothelial cells, extracellular matrix and platelets under physiological shear stresses. We use this system to identify pathways and compounds that can potentially be used to inhibit cancer adhesion under flow by screening anti-inflammatory compounds, integrin inhibitors and a kinase inhibitor library. In particular, we identify several small molecule inhibitors of FLT-3 and AKT that are potent inhibitors of cancer cell adhesion to endothelial cells and platelets under flow. In addition, we found that many kinase inhibitors lead to increased adhesion of cancer cells in flow-based but not static assays. This finding suggests that even compounds that reduce cell proliferation might also enhance cancer cell adhesion during metastasis. Overall, our results validate a novel platform for investigating the mechanisms of cell adhesion under biophysical flow conditions and identify several potential inhibitors of cancer cell adhesion during metastasis.

The ageing practitioner: ANZCA's recommendations.

OBJECTIVES: The aim is to present recommendations of the Australian and New Zealand College of Anaesthetists (ANZCA) with respect to practice implications for ageing specialists, together with brief discussion of effects of ageing on professional medical capabilities and recommendations on preparing to retire from medical practice. CONCLUSIONS: Practitioners should recognise that planning for retirement is part of good management of a medical career, and that the ageing process will inevitably compromise their ability to treat patients safely unless they retire at the appropriate time. Planning should include adequate financial preparation, and cultivation of interests and friends outside medicine. Practitioners should also realise that insight is likely to be compromised, so that they should seek colleagues who are trusted to advise them if/when they begin to lose competency. Lastly all practitioners should ensure that they consult a General Practitioner frequently, and that they have arranged all the proper legal instructions such as a Will, a Power of Attorney and an Advanced Health Directive.The ANZCA recommendations concerning ageing specialists have wide application to all medical specialties, not just for anaesthetists, and therefore all Medical Colleges should generate their own specific recommendations for ageing practitioners and the general effects of fatigue particularly for aged practitioners.

Anaesthesia for endoscopic sinus surgery.

Endoscopic sinus surgery is commonly performed and has a low risk of major complications. Intraoperative bleeding impairs surgical conditions and increases the risk of complications. Remifentanil appears to produce better surgical conditions than other opioid analgesics, and total intravenous anaesthesia with propofol may provide superior conditions to a volatile-based technique. Moderate hypotension with intraoperative beta blockade is associated with better operating conditions than when vasodilating agents are used. Tight control of CO(2) does not affect the surgical view. The use of a laryngeal mask may be associated with improved surgical conditions and a smoother emergence. It provides airway protection equivalent to that provided by an endotracheal tube in well-selected patients, but offers less protection from gastric regurgitation. Post-operatively, multimodal oral analgesia provides good pain relief, while long-acting local anaesthetics have been shown not to improve analgesia.

Systematic errors and susceptibility to noise of four methods for calculating anatomical dead space from the CO2 expirogram.

BACKGROUND: Anatomical dead space is usually measured using the Fowler equal area method. Alternative methods include the Hatch, Cumming, and Bowes methods, in which first, second, and third order polynomials, respectively, fitted to an expired CO2 volume vs expired volume curve, intercept the x-axis at the anatomical dead space. This study assessed systematic errors and susceptibility to noise of the Fowler, Hatch, Cumming, and Bowes dead spaces calculated over 40-80% of the CO2 expirogram. METHODS: Simulated CO2 expirograms with 220 ml anatomical dead space and varying alveolar plateau slopes were generated digitally and zero-mean Gaussian noise added. CO2 expirograms were recorded in 10 anaesthetized human subjects. Anatomical dead space was calculated by the Fowler, Hatch, Cumming, and Bowes methods. RESULTS: The Fowler, Hatch, Cumming, and Bowes methods displayed systematic biases of -1.8%, 13.2%, 2.4%, and -1.3%, respectively, at a normalized simulated alveolar plateau slope of 1.6 litre(-1). At a noise level of 0.0066 vol/vol, the standard deviations of recovered simulated dead spaces were 70.6, 1.8, 2.4, and 3.7 ml, respectively. The Hatch, Cumming, and Bowes methods applied to human expirograms differed significantly from that of Fowler by 13, -4, and -11 ml, respectively. In the human study, the Hatch and Cumming methods yielded the lowest intra-individual dead space variability. CONCLUSIONS: The Fowler method shows greatest susceptibility to measurement noise and the Hatch method exhibits the largest systematic error. The Cumming method, which exhibits both low bias and low noise susceptibility, is preferred for estimating anatomical dead space from CO2 expirograms.

