Effects of chronic hypoxia on diaphragm function in deer mice native to high altitude.

AIM: We examined the effects of chronic hypoxia on diaphragm function in high- and low-altitude populations of Peromyscus mice. METHODS: Deer mice (P. maniculatus) native to high altitude and congeneric mice native to low altitude (P. leucopus) were born and raised in captivity to adulthood and were acclimated to normoxia or hypobaric hypoxia (12 or 9 kPa, simulating hypoxia at 4300 and 7000 m) for 6-8 weeks. We then measured indices of mitochondrial respiration capacity, force production, and fatigue resistance in the diaphragm. RESULTS: Mitochondrial respiratory capacities (assessed using permeabilized fibres with single or multiple inputs to the electron transport system), citrate synthase activity (a marker of mitochondrial volume), twitch force production, and muscle fatigue resistance increased after exposure to chronic hypoxia in both populations. These changes were not well explained by variation in the fibre-type composition of the muscle. However, there were several differences in diaphragm function in high-altitude mice compared to low-altitude mice. Exposure to a deeper level of hypoxia (9 kPa vs 12 kPa) was needed to elicit increases in mitochondrial respiration rates in highlanders. Chronic hypoxia did not increase the emission of reactive oxygen species from permeabilized fibres in highlanders, in contrast to the pronounced increases that occurred in lowlanders. In general, the diaphragm of high-altitude mice had greater capillary length densities, produced less force in response to stimulation and had shorter relaxation times. The latter was associated with higher activity of sarcoplasmic reticulum Ca2+ -ATPase (SERCA) activity in the diaphragm of high-altitude mice. CONCLUSION: Overall, our work suggests that exposure to chronic hypoxia increases the capacities for mitochondrial respiration, force production and fatigue resistance of the diaphragm. However, many of these effects are opposed by evolved changes in diaphragm function in high-altitude natives, such that highlanders in chronic hypoxia maintain similar diaphragm function to lowlanders in sea level conditions.

Attitudes of physicians and public to pharmaceutical industry 'gifts'.

BACKGROUND: Few studies have reported the attitudes of both individual doctors and members of the public toward the appropriateness of 'gifts' from pharmaceutical companies. AIMS: To investigate the attitudes of both doctors and members of the public toward the appropriateness of receiving particular 'gifts' from pharmaceutical companies, and to consider whether public acceptability is a suitable criterion for determining the ethical appropriateness of 'gifts'. METHODS: A survey questionnaire of medical specialists in Australia and a survey questionnaire of members of the public itemized 23 'gifts' (valued between AU$10 and AU$2500) and asked whether or not each was appropriate. RESULTS: Both medical specialists and members of the public believe certain 'gifts' from pharmaceutical companies are appropriate but not others. There was a tendency for members of the public to be more permissive than medical specialists. CONCLUSION: Although some professional guidelines place importance on the attitudes of the general public to 'gift' giving, and other guidelines give importance to a need for transparency and public accountability, we question whether public acceptability is a suitable criterion for determining the ethical appropriateness of 'gifts'. We suggest that more weight be given to the need for independence of clinical decision making, with empirical evidence indicating that even small 'gifts' can bias clinicians' judgments, and to important values such as the primacy of patient welfare, autonomy and social justice. We conclude that it is time to eliminate giving and receiving of promotional items between the pharmaceutical industry and members of health professions.

Mediastinal hibernoma simulates a malignant lesion on dual time point FDG imaging.

Dual time point 2-deoxy-2-[18F] fluoro-d-glucose (FDG) positron emission tomography (PET) imaging has been shown to be useful in helping differentiate benign from malignant lesions. An enhancing mediastinal mass of fat and water density was incidentally detected on computed tomography (CT) in a patient being evaluated for thoracic trauma. He subsequently underwent dual time point FDG PET/CT imaging which revealed a significant rise in standard uptake value (SUV) within the lesion over time, favoring a malignant etiology. Biopsy proved the lesion to represent a hibernoma, an uncommon benign fatty tumor. This case exemplifies the complexity of tissue metabolic properties, and the difficulty in establishing absolute criteria for benign and malignant processes.

Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery and previous reviews have found them to be effective in reducing blood loss and the need for transfusion. Recently, questions have been raised regarding the comparative performance of the drugs and the safety of the most popular agent, aprotinin. OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and the internet. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2006. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: This review summarises data from 211 RCTs that recruited 20,781 participants. Data from placebo/inactive controlled trials, and from head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of operative blood loss, but the differences were small. Aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.61 to 0.71). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.54 to 0.69) and it was 0.75 (95% CI 0.58 to 0.96) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared superior in reducing the need for RBC transfusion: RR 0.83 (95% CI 0.69 to 0.99). Aprotinin reduced the need for re-operation due to bleeding: RR 0.48 (95% CI 0.35 to 0.68). This translates into an absolute risk reduction of just under 3% and a number needed-to-treat (NNT) of 37 (95% CI 27 to 56). Similar trends were seen with TXA and EACA, but the data were sparse and the differences failed to reach statistical significance. The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias. Evidence of publication bias was not observed in trials reporting re-operation rates. Adjustment for these effects reduced the magnitude of estimated benefits but did not negate treatment effects. However, the apparent advantage of aprotinin over the lysine analogues was small and may be explained by publication bias and non-equivalent drug doses. Aprotinin did not increase the risk of myocardial infarction (RR 0.92, 95% CI 0.72 to 1.18), stroke (RR 0.76, 95% CI 0.35 to 1.64) renal dysfunction (RR 1.16, 95% CI 0.79 to 1.70) or overall mortality (RR 0.90, 95% CI 0.67 to 1.20). The analyses of myocardial infarction and death included data from the majority of subjects recruited into the clinical trials of aprotinin. However, under-reporting of renal events could explain the lack of effect seen with aprotinin. Similar trends were seen with the lysine analogues but data were sparse. These results conflict with the results of recently published non-randomised studies. AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the need for allogeneic red cell transfusion. Based on the results of randomised trials their efficacy does not appear to be offset by serious adverse effects. In most circumstances the lysine analogues are probably as effective as aprotinin and are cheaper; the evidence is stronger for tranexamic acid than for aminocaproic acid. In high risk cardiac surgery, where there is a substantial probability of serious blood loss, aprotinin may be preferred over tranexamic acid. Aprotinin does not appear to be associated with an increased risk of vascular occlusion and death, but the data do not exclude an increased risk of renal failure. There is no need for further placebo-controlled trials of aprotinin or lysine analogues in cardiac surgery. The principal need is for large comparative trials to assess the relative efficacy, safety and cost-effectiveness of anti-fibrinolytic drugs in different surgical procedures.

Cell salvage for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood, have prompted reconsideration of the use of allogeneic (blood from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Current Contents and the websites of international health technology assessment agencies. The reference lists in identified trials and review articles were also searched, and study authors were contacted to identify additional studies. The searches were updated in January 2004. SELECTION CRITERIA: Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage, or to a control group, who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, extracted data and assessed methodological quality. The main outcomes measures were the number of patients exposed to allogeneic red cell transfusion, and the amount of blood transfused. Other outcomes measured were re-operation for bleeding, blood loss, post-operative complications (thrombosis, infection, non-fatal myocardial infarction, renal failure), mortality, and length of hospital stay (LOS). MAIN RESULTS: Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 39% (relative risk [RR] = 0.61: 95% confidence interval [CI] 0.52 to 0.71). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 23% (95% CI 16% to 30%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.42 (95% CI 0.32 to 0.54) compared to 0.77 (95% CI 0.68 to 0.87) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.67 units of allogeneic RBC per patient (weighted mean difference was -0.64; 95% CI -0.89 to -0.45). Cell salvage did not appear to impact adversely on clinical outcomes. AUTHORS' CONCLUSIONS: The results suggest cell salvage is efficacious in reducing the need for allogeneic red cell transfusion in adult elective surgery. However, the methodological quality of trials was poor. As the trials were unblinded and lacked adequate concealment of treatment allocation, transfusion practices may have been influenced by knowledge of the patients' treatment status biasing the results in favour of cell salvage.

Giving and receiving of gifts between pharmaceutical companies and medical specialists in Australia.

