Search

Cytochromes P450, a family of heme-containing monooxygenases that catalyze a diverse range of oxidative reactions, are so-called due to their maximum absorbance at 450nm, ie, "Pigment-450nm," when bound to carbon monoxide. They have appeal both academically and commercially due to their high degree of regio- and stereoselectivity, for example, in the area of active pharmaceutical ingredient synthesis. Despite this potential, they often exhibit poor stability, low turnover numbers and typically require electron transport protein(s) for catalysis. P450 systems exist in a variety of functional domain architectures, organized into 10 classes. P450s are also divided into families, each of which is based solely on amino acid sequence homology. Their catalytic mechanism employs a very complex, multistep catalytic cycle involving a range of transient intermediates. Mutagenesis is a powerful tool for the development of improved biocatalysts and has been used extensively with the archetypal Class VIII P450, BM3, from Bacillus megaterium, but with the increasing scale of genomic sequencing, a huge resource is now available for the discovery of novel P450s., (© 2016 Elsevier Inc. All rights reserved.)

We performed a pilot study in which 22 kidney recipients (14 LD: 8 DCD) were given alemtuzumab induction (30 mg day 0 and 1), steroids (500 mg mp day 0 and 1, none thereafter), mycophenolate mofetil (MMF) maintenance (500 mg b.i.d) and sirolimus (concentration controlled 8-12 ng/mL). With a mean follow-up of 15.9 months, patient survival is (21/22) 96% and graft survival (19/22) 87%. Acute rejections occurred in (8) 36.3% (two humoral). Of 19 surviving grafts, 18 (95%) remain steroid and 15 (79%) CNI-free. At 1 year, mean creatinine was 1.43 mg/dL. Overall infection rates were low, but 2 patients developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, respectively, resulting in mortality in one and a graft loss in the other. No cancer or PTLD was observed. Leukopenia was common and MMF dose was reduced or eliminated in 6/22 (27%) patients. The reported higher than expected rate of acute rejection, leukopenia and possible pulmonary toxicity suggests excessive morbidity. Modifications such as an initial period of CNI use should be considered.

Safety initiatives in hospitals should focus on common health care interventions that when used appropriately can improve important health outcomes, and when used inappropriately or not at all, result in substantial harm. We suggest that errors of omission should be a safety priority. We focus on preventive health care interventions, and describe five steps that can improve patients' safety by changing clinician behaviour. The steps are to: do an environmental scan; understand current behaviour, target behaviour for change (why, what, when, where, and who); adopt effective strategies to change behaviour; and synergise.

Background: Resuscitation directives should be a sign of patient's preference. Our objective was to ascertain prevalence, predictors, and procurement pattern of cardiopulmonary resuscitation directives within 24 h of admission to the intensive-care unit (ICU)., Methods: We enrolled 2916 patients aged 18 years and older from 15 ICUs in four countries, and recorded whether, when, and by whom their cardiopulmonary resuscitation directives were established. By polychotomous logistic regression we identified factors associated with a resuscitate or do-not-resuscitate directive., Findings: Of 2916 patients, 318 (11%; 95% CI 9.8-12.1) had an explicit resuscitation directive. In 159 (50%; 44.4-55.6) patients, the directive was do-not-resuscitate. Directives were established by residents for 145 (46%; 40.0-51.3) patients. Age strongly predicted do-not-resuscitate directives: for 50-64, 65-74, and 75 years and older, odds ratios were 3.4 (95% CI 1.6-7.3), 4.4 (2.2-9.2), and 8.8 (4.4-17.8), respectively. APACHE II scores greater than 20 predicted resuscitate and do-not-resuscitate directives in a similar way. An explicit directive was likely for patients admitted at night (odds ratio 1.4 [1.0-1.9] and 1.6 [1.2-2.3] for resuscitate and do-not-resuscitate, respectively) and during weekends (1.9 [1.3-2.7] and 2.2 [1.5-3.2], respectively). Inability to make a decision raised the likelihood of a do-not-resuscitate (3.7 [2.6-5.4]) than a resuscitate (1.7 [1.2-2.3]) directive (p=0.0005). Within Canada and the USA, cities differed strikingly, as did centres within cities., Interpretation: Cardiopulmonary resuscitation directives established within 24 h of admission to ICU are uncommon. As well as clinical factors, timing and location of admission might determine rate and nature of resuscitation directives.