A tidally breathing model of ventilation, perfusion and volume in normal and diseased lungs.

BACKGROUND: To simulate the short-term dynamics of soluble gas exchange (e.g. CO2 rebreathing), model structure, ventilation-perfusion (VA/Q) and ventilation-volume (VA/VA) parameters must be selected correctly. Some diseases affect mainly the VA/Q distribution while others affect both VA/Q and VA/VA distributions. Results from the multiple inert gas elimination technique (MIGET) and multiple breath nitrogen washout (MBNW) can be used to select VA/Q and VA/VA parameters, but no method exists for combining VA/Q and VA/VA parameters in a multicompartment lung model. METHODS: We define a tidally breathing lung model containing shunt and up to eight alveolar compartments. Quantitative and qualitative understanding of the diseases is used to reduce the number of model compartments to achieve a unique solution. The reduced model is fitted simultaneously to inert gas retentions calculated from published VA/Q distributions and normalized MBNWs obtained from similar subjects. Normal lungs and representative cases of emphysema and embolism are studied. RESULTS: The normal, emphysematous and embolism models simplify to one, three and two alveolar compartments, respectively. CONCLUSIONS: The models reproduce their respective MIGET and MBNW patient results well, and predict disease-specific steady-state and dynamic soluble and insoluble gas responses.

Sources of error in partial rebreathing pulmonary blood flow measurements in lungs with emphysema and pulmonary embolism.

BACKGROUND: Studies of the accuracy of partial rebreathing measurements of pulmonary blood flow (PBF) in patients with abnormal lungs have not fully explained the sources of error. METHODS: We used computer models of emphysema and pulmonary embolism incorporating both ventilation-perfusion (V/Q) and ventilation-volume (V/V) heterogeneity to investigate systematic errors in partial rebreathing PBF measurements. We studied (i) errors produced under usual conditions, (ii) effects of recirculation, (iii) effects of alveolar-proximal airway and alveolar-capillary PCO2 and VCO2 differences, (iv) effects of alveolar V/Q inhomogeneity and (v) effects of rebreathing time. RESULTS: In the pulmonary embolism model the systematic error is only acceptable (<10%) when the simulated PBF is low (2-3 litre min(-1)). In the emphysema model PBF is underestimated by more than 20% at all cardiac outputs studied. Four sources of systematic errors were found. (i) Alveolar-proximal airway PCO2 gradients and flux differences between the proximal airway and alveolar compartments contribute most to the systematic error. (ii) V/Q inhomogeneity causes PCO2 gradients between the alveolar compartments and pulmonary capillary blood, and between pulmonary capillary compartments. (iii) Rebreathing times are inadequate in the presence of V/V mismatch. (iv) The apparent effect of venous blood recirculation is small in emphysema but significant in pulmonary embolism. CONCLUSIONS: We conclude that PBF cannot be measured accurately by partial rebreathing in lungs with emphysema or embolism. Systematic errors are caused mainly by errors in end-tidal PCO2 values.

The effect of bi-level positive airway pressure mechanical ventilation on gas exchange during general anaesthesia.

BACKGROUND: Atelectasis may occur and ventilation-perfusion mismatch may increase during general anaesthesia with neuromuscular paralysis and mechanical ventilation, though preservation of some intermittent muscle contraction might mitigate this process. There is still no ideal manoeuvre to minimize such mismatch or atelectasis. Bi-level positive airway pressure (BiPAP) ventilation adjusts to extra breaths and improves gas exchange during recovery of diaphragm function after neuromuscular paralysis. We hypothesize that BiPAP ventilation may limit the development of pulmonary shunt and may improve ventilation-perfusion mismatch when compared with standard IPPV, with or without PEEP when neuromuscular paralysis has been used during surgery. METHODS: Twenty ventilated patients either on BiPAP or IPPV with or without PEEP were studied randomly using the multiple inert gas elimination technique (MIGET) at 60 and 120 min after rocuronium at induction and after 60 min. Non-invasive cardiac output (NICO) monitoring and plasma concentrations of rocuronium were measured. We compared the data of MIGET, gas exchange, haemodynamic variables and pulmonary mechanics measurements between the different ventilatory modes. RESULTS: Intrapulmonary shunt (blood flow to V(A)/Q < 0.005) did not increase at 60 min of anaesthesia in any of the different ventilation modes compared with the shunt value before anaesthesia. Log standard deviation of perfusion increased in IPPV, with and without PEEP groups, compared with the baseline (P< 0.05) but did not increase in the BiPAP group. BiPAP ventilation generated a higher level of Pa(O2)than IPPV with or without PEEP (P<0.05). CONCLUSION: BiPAP ventilation was beneficial in decreasing ventilation-perfusion mismatch and improving oxygenation when compared with conventional IPPV (with or without PEEP).