BACKGROUND: This study investigated the 'gift-relationship' between pharmaceutical companies and doctors. METHODS: The study was based on a survey questionnaire of 823 medical specialists from across Australia. The aim of this study was to investigate gifts offered to medical specialists in Australia by pharmaceutical companies, financial support actively sought by medical specialists for activities other than research and to consider what is ethically appropriate. RESULTS: A high percentage of specialists received offers of food (96%), items for the office (94%), personal gifts (51%) and journals or textbooks (50%). Most specialists were invited to product launches, symposia or educational events (75-84%) and 52% received offers of travel to conferences. A high proportion of offers were accepted (66-79%) except invitations to product launches (49%), sponsored symposia (53%) and offers of travel that included partners (27%). Fifteen per cent of specialists requested financial support from pharmaceutical companies for activities and items, including conferences, travel, educational activities, salaries and donations to specific funds. The study outlined guidelines on gifts from pharmaceutical companies and differing standards applying to gifts and grants for travel. We found that, although most gifts and requests for support complied with professional and pharmaceutical industry guidelines, some--including personal gifts, tickets to sporting events, entertainment and travel expenses for specialists' partners--did not. CONCLUSION: To ensure that physicians' judgements are free from real or perceived influence from industry and to maintain public trust, we support a shift towards more conservative standards on gifts and support for travel evident in recent guidelines.

Systematic review and meta-analysis of the use of fibrin sealant to prevent seroma formation after breast cancer surgery.

BACKGROUND: The use of fibrin sealant has been proposed as a means of preventing seroma formation following breast cancer surgery. Conflicting trial results require the efficacy of fibrin sealant to be reviewed critically. METHODS: A systematic review of randomized controlled trials was conducted to examine the efficacy of fibrin sealants in reducing postoperative drainage and seroma formation after breast cancer surgery. Studies were identified by computer searches of Medline, Embase, the Cochrane Central Register of Controlled Trials and manufacturer websites (to June 2005), and bibliographic searches of published articles. Trials were eligible for inclusion if they reported data on postoperative drainage and the number of patients who developed a seroma. RESULTS: Eleven trials met the criteria for inclusion. Generally, the trials were small and of poor methodological quality. Fibrin sealant did not reduce the rate of postoperative seroma (relative risk 1.14, 95 per cent confidence interval (c.i.) 0.88 to 1.46), the volume of drainage (weighted mean difference - 117.7, 95 per cent c.i. - 259.2 to 23.8 ml), or the length of hospital stay (weighted mean difference - 0.38, 95 per cent c.i. - 1.58 to 0.83 days). CONCLUSIONS: The current evidence does not support the use of fibrin sealant in breast cancer surgery to reduce postoperative drainage or seroma formation.

Blood transfusion and autologous donation: a survey of post-surgical patients, interest group members and the public.

Before planned surgery, patients may choose autologous donation in order to avoid the small, but potential, risks of receiving an allogeneic blood transfusion. This study examined the perceived risks of allogeneic blood transfusions, preferences and willingness to pay for autologous donation and the desired role in the decision-making process in three populations: post-surgical patients, special interest group members and the general public. Quantitative and qualitative data were collected from 206 respondents with the help of computer-assisted semi-structured telephone interviews. Thirty-three per cent of the sample voiced concerns about receiving allogeneic blood transfusions. The risks of hepatitis C virus, human immunodeficiency virus, variant Creutzfeldt-Jakob disease and a haemolytic reaction were perceived as being low, but were rated as numerically higher than those of other life events that have equal probability. Autologous donation was perceived as removing all the risks associated with transfusion, and respondents were willing to pay a median $976 AUD ($664 US) to use this technique. Over 80% of respondents preferred to be involved in making the decision about whether to use autologous donation. Even though autologous donation is not 'risk-free' and the blood supply is very safe, people overestimate the associated risks and have a preference for their own blood. Decision aids presenting balanced information on the advantages and disadvantages of both allogeneic and autologous blood may be required.

The implausibility of leukemia induction by formaldehyde: a critical review of the biological evidence on distant-site toxicity.