Health-care professionals (HCPs) can provide protocol-based care that has a measurable impact on critically ill patients beyond their liberation from mechanical ventilation (MV). Randomized controlled trials have demonstrated that protocols for liberating patients from MV driven by nonphysician HCPs can reduce the duration of MV. The structure and features of protocols should be adapted from published protocols to incorporate patient-specific needs, clinician preferences, and institutional resources. As a general approach, shortly after patients demonstrate that their condition has been stabilized on the ventilator, a spontaneous breathing trial (SBT) is safe to perform and is indicated. Ventilator management strategies for patients who fail a trial of spontaneous breathing include the following: (1) consideration of all remediable factors (such as electrolyte derangements, bronchospasm, malnutrition, patient positioning, and excess secretions) to enhance the prospects of successful liberation from MV; (2) use of a comfortable, safe, and well-monitored mode of MV (such as pressure support ventilation); and (3) repeating a trial of spontaneous breathing on the following day. For patients who pass the SBT, the decision to extubate must be guided by clinical judgment and objective data to minimize the risk of unnecessary reintubations and self-extubations. Protocols should not represent rigid rules but, rather, guides to patient care. Moreover, the protocols may evolve over time as clinical and institutional experience with them increases. Useful protocols aim to safely and efficiently liberate patients from MV, reducing unnecessary or harmful variations in approach.

We identified three randomized controlled trials (RCTs) that addressed whether preextubation steroid administration reduces postextubation complications in children. The pooled analysis of primary extubation in children demonstrated significantly less stridor (relative risk [RR], 0.57; 95% confidence interval [CI], 0.40 to 0.81) and a trend toward less reintubation (RR, 0.50; 95% CI, 0.02 to 13.87) with corticosteroids. One non-RCT in children who had failed extubation the first time found a significant reduction in duration of prolonged reintubation (> or = 6 days) and in failed reextubations. The four RCTs in adults reported very low reintubation rates, and no conclusions can be drawn. Only one RCT assessed postextubation stridor and found little difference. Overall, we found that corticosteroids decreased the risk of postextubation stridor in children by about 40%. However, the effect of corticosteroids in children and adults to reduce postextubation complications such as reintubation is uncertain.

In contrast to primarily deductive quantitative research, qualitative research aims to interpret data to develop theoretical insights that describe and explain phenomena such as interactions, experiences, roles, perspectives, and organizations. In this review, we summarize qualitative studies that used primarily in-depth personal interviews as a data collection method and a grounded theory analytic approach. The liberal use of illustrative excerpts and interpretive descriptions offer clinicians vicarious accounts of patient experiences of weaning from mechanical ventilation. Important experiences of patients during their weaning from mechanical ventilation included frustration, uncertainty, hopelessness, fear, and lack of mastery. The extent to which, in at least some patients, these experiences were determinants of weaning failure, consequences of weaning failure, or both, was difficult to establish. An assumption of this genre of research is that if clinicians understand the lived experiences of patients, they can better appreciate patient needs during the weaning process, and by inference, their role as clinicians during weaning from mechanical ventilation.

We identified 16 randomized controlled trials (RCTs) of methods for weaning patients from mechanical ventilation, 8 of which were trials of discontinuation assessment strategies, 5 of which were trials of stepwise reduction in mechanical ventilatory support, and 3 of which were trials comparing alternative ventilation modes for weaning periods lasting < 48 h. We found that different thresholds for deciding when a patient is ready for a trial of spontaneous breathing, different criteria for a successful trial, and different thresholds for extubation may overwhelm the impact of alternative ventilation strategies. Nevertheless, the results of these studies suggest the possibility that multiple daily T-piece weaning or pressure support may be superior to synchronized intermittent mandatory ventilation. Other RCTs suggest that early extubation with the back-up institution of noninvasive positive-pressure ventilation as needed may be a useful strategy in selected patients.

