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Biomedical subjects

T W Evans

Publications and source records attributed to T W Evans.

At least 37 records · Page 2Linked to original sources
PubMed2001

Characterization of the effects of isoprostanes on platelet aggregation in human whole blood.

We tested the effects of 11 commercially-available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer. None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a sub-threshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8-iso PGE(1)>8-iso PGE(2)>8-iso PGF(2alpha)>8-iso PGF(3alpha)>8-iso-13,14-dihydro-15-keto PGF(2alpha)). Blood incubated with LPS to induce a gross inflammatory response exhibited a time dependent (2 - 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619-induced aggregation were enhanced in blood treated with LPS. L-NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L-NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action. Thus, in human whole blood the action of 8-iso PGE(1), 8-iso PGE(2), 8-iso PGF(2alpha), 8-iso PGF(3alpha), and 8-iso-13,14-dihydro-15-keto PGF(2alpha) is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

The iron paradox of heart and lungs and its implications for acute lung injury.

Iron is an essential requirement for the growth, development, and long term survival of most aerobic organisms. When control over safe iron sequestration is lost or compromised, leading to the release of low molecular mass forms of iron, the heart appears to be particularly sensitive to iron toxicity with cardiomyopathies often developing as a consequence. Iron toxicity, leading to iron-overload, is often treated in humans with the iron chelator desferrioxamine mesylate. Such treatment regimens designed to protect the heart can, however, often lead to lung injury and, in fact, several compounds with known iron chelating properties can induce severe lung dysfunction and injury. Based on these clinical observations and our recent laboratory data, we propose that the lungs actively accumulate reactive forms of iron for use in cellular growth and proliferation, and for the oxidative destruction of microbes, whereas the heart responds in the opposite way by actively removing iron which it finds extremely toxic.

Animals↗
PubMed2001

Mechanical ventilation in acute respiratory distress syndrome.

The acute respiratory distress syndrome occurs commonly in critical care. There is an increasing volume of clinical and experimental evidence that poor ventilatory technique that is injurious to the lungs can propagate the systemic inflammatory response and adversely affect mortality. Many ventilatory techniques have been hypothesized to 'protect' the lungs during mechanical ventilation, including tidal volume limitation, high positive end-expiratory pressure, pressure-controlled inverse ratio ventilation, and prone positioning. Experimental techniques include liquid ventilation, surfactant administration and extracorporeal gas exchange. Despite excellent rationale for their use, few techniques, apart from tidal volume limitation, have been shown to improve survival in randomized controlled trials.

Journal Article↗
PubMed2001

Influence of direct and indirect etiology on acute outcome and 6-month functional recovery in acute respiratory distress syndrome.

OBJECTIVE: To assess the possibility that acute respiratory distress syndrome (ARDS) of pulmonary and nonpulmonary origins represent two distinct syndromes. DESIGN: Analysis of data collected prospectively from an inception cohort of 117 patients with ARDS. SETTING: Adult intensive care unit (ICU), university/postgraduate hospital. MEASUREMENTS AND MAIN RESULTS: Differences were sought in mortality and 6-month functional outcome between patients developing ARDS due to pulmonary (group 1) and nonpulmonary (group 2) pathology. Group 1 patients displayed a trend toward increased ICU and in-hospital mortality (42.1% vs. 23.2%, p = .10, and 47.4% vs. 27.9%, p = .11, respectively). No difference was found in ICU length of stay (46.3 +/- 4.9 vs. 39.0 +/- 4.8 days for groups 1 and 2, respectively) nor in duration of positive-pressure ventilation (26.2 +/- 4.3 vs. 20.6 +/- 3.2 days). However, the need for pressure-controlled inverse ratio ventilation was significantly greater in group 1 (16.9 +/- 3.2 vs. 9.1 +/- 1.3 days; p = .033). In survivors, reductions in total lung capacity at 6 months (68.1 +/- 4.6 vs. 61.8 +/- 4.6% predicted for groups 1 and 2, respectively; p = .4), accessible lung volume (74.4 +/- 4.4 vs. 68.9 +/- 4.9% predicted; p = .56), and forced expiratory volume (77.8 +/- 2.9 vs. 80.3 +/- 2.4% predicted; p = .57) did not differ between groups. Gas transfer coefficient was well preserved (84.5 +/- 4.6 vs. 86.6 +/- 4.7% predicted; p = .80). CONCLUSIONS: These data suggest a trend toward higher mortality and ventilatory requirements in ARDS of direct etiology, generating a hypothesis worthy of further exploration.

APACHE↗
PubMed2001

Tissue oxygenation and perfusion in patients with systemic sepsis.

