Progress in ARDS research: a protection racket?
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
T W Evans
Publications and source records attributed to T W Evans.
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↗
Inducible nitric oxide synthase: a tissue-specific affair?
Explore the source record for details and available documents.
Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome.
Activated neutrophils play a major role in the pathogenesis of acute respiratory distress syndrome (ARDS), and persistence of pulmonary neutrophilia is related to poor survival. Interleukin (IL)-8 is implicated in recruiting neutrophils to the lungs but it has been postulated that granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), which can promote the survival of neutrophils by delaying apoptosis, may prolong the inflammatory response. The aim of this study was to investigate the levels of GM-CSF and G-CSF in the lungs of patients with ARDS and determine their relationship relative to IL-8 with levels of neutrophils and clinical outcome. The lungs of 31 patients with ARDS were sampled by means of bronchoalveolar lavage (BAL) and assays of the three cytokines were conducted via enzyme-linked immunosorbent assay. GM-CSF, G-CSF and IL-8 were all increased in the patients compared to healthy controls but concentrations of GM-CSF were much lower than those of G-CSF and IL-8 (GM-CSF<G-CSF<IL-8). Levels of G-CSF and IL-8, but not GM-CSF, correlated strongly with each other (rS=0.86, p<0.001) and with BAL neutrophil counts, and only levels of G-CSF were significantly higher in nonsurvivors than survivors (p<0.05). This evidence indicates that granulocyte colony-stimulating factor as well as interleukin-8 plays a role in the mechanisms of pulmonary neutrophilia in acute respiratory distress syndrome, whereas the role of granulocyte-macrophage colony-stimulating factor remains unclear. The higher levels of granulocyte colony-stimulating factor in nonsurvivors, together with previous reports that recombinant granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor occasionally induce acute lung injury, emphasize that the role of these mediators in pathogenesis needs to be elucidated.
Adolescent↗
Acute respiratory distress syndrome secondary to cardiopulmonary bypass: do compromised plasma iron-binding anti-oxidant protection and thiol levels influence outcome?
OBJECTIVES: Cardiopulmonary bypass (CPB) surgery is often associated with mild lung injury and in some patients leads to acute lung injury and acute respiratory distress syndrome (ARDS). Aberrant plasma iron chemistry (increased iron loading of transferrin and/or the presence of redox-active low molecular mass iron) and increased plasma thiol levels are features of this type of surgery and represent a potential pro-oxidant risk for oxidative damage. Oxidative damage is a feature of ARDS, and we hypothesized that pro-oxidant forces may contribute to the onset and progression of ARDS. DESIGN: Prospective, single center, observational study. SETTING: University-affiliated tertiary referral cardiothoracic center. PATIENTS: A total of 19 patients with ARDS secondary to CPB surgery and 64 patients with ARDS secondary to a variety of other predisposing causes. INTERVENTIONS: Supportive techniques appropriate to the treatment of ARDS. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected into lithium heparin tubes for all patient groups on the first day of the admission of patients to the intensive care unit immediately after the diagnosis of ARDS. Plasma was immediately assayed for thiol content and total protein and albumin levels. Plasma from patients with ARDS secondary to CPB surgery was also assayed for changes in iron chemistry. Nonsurviving patients with ARDS secondary to CPB surgery displayed significantly greater levels of aberrant iron chemistry (elevated levels of iron saturation of transferrin) with decreased iron-binding antioxidant protection and elevated plasma thiol levels than did survivors. Plasma thiol levels in patients with ARDS secondary to other predisposing causes were (with the exception of lung-surgery patients) significantly elevated in survivors compared with those in nonsurvivors of the syndrome. CONCLUSIONS: Increased levels of plasma thiol appear to be associated with mortality in patients with ARDS secondary to CPB surgery.
APACHE↗
Leukocytes in sepsis: do they just keep rolling along?
Explore the source record for details and available documents.
Animals↗
The prostacyclin-mimetic cicaprost inhibits endogenous endothelin-1 release from human pulmonary artery smooth muscle cells.
There is increasing evidence supporting a role for endothelin-1 (ET-1) in human pulmonary hypertension. The aim of this study was to determine the relative roles of human pulmonary microvascular endothelial cells (HPMVE) and human pulmonary artery smooth muscle (HPASM) cells to produce ET-1 under inflammatory conditions and to investigate further possible control mechanisms of ET-1 production by HPASM. Although HPMVE cells produced more ET-1 than HPASM when cultured with fetal calf serum (FCS) alone and after treatment with cytokines; HPASM produced significant amounts of ET-1 after stimulation with cytokines. Cytokine-stimulated increase in ET-1 production by HPASM was inhibited by cicaprost, a prostacyclin analogue, and other agents that are known to increase intracellular cyclic AMP. Cicaprost also inhibited proliferation of HPASM in response to FCS lending support to the theory that part of the clinical benefit seen in long-term treatment with prostacyclin in pulmonary hypertension may be a result of inhibition of ET-1 production in these cells.