Formaldehyde is a naturally occurring biological compound that is present in tissues, cells, and bodily fluids. It is also a potent nasal irritant, a cytotoxicant at high doses, and a nasal carcinogen in rats exposed to high airborne concentrations. The normal endogenous concentration of formaldehyde in the blood is approximately 0.1 mM in rats, monkeys, and humans, and it is 2- to 4-fold higher in the liver and nasal mucosa of the rat. Inhaled formaldehyde enters the one-carbon pool, and the carbon atom is rapidly incorporated into macromolecules throughout the body. Oxidation to formate catalyzed by glutathione-dependent and -independent dehydrogenases in nasal tissues is a major route of detoxication and generally precedes incorporation. The possibility that inhaled formaldehyde might induce various forms of distant-site toxicity has been proposed, but no convincing evidence for such toxicity has been obtained in experimental studies. This review summarizes the biological evidence that pertains to the issue of leukemia induction by formaldehyde, which includes: (1) the failure of inhaled formaldehyde to increase the formaldehyde concentration in the blood of rats, monkeys, or humans exposed to concentrations of 14.4, 6, or 1.9 ppm, respectively; (2) the lack of detectable protein adducts or DNA-protein cross-links (DPX) in the bone marrow of normal rats exposed to [3H]- and [14C]formaldehyde at concentrations as high as 15 ppm; (3) the lack of detectable protein adducts or DPX in the bone marrow of glutathione-depleted (metabolically inhibited) rats exposed to [3H]- and [14C]formaldehyde at concentrations as high as 10 ppm; (4) the lack of detectable DPX in the bone marrow of Rhesus monkeys exposed to [14C]formaldehyde at concentrations as high as 6 ppm; (5) the failure of formaldehyde to induce leukemia in any of seven long-term inhalation bioassays in rats, mice, or hamsters; and (6) the failure of formaldehyde to induce chromosomal aberrations in the bone marrow of rats exposed to airborne concentrations as high as 15 ppm or of mice injected intraperitoneally with formaldehyde at doses as high as 25 mg/kg. Biological evidence that might be regarded as supporting the possibility of leukemia induction by formaldehyde includes: (1) the detection of cytogenetic abnormalities in circulating lymphocytes in seven studies of human subjects exposed to ambient concentrations in the workplace (but not in seven other studies of human subjects or in rats exposed to 15 ppm); (2) the induction of leukemia in rats in a single questionable drinking water study with formaldehyde concentrations as high as 1.5 g/L (but not in three other drinking water studies with concentrations as high as 1.9 or 5 g/L); (3) the detection of chromosomal aberrations in the bone marrow of rats exposed to very low concentrations of formaldehyde (0.4 or 1.2 ppm) (but not in another study at concentrations as high as 15 ppm); and (4) an apparent increase in the fraction of protein-associated DNA (assumed to be due to DPX) in circulating lymphocytes of humans exposed to ambient concentrations in the workplace (1-3 ppm). This evidence is regarded as inconsequential for several reasons, including lack of reproducibility, inadequate reporting of experimental methods, inconsistency with other data, or insufficient analytical sensitivity, and therefore, it provides little justification for or against the possibility that inhaled formaldehyde may be a leukemogen. In contrast to these inconclusive findings, the abundance of negative evidence mentioned above is undisputed and strongly suggests that there is no delivery of inhaled formaldehyde to distant sites. Combined with the fact that formaldehyde naturally occurs throughout the body, and that multiple inhalation bioassays have not induced leukemia in animals, the negative findings provide convincing evidence that formaldehyde is not leukemogenic.

Desmopressin for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Public concerns regarding the safety of transfused blood have prompted re-consideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and of a range of techniques designed to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of desmopressin acetate (1-deamino-8-D-arginine-vasopressin; DDAVP), in reducing perioperative blood loss and the need for red cell transfusion in patients who do not have congenital bleeding disorders. SEARCH STRATEGY: Articles were identified by: computer searches of MEDLINE, EMBASE, Current Contents (to May 2003), and the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 1, 2003). References in the identified trials and review articles were searched and authors contacted to identify additional studies. SELECTION CRITERIA: Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to DDAVP, or to a control group, who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Trial quality was assessed using criteria proposed by Schulz et al. (Schulz 1995) and Jadad et al. (Jadad 1996). Main outcomes measured were: the number of patients exposed to allogeneic red cell transfusion, and the amount of blood transfused. Other outcomes measured were: re-operation for bleeding, blood loss, post-operative complications (thrombosis, infection, non-fatal myocardial infarction), mortality, and length of hospital stay (LOS). MAIN RESULTS: Eighteen trials of DDAVP (n=1295) reported data on the number of patients transfused with allogeneic RBC transfusion. In subjects treated with DDAVP, the pooled relative risk of exposure to perioperative allogeneic RBC transfusion was 0.95 (95%CI = 0.86 to 1.06). The use of DDAVP did not significantly reduce blood loss; weighted mean difference (WMD) = -114.3ml: 95% confidence interval (95%CI) = -258.8 to 30.2ml per patient) or the volume of RBC transfused (WMD = -0.35 units: 95%CI = -0.70 to 0.01 units). In DDAVP-treated patients the relative risk of requiring re-operation due to bleeding was 0.69 (95%CI = 0.26 to 1.83). There was no statistically significant effect overall for mortality and non-fatal myocardial infarction in DDAVP-treated patients compared with control (RR = 1.72: 95%CI = 0.68 to 4.33) and (RR = 1.38: 95%CI = 0.77 to 2.50) respectively. REVIEWER'S CONCLUSIONS: There is no convincing evidence that desmopressin minimises perioperative allogeneic RBC transfusion in patients who do not have congenital bleeding disorders. These data suggest that there is no benefit from using DDAVP as a means of minimising perioperative allogeneic RBC transfusion.