OBJECTIVE: Multiple organ dysfunction is associated with systemic sepsis. To investigate whether this is attributable to peripheral tissue hypoperfusion and/or cellular hypoxia, simultaneous measurements of tissue perfusion and oxygenation were made in patients with severe sepsis and in controls. DESIGN: Prospective, observational study. SETTING: Adult intensive care unit, tertiary referral center. PATIENTS: Volunteers (group C, n = 7), patients undergoing cardiopulmonary bypass (group B, n = 6), and patients with severe sepsis (group S, n = 6). INTERVENTIONS: Limb ischemia and reperfusion. MEASUREMENTS AND MAIN RESULTS: Tissue oxygenation and microvascular flow were measured by using microelectrodes inserted into brachoradialis muscle and overlying subcutaneous tissue. Forearm cutaneous red cell flux and regional blood flow were measured simultaneously. Responses to 20 mins of limb ischemia and subsequent reperfusion were observed. Baseline muscle tissue oxygenation was greater in sepsis (1.7 +/- 0.2, 1.5 +/- 0.7, and 4.4 +/- 0.6 kPa for groups C, B, and S, respectively, mean +/- sem, p <.05), although baseline subcutaneous tissue oxygenation did not vary between groups. During ischemia tissue oxygenation, values decreased in muscle (to 1.3 +/- 0.2, 1.0 +/- 0.4, and 1.5 +/- 0.4 kPa for groups C, B, and S, respectively) and subcutaneous tissue (to 2.0 +/- 0.3, 1.7 +/- 0.5, and 2.3 +/- 0.2 kPa for groups C, B, and S, respectively). Decline in tissue oxygen tension was initially more rapid in septic muscle compared with controls (25% decrease, 68 +/- 23 vs. 176 +/- 38 for group S vs. group C, p <.05, and 50% decrease, 126 +/- 34 vs. 398 +/- 72 secs for group S vs. group C, p <.01). However, overall rate of tissue decline was similar (95% decrease, 444 +/- 122 vs. 614 +/- 96 for group S vs. group C, p >.05). After reperfusion, significant differences in muscle tissue oxygenation reappeared between groups (2.0 +/- 0.3, 1.5 +/- 0.7, and 4.0 +/- 0.4 kPa for groups C, B, and S, respectively, p <.05). There were no differences in time to 25%, 50%, or 95% tissue oxygen recovery. Whole limb reperfusion was significantly less in patient groups compared with controls (10.6 +/- 0.9, 4.5 +/- 1.2, and 4.3 +/- 1.6 mL x 100 mL(-1) x min(-1) for groups C, B, and S, respectively, p <.05). CONCLUSIONS: Significant differences in tissue oxygenation distribution between muscle and subcutaneous tissues occur in patients with severe sepsis. High baseline muscle tissue oxygen levels are accompanied by rapid extraction of oxygen during stagnant ischemia.

Adult↗
PubMed2001

Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT study.

PURPOSE: To determine computed tomographic (CT) differences between acute respiratory distress syndrome (ARDS) due to pulmonary injury (ARDS(p)) and extrapulmonary injury (ARDS(ex)). MATERIALS AND METHODS: CT appearances in 41 patients (27 male, 14 female; mean age, 47.1 years +/- 17.1 [SD]; age range, 17-79 years; those with ARDS(p), n = 16; those with ARDS(ex), n = 25) were categorized as typical or atypical of ARDS by two observers. The extent of individual CT patterns was also quantified. RESULTS: Typical CT appearances were more frequent in ARDS(ex) than ARDS(p) (18 [72%] of 25 vs five [31%] of 16 patients, respectively; P <.01). Sensitivity, specificity, and accuracy of a typical CT pattern for the diagnosis of ARDS(ex) were 72%, 69%, and 71%, respectively. Atypical appearances were characterized by more extensive nondependent intense parenchymal opacification (IPO) (P =.03) and cysts (P =.05), whereas typical CT appearances had more extensive dependent IPO (P =.01). Typical appearances at CT were independently related to the cause of ARDS (odds ratio, 8.9; 95% CI: 1.8, 44.2; P <.01) but were independent of the time from intubation. Foci of nondependent IPO were more extensive in ARDS(p) (P =.05) than ARDS(ex), but this finding was ascribable to differences in time to CT (after intubation) between ARDS(p) and ARDS(ex). CONCLUSION: The differentiation between ARDS(p) and ARDS(ex) can, with some caveats, be based on whether the CT appearances are typical or atypical of ARDS but not on any individual CT pattern in isolation.

Adolescent↗
PubMed2001

Pulmonary perfusion in supine and prone positions: an electron-beam computed tomography study.