Cell Division↗
Measurement of ceruloplasmin in the lungs of patients with acute respiratory distress syndrome: is plasma or local production the major source?
BACKGROUND: Oxidant-induced tissue damage is thought to contribute to the lung injury seen in patients with acute respiratory distress syndrome (ARDS). Ceruloplasmin (CP) is a major circulating antioxidant, increased levels of which have been measured in bronchoalveolar lavage fluid (BALF) taken from such patients. Traditionally, CP detected in these circumstances was thought to be plasma-derived, moving into the alveolar spaces as a consequence of the increased alveolar-capillary permeability that characterises ARDS. However, recent studies in murine models suggest that CP may be synthesised in the airways and even alveoli under physiological conditions. OBJECTIVES: The aims of this investigation were therefore to identify the source of any increased levels of CP detectable in BALF taken from patients with established ARDS. METHODS: Matched BALF and plasma samples taken from patients with ARDS (n = 46) and from controls without lung disease (n = 11) were analysed for CP (132 kD) and plasma specific albumin (ALB, 68 kD) and (alpha(2)-macroglobulin (alpha(2)-M, 820 kD). RESULTS: All three proteins were increased in BALF taken from patients with ARDS compared to controls (p < 0.01, ALB and CP; p < 0.001, alpha(2)-M). When protein levels were expressed as the ratios of BALF: plasma (designated Q), Q(CP) and Q(alpha2)-M increased in parallel to Q(ALB) (p < 0.001), indicating that all increases were primarily plasma-derived. Their relative coefficients of excretion (RCE: Q(CP)/Q(ALB) and Q(alpha2)-M/Q(ALB)) demonstrated that the larger molecular weight protein, alpha(2)-M, gave the best discrimination between patients with ARDS and normal controls (0.85 vs. 0.04; p < 0. 01), indicating that this was the most sensitive marker of alveolar-capillary permeability. CONCLUSIONS: Increased levels of CP in BALF from patients with ARDS are mainly attributable to plasma exudation.
Adult↗
Acute respiratory distress syndrome in adults.
The acute respiratory distress syndrome (ARDS) can arise from a range of predisposing insults. Mortality rates are high for patients with ARDS and survivors require extended and expensive intensive care treatment. This article presents evidence that implicates the production of toxic and damaging reactive oxygen species in the pathogenesis of ARDS.
Adult↗
Haem oxygenase shows pro-oxidant activity in microsomal and cellular systems: implications for the release of low-molecular-mass iron.
Haem oxygenase-1 (HO-1) is a highly inducible stress protein that removes haem from cells with the release of biliverdin, carbon monoxide and low-molecular-mass iron (LMrFe). Several antioxidant functions have been ascribed to HO; its induction is considered to be a protective event. However, LMrFe produced during haem catabolism might elicit a pro-oxidant response, with deleterious consequences. We therefore investigated the delicate balance between pro-oxidant and antioxidant events with the use of a microsomal lipid peroxidation (LPO) system. By using microsomal-bound HO in an NADPH-dependent LPO system, we assessed the pro-oxidant nature of the released LMrFe and the antioxidant effect of the released bilirubin. Hb, a biologically relevant substrate for HO, was included with the microsomes to supplement the source of haem iron and to promote LPO. We found significant increases in microsomal LPO, by using the thiobarbituric acid (TBA) test, after incubation with Hb. This Hb-stimulated peroxidation was inhibited by HO inhibitors and by iron chelators, suggesting a HO-driven, iron-dependent mechanism. GLC-MS was employed to measure the specific LPO product 4-hydroxy-2-nonenal and to confirm our TBA test results. A HO inhibitor attenuated an increase in intracellular LMrFe that occurred after treatment of rat pulmonary artery smooth-muscle cells with Hb. Additionally, exogenously added bilirubin at an equimolar concentration to the LMrFe present in both microsomal and liposomal systems was unable to prevent the pro-oxidant effect of the iron. Under certain circumstances HO can act as a pro-oxidant and seems to have a role in stimulating microsomal LPO.
Animals↗
Legal safeguards for the audit process. Are essential for effective clinical governance.
Explore the source record for details and available documents.
Confidentiality↗
Acute respiratory distress syndrome.
Outcome in acute respiratory distress syndrome (ARDS) is influenced by a number of factors, including the nature of the precipitating condition and the extent to which multiorgan failure ensues. Most studies of potential therapeutic interventions have been unsuccessful due to the enrollment of limited numbers of patients with a wide variety of pathologies of varying severity. Moreover, the value of initiating single-agent interventions at varying time points in what is an evolving and complex inflammatory process must be questioned. Mortality may therefore represent an inappropriate end-point for clinical trials, which are increasingly focusing on ventilator-free days. Despite these uncertainties, survival appears to be improving, possibly due to the application of supportive techniques in a protocol-driven fashion to patients in whom the underlying condition has been rigorously treated.
Clinical Trials as Topic↗