Cell salvage for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood, have prompted reconsideration of the use of allogeneic (blood from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. SEARCH STRATEGY: Articles were identified by: computer searches of MEDLINE, EMBASE, Current Contents (to July 2002), the Cochrane Controlled Trials Register (Issue 2, 2002) and websites of international health technology assessment agencies. References in the identified trials and review articles were searched and authors contacted to identify additional studies. SELECTION CRITERIA: Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage, or to a control group, who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Trial quality was assessed using criteria proposed by Schulz et al. (Schulz 1995) and Jadad et al. (Jadad 1996). Main outcomes measured were: the number of patients exposed to allogeneic red cell transfusion, and the amount of blood transfused. Other outcomes measured were: re-operation for bleeding, blood loss, post-operative complications (thrombosis, infection, non-fatal myocardial infarction, renal failure), mortality, and length of hospital stay (LOS). MAIN RESULTS: Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 40% (relative risk [RR] = 0.60: 95% confidence interval [CI] = 0.51 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 23% (95%CI = 16% to 30%). In orthopaedic procedures the relative risk (RR) of exposure to RBC transfusion was 0.42 (95%CI = 0.32 to 0.54) compared to 0.78 (95%CI = 0.68 to 0.88) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.64 units of allogeneic RBC per patient (weighted mean difference [WMD] = -0.64: 95%CI = -0.86 to -0.46). Cell salvage did not appear to impact adversely on clinical outcomes. REVIEWER'S CONCLUSIONS: The results suggest cell salvage is efficacious in reducing the need for allogeneic red cell transfusion in adult elective surgery. However, the methodological quality of trials was poor. As the trials were unblinded and lacked adequate concealment of treatment allocation, transfusion practices may have been influenced by knowledge of the patient's treatment status biasing the results in favour of cell salvage.

Fibrin sealant use for minimising peri-operative allogeneic blood transfusion.

BACKGROUND: Fibrin sealants have gained increasing popularity as interventions to improve peri-operative (intra/post-operative) haemostasis and diminish the need for allogeneic red cell transfusion (blood from an unrelated donor). OBJECTIVES: To examine the efficacy of fibrin sealants in reducing peri-operative blood loss and allogeneic red blood cell (RBC) transfusion. SEARCH STRATEGY: Studies were identified by: searches of MEDLINE, EMBASE, Current Contents, the Cochrane Library (July 2002), manufacturer web sites (to July 2002), and bibliographies of published articles. SELECTION CRITERIA: Controlled trials in which adult patients, scheduled for elective surgery, were randomised to fibrin sealant treatment or to a control group who did not receive fibrin sealant treatment. Trials were eligible if they reported data on the number of patients exposed to allogeneic red cell transfusion, the volume of blood transfused, or blood loss (assessed objectively). DATA COLLECTION AND ANALYSIS: Primary outcomes measured were: the number of patients exposed to allogeneic red cells, the amount of blood transfused, and blood loss. Other outcomes measured were: re-operation due to bleeding, infection, mortality, and length of hospital stay. Treatment effects were pooled using a random effects model. MAIN RESULTS: Seven trials, including a total of 388 patients, reported data on peri-operative exposure to allogeneic RBC transfusion. Fibrin sealant treatment, on average, reduced the rate of exposure to allogeneic red cell transfusion by a relative 54% (relative risk [RR] = 0.46: 95%CI = 0.32 to 0.68). Eight trials, including a total of 442 patients, provided data for post-operative blood loss. Fibrin sealant treatment reduced blood loss on average by around 134 per patient (95%CI = 51 to 217 ). However the trials reviewed were small and of poor methodological quality (91% unblinded). REVIEWER'S CONCLUSIONS: Overall the results suggest that fibrin sealants are efficacious in reducing both post-operative blood loss and peri-operative exposure to allogeneic RBC transfusion. However, due to the lack of blinding, transfusion practices may have been influenced by knowledge of the patient's treatment status. This raises concerns about the use of blood transfusion practice as an outcome variable in trials of fibrin sealant. In the case of blood loss, the results must be interpreted with caution, in view of the statistically significant heterogeneity in treatment effect observed. Large, methodologically rigorous, randomised controlled trials of fibrin sealants are needed.