Acute respiratory distress syndrome is characterized by alterations in the ventilation-perfusion ratio. Present techniques for studying regional pulmonary perfusion are difficult to apply in the critically ill. Electron-beam computed tomography was used to study the effects of prone positioning on regional pulmonary perfusion in six healthy subjects. Contrast-enhanced sections were obtained sequentially in the supine, prone, and (original) supine positions at full inspiration. Regions of interest were placed along the nondependent to dependent axis and relative perfusion calculated. When corrected for the redistribution of lung parenchyma, a gravitational gradient of pulmonary perfusion existed in both supine and prone positions. The distribution of perfusion between the supine or prone positions did not differ, but data analysis using smaller regions of interest demonstrated marked heterogeneity of perfusion between anatomically adjacent regions of lung. The distribution of lung parenchyma was more uniform in the prone position. Gravity was estimated to be responsible for 22-34% of perfusion heterogeneity in the supine and 27-41% in the prone positions. These data support the hypothesis that factors other than gravity may be at least as important in determining the distribution of pulmonary perfusion in humans. The influence of nongravitational factors may not be detectable if techniques that sample large tissue volumes are employed.

Adult↗
PubMed2001

Endogenously released endothelin-1 from human pulmonary artery smooth muscle promotes cellular proliferation: relevance to pathogenesis of pulmonary hypertension and vascular remodeling.

Endothelin (ET)-1 is a potent vasoconstrictor and comitogen/ proliferation factor for vascular smooth muscle (VSM). As such, it has been implicated in the vascular wall remodeling observed in pulmonary hypertension (PH). Although the endothelium is considered the main source of ET-1, it can be released by other cells including VSM and may mediate proliferation in an autocrine manner. We investigated this possibility using human pulmonary artery smooth-muscle (HPASM) cells. Serum stimulated the release of ET-1 from HPASM cells in a concentration-dependent fashion and caused proliferation as determined by [(3)H]thymidine uptake and increase in cell number. Addition of an ET-A receptor antagonist (BQ123) or an inhibitor of ET-1 synthesis (phosphoramidon) reduced the proliferation induced by serum, confirming an autocrine role for ET-1. In addition, treatment of HPASM cells with two drug types used in the management of PH-cicaprost, a stable prostacyclin-mimetic; or diltiazem, a calcium-channel blocker-reduced ET-1 release from these cells. We conclude that ET-1 released from HPASM cells has an autocrine function in serum-induced proliferation, with important implications for the pathogenesis of human vascular remodeling. Drugs used in the treatment of PH may act, at least in part, by inhibiting this autocrine loop.

Base Sequence↗
PubMed2001

Regional transcapillary albumin exchange in rodent endotoxaemia: effects of fluid resuscitation and inhibition of nitric oxide synthase.

Sepsis is characterized by increased microvascular permeability and regional variations in capillary perfusion, which may be modulated by nitric oxide (NO) and reversed by fluid resuscitation (FR). The effects of saline FR and NO synthase blockade [by N(G)-nitro-L-arginine methyl ester (L-NAME)] on microvascular albumin transport and perfused capillary density were assessed in anaesthetized Wistar rats with acute normodynamic endotoxaemia. Separate dual-isotope techniques were employed to measure the permeability index (PI(A)) and the permeabilityxsurface area product index (PI(B)), which provide different and complementary information regarding blood-tissue albumin exchange. PI(A) represents the tissue/blood distribution volume ratio of albumin. PI(B) is a composite measure of endothelial permeability and the vascular surface area available for albumin exchange, and therefore takes into account the effect of altered blood volume. Capillary density was quantified by fluorescence microscopy following circulation of Evans Blue-labelled albumin. Compared with controls, PI(A) was reduced significantly in lipopolysaccharide (LPS)-treated animals in skeletal muscle and skin, probably due to blood volume redistribution rather than to changes in permeability. PI(B) was increased significantly in LPS-treated animals in the kidney, mesentery, skeletal muscle, skin and lung, and in the small bowel following FR. FR also improved the LPS-induced metabolic base deficit, but did not alter capillary density. L-NAME significantly attenuated the LPS-induced rise in PI(B) in the lung. In conclusion, acute endotoxaemia induces tissue-dependent variations in microvascular albumin exchange. FR improves acid-base disturbance in endotoxaemia, through mechanisms other than microvascular recruitment. NO appears to increase microvascular permeability in endotoxaemia, an effect that may be attenuated by L-NAME, particularly in the lung.

Acute Disease↗
PubMed2001

Iron signalling regulated directly and through oxygen: implications for sepsis and the acute respiratory distress syndrome.

Reactive oxygen species produced at toxic levels are damaging species. When produced at sub-toxic levels, however, they are involved as second messengers in numerous signal transduction pathways. In addition to these findings, we can add the concept that iron (often viewed as the "villain" in free radical biology) can also be considered as a signalling species. Iron is intimately involved in the regulation of its own storage, compartmentalization and turnover. During adult respiratory distress syndrome (ARDS) and sepsis, such regulation may be aberrant or altered in some predisposed way. Such changes may have profound implications for tissue damage, and for the modulation of the inflammatory response in these patients. The search for a genetic predisposition in patients that leads to the development of ARDS associated with abnormalities in iron turnover and signalling would seem to be an important and logical progression for studies into the disease. These may lead eventually to the design of effective treatment regimens that involve the control of iron.