Background: Increases in blood flow support oxygen (O2) delivery with hemodilution. However, with alpha-stat management, the cerebral response to hemodilution is blunted. We tested the hypothesis that carbon dioxide (CO2) management is a primary determinant of the cerebral blood flow (CBF) response to hemodilution during hypothermic bypass., Methods: Following Animal Care Committee approval, 15 dogs underwent bypass at 18 degrees C (pH-stat, n = 7 or alpha-stat, n = 8). Measurements were obtained after progressive hemodilution, and cerebral blood flow was determined by sagittal sinus outflow. Arterial pressure was maintained at 60 to 70 mm Hg. The CBF response to hemodilution and cerebral metabolic rate were compared in the two groups of animals., Results: In both groups, hemodilution increased CBF. At every hematocrit, CBF and O2 delivery in the pH-stat group exceeded that of alpha-stat group, although O2 demand did not differ between groups. While absolute CBF in the pH-stat group was greater at every hematocrit, the relative change in CBF from control and the slope of the CBF-Hct relationship did not differ between groups., Conclusions: pH-stat management is associated with a greater absolute CBF and a greater ratio of cerebral O2 supply to demand for any degree of hemodilution. However, over the range of hematocrits common in practice, CO2 management per se does not determine the cerebral response to hemodilution.

Background: Cerebral embolization is a major cause of central nervous dysfunction after cardiopulmonary bypass. Experimental studies demonstrate that reductions in arterial carbon dioxide tension (PaCO2) can reduce cerebral embolization during cardiopulmonary bypass. This study examined the effects of brief PaCO2 manipulations on cerebral embolization in patients undergoing cardiac valve procedures., Methods: Patients were prospectively randomized to either hypocapnia (PaCO2 = 30 to 32 mm Hg, n = 30) or normocapnia (PaCO2 = 40 to 42 mm Hg, n = 31) before aortic cross-clamp removal. With removal of the aortic cross-clamp embolic signals were recorded by transcranial Doppler ultrasonography for the next 15 minutes., Results: Despite significant differences in PaCO2, groups did not differ statistically in total cerebral emboli counts. The mean number of embolic events was 107 +/- 100 (median, 80) in the hypocapnic group and 135 +/- 115 (median, 96) in the normocapnic group, respectively (p = 0.315)., Conclusions: Due to the high between-patient variability in embolization, reductions in PaCO2 did not result in a statistically significant decrease in cerebral emboli. In contrast to experimental studies, the beneficial effect of hypocapnia on cerebral embolization could not be demonstrated in humans.

Background: Cardiopulmonary bypass (CPB) may decrease oxygen delivery relative to the nonbypass state. We predicted that a hierarchy of regional blood flow could be characterized under hypothermic (27 degrees C) CPB., Methods: Ten pigs underwent bypass at 27 degrees C. Fluorescent microspheres were administered before and during CPB at four randomized flows: 1.9, 1.6, 1.3, and 1.0 L x min(-1) x m(-2). At completion, tissue samples were obtained from brain, renal cortex and medulla, pancreas, small bowel, and limb muscle for regional blood flow determination., Results: Cerebral blood flow remained unchanged between CPB flows of 1.9 and 1.3 L x min(-1) x m(-2). Renal perfusion was stable between flows of 1.9 and 1.6 L x min(-1) x m(-2), whereas perfusion of small bowel decreased linearly with pump flow. Pancreatic perfusion was unchanged over the range of flows studied; muscle blood flow was profoundly reduced at the highest CPB flow and further decreased if pump flow was reduced below 1.6 L x min(-1) x m(-2)., Conclusions: This study characterizes the organ-specific hierarchy of blood flow and oxygen distribution during hypothermic CPB. These dynamics are relevant to clinical decisions for perfusion management.