Platelet-rich-plasmapheresis for minimising peri-operative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have generated considerable enthusiasm for the use of technologies intended to reduce the use of allogeneic blood (blood from an unrelated donor). Platelet-rich plasmapheresis (PRP) offers an alternative approach to blood conservation. OBJECTIVES: To examine the evidence for the efficacy of PRP in reducing peri-operative allogeneic red blood cell (RBC) transfusion, and the evidence for any effect on clinical outcomes such as mortality and re-operation rates. SEARCH STRATEGY: Studies were identified by: computer searches of MEDLINE, EMBASE, Current Contents, and the Cochrane Library (to June 2001). These searches were supplemented by checking the reference lists of published articles, reports, and reviews. SELECTION CRITERIA: Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to PRP, or to a control group who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Main outcomes measured were: the number of patients receiving an allogeneic RBC transfusion, and the amount of RBC transfused. Trial quality was assessed using criteria proposed by Schulz et al. (Schulz 1995) and Jadad et al. (Jadad 1996). MAIN RESULTS: Nineteen trials of PRP were identified that reported data for the number of patients exposed to allogeneic RBC transfusion. These trials evaluated a total of 1452 patients. The pooled relative risk (RR) of exposure to allogeneic blood transfusion in those patients randomised to PRP was 0.71 (95%CI: 0.56, 0.90), equating to a relative risk reduction (RRR) of 29%; the average absolute risk reduction (ARR) was 19% (RD = -0.19: 95%CI: -0.29, -0.09). On average, PRP did not significantly reduce the total volume of RBC transfused (weighted mean difference [WMD] = -0.69: 95%CI: -1.93, 0.56 units). Substantial statistical heterogeneity was observed (p < 0.001). Trials provided inadequate data regarding the impact of PRP on morbidity, mortality, and hospital length of stay. The majority of trials were small and of poor methodological quality. REVIEWER'S CONCLUSIONS: Although the results suggest that PRP is effective in reducing allogeneic RBC transfusion in adult patients undergoing elective surgery, there was considerable heterogeneity in treatment effects and the trials were of poor methodological quality. As the majority of trials were unblinded, transfusion practices may have been influenced by knowledge of the patient's allocation status, potentially exaggerating the true magnitude of the beneficial effect of PRP. The available studies provided inadequate data for firm conclusions to be drawn regarding the impact of PRP on clinically important endpoints.

Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.

BACKGROUND: Most clinical practice guidelines recommend restrictive red cell transfusion practices with the goal of minimising exposure to allogeneic blood (from an unrelated donor). The purpose of this review is to compare clinical outcomes in patients randomised to restrictive versus liberal transfusion thresholds (triggers). OBJECTIVES: To examine the evidence on the effect of transfusion thresholds, on the use of allogeneic and/or autologous blood, and the evidence for any effect on clinical outcomes. SEARCH STRATEGY: Trials were identified by: computer searches of OVID Medline (1966 to December 2000), Current Contents (1993 to Week 48 2000), and the Cochrane Controlled Trials Register (2000 Issue 4). References in identified trials and review articles were checked and authors contacted to identify any additional studies. SELECTION CRITERIA: Controlled trials in which patients were randomised to an intervention group or to a control group. Trials were included where the intervention groups were assigned on the basis of a clear transfusion "trigger", described as a haemoglobin (Hb) or haematocrit (Hct) level below which a RBC transfusion was to be administered. DATA COLLECTION AND ANALYSIS: Trial quality was assessed using criteria proposed by Schulz et al. (1995). Relative risks of requiring allogeneic blood transfusion, transfused blood volumes and other clinical outcomes were pooled across trials using a random effects model. MAIN RESULTS: Ten trials were identified that reported outcomes for a total of 1780 patients. Restrictive transfusion strategies reduced the risk of receiving a red blood cell (RBC) transfusion by a relative 42% (RR=0.58: 95%CI=0.47,0.71). This equates to an average absolute risk reduction (ARR) of 40% (95%CI=24% to 56%). The volume of RBCs transfused was reduced on average by 0.93 units (95%CI=0.36,1.5 units). However, heterogeneity between these trials was statistically significant (p<0.00001) for these outcomes. Mortality, rates of cardiac events, morbidity, and length of hospital stay were unaffected. Trials were of poor methodological quality. REVIEWER'S CONCLUSIONS: The limited published evidence supports the use of restrictive transfusion triggers in patients who are free of serious cardiac disease. However, most of the data on clinical outcomes were generated by a single trial. The effects of conservative transfusion triggers on functional status, morbidity and mortality, particularly in patients with cardiac disease, need to be tested in further large clinical trials. In countries with inadequate screening of donor blood the data may constitute a stronger basis for avoiding transfusion with allogeneic red cells.