Adult↗
PubMed2000

Effects of nitric oxide-modulating amino acids on coronary vessels: relevance to sepsis.

Excessive nitric oxide (NO) production in septic shock is thought to contribute to the associated profound hypotension. Here we show that despite induction of NO synthase (NOS) in the hearts of endotoxin-treated rats, coronary vascular responses to the contractile peptide endothelin-1, were not modified. This was not due to any change in the expression of endothelin receptors. However, when the substrate for NOS, L-arginine, was added to the perfusate, increases in coronary perfusion pressure stimulated by endothelin were reduced in hearts from endotoxin-treated animals compared to those from controls. In addition, L-glutamine, which blocks the generation of L-arginine from intracellular stores, enhanced the increase in perfusion pressure stimulated by endothelin-1. These data suggest that L-arginine becomes rate limiting for the production of NO in the coronary vessels during septic shock. Moreover, it suggests that vascular reactivity may be modulated positively or negatively by supplementation with the relevant amino acids.

Animals↗
PubMed2000

Acute renal failure following cardiopulmonary bypass: a changing picture.

OBJECTIVE: To assess the incidence of acute renal failure (ARF) developing perioperatively in adult patients requiring cardiopulmonary bypass surgery (CPB) and to make comparisons with data from the same institution published earlier. DESIGN: Prospective, observational. SETTING: Tertiary referral centre for cardiopulmonary medicine. PATIENTS AND PARTICIPANTS: All patients admitted to the intensive care unit (ICU) who developed ARF perioperatively necessitating continuous veno-venous haemofiltration (CVVH) during the 24 months January 1997-December 1998. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Of 2337 adult patients undergoing cardiac surgery, 47 (2.0%) needed CVVH. Patients were excluded from analysis who underwent cardiac transplantation (n = 4), pericardial surgery (n = 3) or insertion of a left ventricular assist device (n = 1). Of the remaining 39, 21 patients died in ICU (53.8% mortality). Relatively more non-survivors suffered from diabetes, hypertension and preoperative renal dysfunction. A previous report from our Unit revealed that, in 1989-90, 2.7% of all patients undergoing CPB required CVVH with an in-hospital mortality of 83%. The current study population were older (65.3 vs 56.0 years in 1990), and more severely ill as evidenced by a higher percentage of patients requiring redo (30% vs 8.6% in 1990) and emergency (50% vs 25.7% in 1990) surgery. CONCLUSIONS: The need for CVVH following CPB may be diminishing despite increased risk factors. ARF-associated mortality in these circumstances is falling.

Acute Kidney Injury↗
PubMed2000

Acute lung injury and acute respiratory distress syndrome after pulmonary resection.

BACKGROUND: In this study we investigate the frequency and mortality of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after pulmonary resection. METHODS: Patients that underwent pulmonary resection at the Royal Brompton Hospital between 1991 and 1997 were included. The case notes of all patients developing postoperative complications were retrospectively reviewed. RESULTS: The overall combined frequency of ALI and ARDS was 3.9%. The frequency was higher in patients over 60 years of age, males and those undergoing resection for lung cancer. ALI/ARDS caused 72.5% of the total mortality after resection in this series. CONCLUSIONS: In our experience ALI and ARDS are major causes of mortality after lung resection.

Adolescent↗
PubMed2000

The pathogenesis of lung injury following pulmonary resection.

Postpneumonectomy pulmonary oedema (PPO) develops in approximately 5% of patients undergoing pneumonectomy or lobectomy, and has a high associated mortality (>50%). In its extreme form, PPO follows a clinical and histopathological course indistinguishable from acute respiratory distress syndrome. Perioperative fluid overload, impaired lymphatic drainage following node dissection and trauma caused by surgical manipulation have been implicated in the pathogenesis of PPO. However, PPO more probably represents the pulmonary manifestation of a panendothelial injury consequent upon inflammatory processes induced by the surgical procedure, which involves collapse and re-expansion of the operative lung to permit hilar dissection and pulmonary resection. High inspired oxygen concentrations are required to overcome the effects of shunt. Animal studies have shown that pulmonary ischaemia/reperfusion can result in oedema formation, possibly due to the generation of pro-oxidant forces. Moreover, plasma taken from patients undergoing lobectomy or pneumonectomy (but not lesser resections) shows evidence of oxidative damage. Such evidence suggests either that the high inspired oxygen concentrations associated with one-lung ventilation, or ischaemia/reperfusion injury, may modulate post-pneumonectomy pulmonary oedema. Mechanisms by which redox imbalance may result in tissue damage and postpneumonectomy pulmonary oedema are discussed.

Female↗