Effects of alveolar dead-space, shunt and V/Q distribution on respiratory dead-space measurements.

BACKGROUND: Respiratory dead-space is often increased in lung disease. This study evaluates the effects of increased alveolar dead-space (Vd(alv)), pulmonary shunt, and abnormal ventilation perfusion ratio (/) distributions on dead-space and alveolar partial pressure of carbon dioxide (Pa(co(2))) calculated by various methods, assesses a recently published non-invasive method (Koulouris method) for the measurement of Bohr dead-space, and evaluates an equation for calculating physiological dead-space (Vd(phys)) in the presence of pulmonary shunt. METHODS: Pulmonary shunt, / distribution and Vd(alv) were varied in a tidally breathing cardiorespiratory model. Respiratory data generated by the model were analysed to calculate dead-spaces by the Fowler, Bohr, Bohr-Enghoff and Koulouris methods. Pa(co(2)) was calculated by the method of Koulouris. RESULTS: When Vd(alv) is increased, Vd(phys) can be recovered by the Bohr and Bohr-Enghoff equations, but not by the Koulouris method. Shunt increases the calculated Bohr-Enghoff dead-space, but does not affect Fowler, Bohr or Koulouris dead-spaces, or Vd(phys) estimated by the shunt-corrected equation if pulmonary artery catheterization is available. Bohr-Enghoff but not Koulouris or Fowler dead-space increases with increasing severity of / maldistribution. When alveolar Pco(2) is increased by any mechanism, Pa(co(2)) calculated by Koulouris' method does not agree well with average alveolar Pco(2). CONCLUSIONS: Our studies show that increased pulmonary shunt causes an apparent increase in Vd(phys), and that abnormal / distributions affect the calculated Vd(phys) and Vd(alv), but not Fowler dead-space. Dead-space and Pa(co(2)) calculated by the Koulouris method do not represent true Bohr dead-space and Pa(co(2)) respectively, but the shunt-corrected equation performs well.

Pharmacokinetics of sevoflurane uptake into the brain.

Two recent studies have examined the pharmacokinetics of sevoflurane in adults. Lu et al.(Pharmacokinetics of sevoflurane uptake into the brain and body, Anaesthesia 2003; 58: 951-6) observed that jugular bulb sevoflurane concentration initially rose unexpectedly rapidly and then approached arterial concentrations unexpectedly slowly, suggesting that a blood-brain diffusion barrier exists. They also observed a large alveolar-arterial sevoflurane gradient, suggesting that an alveolar-arterial diffusion barrier exists. Nakamura et al. (Predicted sevoflurane partial pressure in the brain with an uptake and distribution model: Comparison with the measured value in internal jugular vein blood. Journal of Clinical Monitoring and Computing 1999; 15: 299-305) found no diffusion barriers. We used a computer model to analyse both data sets and show that the observations of Lu et al. can be explained by contamination of jugular samples with extracerebral blood. It is possible that the alveolar-arterial gradients observed by Lu et al. are due to discrepancies in conversions between blood concentrations and gas partial pressures. Our study suggests that there is no blood-brain diffusion barrier for sevoflurane and that the data of Lu et al. must be interpreted with caution.

Consent and anaesthetic risk.

The incidences of mortality and morbidity associated with anaesthesia were reviewed. Most of the published incidences for common complications of anaesthesia vary considerably. Where possible, a realistic estimate of the incidence of each morbidity has been made, based on the best available data. Perception of risk and communication of anaesthetic risk to patients are discussed. The incidences of anaesthetic complications are compared with the relative risks of everyday events, using a community cluster logarithmic scale, in order to place the risks in perspective when compared with other complications and with the inherent risks of surgery. Documentation of these risks and discussion with patients should allow them to be better informed of the relative risks of anaesthetic complications. Depending on specific comorbidities and the severity of operation, these risks associated with anaesthesia may increase for any one individual.