Pre-operative autologous donation for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Public concerns regarding the safety of transfused blood have prompted re-consideration of the indications for the transfusion of allogeneic red cells (blood from an unrelated donor), and a range of techniques designed to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of pre-operative autologous blood donation (PAD) in reducing the need for peri-operative allogeneic red blood cell (RBC) transfusion. SEARCH STRATEGY: Articles were identified by: computer searches of OVID MEDLINE, EMBASE, and Current Contents (to March 2001) and web sites of international health technology assessment agencies (to January 2001). References in the identified trials were checked and authors contacted to identify additional studies. SELECTION CRITERIA: Randomised controlled trials with a concurrent control group in which adult patients, scheduled for non-urgent surgery, were randomised to PAD, or to a control group who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Trial quality was assessed using criteria proposed by Schulz et al (1995) and Jadad et al (1996). The principle outcomes were: the number of patients exposed to allogeneic red blood cells, and the amount of blood transfused. Other clinical outcomes are detailed in the review. MAIN RESULTS: Overall PAD reduced the risk of receiving an allogeneic blood transfusion by a relative 63% (RR=0.37: 95%CI:0.26,0.54). The absolute reduction in risk of allogeneic transfusion was 43.8% (RD=-0.438: 95%CI: -0.607,-0.268). In contrast the results show that the risk of receiving any blood transfusion (allogeneic and/or autologous) is actually increased by pre-operative autologous blood donation (RR=1.29: 95%CI: 1.12,1.48). Trials were unblinded and allocation concealment was not described in 87.5% of the trials. REVIEWER'S CONCLUSIONS: Although the trials of PAD showed a reduction in the need for allogeneic blood the methodological quality of the trials was poor and the overall transfusion rates (allogeneic and/or autologous) in these trials were high, and were increased by recruitment into the PAD arms of the trials. This raises questions about the true benefit of PAD. In the absence of large, high quality trials using clinical endpoints, it is not possible to say whether the benefits of PAD outweigh the harms.

Systematic review of the use of fibrin sealant to minimize perioperative allogeneic blood transfusion.

BACKGROUND: Fibrin sealants have become popular in improving perioperative haemostasis and reducing the need for allogeneic red cell transfusion. METHODS: A systematic review of randomized controlled trials was conducted to examine the efficacy of fibrin sealants in reducing perioperative blood loss and allogeneic red blood cell transfusion. Studies were identified by computer searches of Medline, Embase, Current Contents, the Cochrane Library, manufacturer websites (to January 2001), and bibliographic searches of published articles. Trials were eligible for inclusion if they involved adult elective surgery and reported quantitative data on blood loss, the proportion of patients exposed to allogeneic red cell transfusion and/or the volume of blood transfused. RESULTS: Twelve trials met the criteria for inclusion. Fibrin sealants reduced the rate of allogeneic blood transfusion (relative risk 0.40 (95 per cent confidence interval (c.i.) 0.26 to 0.61); five trials with 275 subjects) and reduced blood loss (weighted mean difference--151.68 (95 per cent c.i. - 251.91 to - 51.46) ml; seven trials with 391 subjects). Generally, the trials were small and of poor methodological quality. CONCLUSION: Overall the results suggest that fibrin sealants are efficacious. Owing to lack of blinding, transfusion practices may have been influenced by knowledge of the patient's treatment status. This raises concern about blood transfusion practice as a response variable. Large methodologically rigorous trials of fibrin sealants with clinical outcomes are needed.

Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor.