Background: Correcting the decrease in oxygen delivery from anemia using allogeneic RBC transfusions has been hypothesized to help with increased oxygen demands during weaning from mechanical ventilation. However, it is also possible that transfusions hinder the process because RBCs may not be able to adequately increase oxygen delivery. In this study, we determined whether a liberal RBC transfusion strategy improved outcomes related to mechanical ventilation., Methods: Seven hundred thirteen patients receiving mechanical ventilation, representing a subgroup of patients from a larger trial, were randomized to either a restrictive transfusion strategy, receiving allogeneic RBC transfusions at a hemoglobin concentration of 7.0 g/dL (and maintained between 7.0 g/dL and to 9.0 g/dL), or to a liberal transfusion strategy, receiving RBCs at 10.0 g/dL (and maintained between 10.0 g/dL and 12.0 g/dL). The larger trial was designed to evaluate transfusion practice rather than weaning per se., Results: Baseline characteristics in the restrictive-strategy group (n = 357) and the liberal-strategy group (n = 356) were comparable. The average durations of mechanical ventilation were 8.3 +/- 8.1 days and 8.3 +/- 8.1 days (95% confidence interval [CI] around difference, - 0.79 to 1.68; p = 0.48), while ventilator-free days were 17.5 +/- 10.9 days and 16.1 +/- 11.4 days (95% CI around difference, - 3.07 to 0.21; p = 0.09) in the restrictive-strategy group vs the liberal-strategy group, respectively. Eighty-two percent of the patients in the restrictive-strategy group were considered successfully weaned and extubated for at least 24 h, compared to 78% for the liberal-strategy group (p = 0.19). The relative risk (RR) of extubation success in the restrictive-strategy group compared to the liberal-strategy group, adjusted for the confounding effects of age, APACHE (acute physiology and chronic health evaluation) II score, and comorbid illness, was 1.07 (95% CI, 0.96 to 1.26; p = 0.43). The adjusted RR of extubation success associated with restrictive transfusion in the 219 patients who received mechanical ventilation for > 7 days was 1.1 (95% CI, 0.84 to 1.45; p = 0.47)., Conclusion: In this study, there was no evidence that a liberal RBC transfusion strategy decreased the duration of mechanical ventilation in a heterogeneous population of critically ill patients.

Clinicians and patients must decide when treatment effects are large enough to more than offset the adverse effects and costs of therapy. Calculation of the number of patients one needs to treat (NNT) in order to prevent one patient from having the target event is one tool to help with this decision. Clinicians should treat patients when the NNT is lower than a threshold NNT at which point the therapeutic risk equals the therapeutic benefit. We aimed: (1) to identify the determinants of the threshold NNT, and (2) to derive equations for the explicit estimation of the threshold NNT and of the minimum expected rate of target event, without treatment, above which treatment is justified. We conceived the threshold number needed to treat to prevent one target event as the point at which the benefits of treating that number of patients equal the negative consequences of treating that same number of patients. After identifying the various elements comprising the treatment impact, we equated the benefits and negative consequences and solved the equation for threshold NNT. We then derived the minimum expected rate of target event which would justify treatment. We derived an equation that relates the threshold NNT to the treatment-attributable adverse event rates (AER) and the relative values (RV) of the adverse events compared to that of the target event prevented. Specifically, the threshold NNT, denoted NNT(T) is given by NNT(T) = 1/(AER(1).RV(1) +...+ AER(n).RV(n)). We also derived a more complex equation which addresses the costs incurred by treatment and costs avoided by preventing target events. Solving the equation that includes costs requires specifying both the value of preventing a target event and the values of adverse treatment effects in economic units. The threshold NNT and the relative risk reduction (RRR) for the target event determine the minimum target event rate above which treatment is justified. This minimum event rate for treatment is 1/(NNT(T).RRR). The values that clinicians and patients use determine the threshold NNT and therefore also the minimum target event rate, without treatment, above which treatment is justified. Quantification of the determinants of the threshold NNT and of the minimum event rate to justify treatment can assist clinicians and patients in the explicit use of underlying values when making treatment decisions.