Percentage decline in masters superathlete track and field performance with aging.

Masters athletic records in track and field events, published in September 1999, were analyzed to evaluate the percentage decline in maximum physiological performance with increasing age. Records were normalized using the 30s age records as the baseline and studied through to the 90s age range. Track running records declined with age in a curvilinear fashion [y = 1-exp((T-T0)/tau)] whereas the walking and field events declined in a linear manner [y = alpha (T-T'0)]. There were significant differences in the rates of percentage decline in the running events over various distances for both males and females, and significant differences between males and females. Decline with aging was greater for females, and for the longer or endurance running events. There were no differences in the rates of declining function for any of the walking events, and the only jumping event to show a significant difference was the high jump performance, which showed the slowest decline. The walking events declined more slowly than the running events, which declined more slowly than the jumping events. Because of the changes in the weights, heights, and distances at different ages, for both males and females, it was not possible to directly compare rates of decline in the various throwing and hurdling events. The strength-dependent throwing events and the pole vault showed the greatest rates of decline with age. In general terms, men's performance declined to 75% of peak performance in sprint events by the early 70s, in the longer track distances by mid to late 60s, and in field events by mid to late 50s. Women's performance declined to a similar extent by their mid 60s in track events, and by late 40s to early 50s in field events. Some of these differences may be due to differences in training effort and/or other competitive aspects, such as the numbers of athletes involved in the sport, and such differences may be reduced in the future with a more professional approach to these events.

The effects of ventilation pattern on carbon dioxide transfer in three computer models of the airways.

We investigate the effects on arterial P(CO(2)) and on arterial-end tidal P(CO(2)) difference of six different ventilation patterns of equal tidal volume, and also of various combinations of tidal volume and respiratory rate that maintain a constant alveolar ventilation. We use predictions from three different mathematical models. Models 1 (distributed) and 2 (compartmental) include combined convection and diffusion effects. Model 3 incorporates a single well-mixed alveolar compartment and an anatomical dead-space in which plug flow occurs. We found that: (i) breathing patterns with longer inspiratory times yield lower arterial P(CO(2)); (ii) varying tidal volume and respiratory rate so that alveolar ventilation is kept constant may change both PA(CO(2)) and the PA(CO(2))-PET(CO(2)) difference; (iii) the distributed model predicts higher end-tidal and arterial P(CO(2)) than the compartmental models under similar conditions; and (iv) P(CO(2)) capnograms predicted by the distributed model exhibit longer phase I and steeper phase II than other models.

Control of in vivo microvessel ingrowth by modulation of biomaterial local architecture and chemistry.

We developed a method for controlling local architecture and chemistry simultaneously in biomaterial implants to control microvessel ingrowth in vivo. Porous polypropylene disks (5 mm in diameter and 40 microm thick) were plasma-coated with a fluoropolymer and then laser-drilled with 50-microm-diameter holes through their thickness. We then oxidized the disks to create hydroxyl functionality on the exposed polypropylene (inside the holes). Acrylamide was grafted to the hydroxyl groups through polymerization in the presence of activating ceric ions. Staining with toluidine blue O demonstrated that grafting occurred only inside the holes. We used the Hoffman degradation reaction to convert the amide groups of acrylamide to amine groups, and then we used ethylene glycol diglycidyl ether to attach biomolecules of interest inside the holes: secreted protein acidic and rich in cysteine (SPARC) peptide Lys-Gly-His-Lys (KGHK; angiogenic), thrombospondin-2 (TSP; antiangiogenic), or albumin (rat; neutral). In vivo testing in a rat subcutaneous dorsum model for a 3-week interval demonstrated a greater vessel surface area (p = 0.032) and a greater number of vessels (p = 0.043) in tissue local to the holes with KGHK-immobilized disks than with TSP-immobilized disks. However, differences between KGHK-immobilized and albumin-immobilized disks were less significant (p = 0.120 and p = 0.289 for the vessel surface area and number of vessels, respectively). The developed methods have potential applications in biomaterial design applications for which selective neovascularization is desired.