Humans and wildlife are frequently exposed to mixtures of endocrine active-compounds (EAC). The objective of the present study was to investigate the potential of the phytoestrogen genistein to influence the reproductive developmental toxicity of the endocrine-active pesticide methoxychlor. Three levels of genistein (0, 300, or 800 ppm) and two levels of methoxychlor (0 or 800 ppm) were used in this study. Sprague-Dawley rats were exposed to the two compounds, either alone or in combinations, through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning. Both compounds, methoxychlor in particular, were associated with reduced body growth at 800 ppm, but pregnancy outcome was not affected by either treatment. An acceleration of vaginal opening (VO) in the exposed female offspring was the only observed effect of genistein at 300 ppm. Exposure to 800 ppm genistein or 800 ppm methoxychlor caused accelerated VO and also altered estrous cyclicity toward persistent estrus in the female offspring. The estrogenic responses to genistein and methoxychlor administered together were apparently accumulative of the effects associated with each compound alone. Methoxychlor, but not genistein, delayed preputial separation (PPS) in the male rats. When administered with methoxychlor, genistein at 800 ppm enhanced the effect of methoxychlor on delaying PPS. Genistein and methoxychlor treatment did not change gender-specific motor activity patterns in either sex. To explore possible mechanisms for interaction between the two compounds on development, we performed estrogen receptor (ER)- and androgen receptor (AR)-based in vitro transcriptional activation assays using genistein and the primary methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). While the in vitro assays supported the estrogenic effects of genistein and methoxychlor and the antiandrogenic effects of methoxychlor, the reactivity of these compounds with ERs alpha and beta could not predict the greater in vivo estrogenic potency of methoxychlor over genistein; nor could the potentiation of the methoxychlor effect on PPS by genistein be predicted based on in vitro HPTE and genistein reactions with the AR. Data from this study indicate that phytoestrogens are capable of altering the toxicological behaviors of other EACs, and the interactions of these compounds may involve complexities that are difficult to predict based on their in vitro steroid receptor reactivities.

Emergence of penicillin-nonsusceptible Streptococcus pneumoniae invasive clones in Canada.

Distinctive international clones of penicillin-nonsusceptible and multidrug-resistant Streptococcus pneumoniae are increasingly being reported. We investigated the spread of these clones in Canada through an active surveillance that was carried out at 11 Canadian pediatric tertiary care centers from 1991 to 1998. All penicillin-nonsusceptible isolates were serotyped, tested for antibiotic susceptibility, and genotyped by pulsed-field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD). Forty-five penicillin-nonsusceptible S. pneumoniae isolates were evaluated. Eleven serotype 9V isolates and six serotype 14 isolates displayed identical RAPD and PFGE fingerprint profiles. Twelve (70%) of these isolates were encountered in Quebec. The 9V/14 clone and the Spanish-French clone had similar PFGE fingerprint patterns. Eight isolates of serotype 23F and two isolates of serogroup 14 had the same fingerprint profiles and displayed resistance to three or more antibiotic drug classes. This clone was first detected in Calgary (Alberta) and in 1996 appeared simultaneously in various regions of Canada. This clone showed a PFGE fingerprint pattern similar to that of the Spanish-U.S. 23F clone. Our data show the emergence across Canada of two international clones of penicillin-nonsusceptible S. pneumoniae: (i) serotypes 9V and 14 related to the Spanish-French clone and (ii) the 23F Spanish-U.S. clone. The source of the first clone was in Quebec and the second international clone was probably originated from the United States. The exact reasons for the successful spread of these clones within Canada and their contribution to increased resistance to antibiotics have yet to be explored.

The impact of specialists on prescribing by general practitioners.

OBJECTIVE: To investigate the direct impact of specialists on prescribing by general practitioners. DESIGN: Cross-sectional, prescription-based study. SUBJECTS AND SETTING: 88 GPs in the Hunter Urban Division of General Practice, Hunter Valley, NSW. MAIN OUTCOME MEASURE: Proportions of specialist-initiated prescriptions for eight commonly prescribed drug classes. RESULTS: The proportion of specialist-initiated prescriptions was greatest for proton pump inhibitors (85%), and lowest for diuretics (8%), newer antidepressants (10%) and H2-receptor antagonists (13%). Specialists initiated 29% of prescriptions for beta-blockers, 26% for calcium-channel blockers, 20% for statins and 19% for angiotensin-converting enzyme inhibitors or angiotensin II antagonists. Specialists were more likely to have been involved in starting therapy with metoprolol than other beta-blockers (51% v 23%) and diltiazem than other calcium-channel blockers (48% v 19%), and this was related to indication for treatment. In contrast, prescriptions for the more recently introduced drugs (angiotensin II antagonists and atorvastatin) were not more likely to have been specialist-initiated than prescriptions for established angiotensin-converting enzyme inhibitors and statins. CONCLUSIONS: The direct impact of specialists on prescribing in the Hunter Urban Division of General Practice is substantial and varies with the drug class. This highlights the need to engage both GPs and specialists in efforts to improve prescribing practices.