Background: Relative to the nonbypass state, cardiopulmonary bypass may decrease whole-body oxygen (O2) delivery. We predicted that during cardiopulmonary bypass, a hierarchy of regional blood flow and O2 delivery could be characterized., Methods: In 8 46.5 +/- 1.2-kg pigs, fluorescent microspheres were used to determine blood flow and O2 delivery to five organ beds before and during 37 degrees C cardiopulmonary bypass at four randomized bypass flows (1.4, 1.7, 2.0, and 2.3 L/min/m2). At completion, 18 tissue samples were obtained from the cerebral cortex (n = 4), renal cortex (n = 2), renal medulla (n = 2), pancreas (n = 3), small bowel (n = 3), and limb muscle (n = 4) for regional blood flow determination., Results: At conventional cardiopulmonary bypass flow (2.3 L/min/m2), whole-body O2 delivery was reduced by 44 +/- 6% relative to the pre-cardiopulmonary bypass state (p < 0.05). Over a range of cardiopulmonary bypass flows (2.3 to 1.7 L/min/m2), brain and kidney maintained their perfusion. Blood flow and O2 delivery to both regions were reduced when the cardiopulmonary bypass flow was reduced to 1.4 L/min/m2. However, perfusion and O2 delivery to other visceral organs (pancreas, small bowel) and skeletal muscle showed pump flow dependency over the range of flows tested., Conclusions: This study characterizes the organ-specific hierarchy of blood flow and O2 distribution during cardiopulmonary bypass. These dynamics are relevant to clinical decisions for perfusion management.

Background: The purpose of this study was to determine the feasibility of differential perfusion of the aortic arch and descending aorta during cardiopulmonary bypass using a cannula designed for aortic segmentation., Methods: Pigs weighing 57 kg (n = 8), underwent cardiopulmonary bypass using the dual lumen aortic cannula. An inflatable balloon separated proximal (aortic arch) and distal (descending aorta) ports. During differential perfusion, the aorta was segmented and the arch and descending aorta perfused differentially using parallel heat exchangers. Ability to independently control brain and body temperature, cardiopulmonary bypass flow rate and mean arterial blood pressure was determined., Results: During differential perfusion cerebral hypothermia (27 degrees C) with systemic normothermia (38 degrees C) was established in 23 minutes. Independent control of arch and descending aortic flow and mean arterial blood pressure was possible. Analysis of internal jugular venous O2 saturation data indicated an increase in the ratio of cerebral O2 supply to demand during differential perfusion., Conclusions: A cannulation system segmenting the aorta allows independent control of cerebral and systemic perfusion. This device could provide significant cerebral protection while maintaining the advantages of warm systemic cardiopulmonary bypass temperatures.

Background: Embolization during cardiopulmonary bypass probably alters cerebral autoregulation. Therefore, using laser Doppler flowmetry we investigated the cerebral blood flow velocity changes in response to changes in arterial pressure, before and after embolization in a canine bypass model., Methods: After Institutional Animal Care and Use Committee approval, 8 anesthetized dogs had a laser Doppler flow probe positioned over the temporoparietal dura. During 37 degrees C cardiopulmonary bypass, the cerebral blood flow velocity response to changing mean arterial pressure (40 to 85 mm Hg in random order) was assessed before and after systemic embolization of 100 mg of 97-microm latex microspheres., Results: Before embolization, cerebral blood flow velocity increased 39% as mean arterial pressure increased from 40 to 85 mm Hg. Following embolization, a 94% increase in cerebral blood flow velocity was demonstrated over the same mean arterial pressure range. The slopes of the curves relating cerebral blood flow velocity to mean arterial pressure were 0.21+/-0.74 and 1.31+/-0.87, before and after embolization (p = 0.016) respectively., Conclusions: Regional cerebral blood flow autoregulation may be impaired by microembolization known to occur during cardiopulmonary bypass, increasing the dependence of cerebral blood flow on mean arterial pressure.

Background: Patients experience cerebral embolization during cardiopulmonary bypass (CPB). This study determined if alterations in temperature and/or PaCO2 can reduce cerebral and ocular embolization., Methods and Results: Forty-four pigs underwent CPB: 24 animals at 28 degrees C, and 20 at 38 degrees C. The two temperature groups were randomized to undergo embolization (67-microm fluorescent microspheres) at either hypercarbia or hypocarbia. Before and after embolization, cerebral and ocular blood flow were determined at normocarbia. Reducing temperature or PaCO2 reduced cerebral and ocular embolization. Hypocarbia reduced cerebral embolization by 60% and 45% in normothermic and hypothermic groups, respectively (p < 0.0001 and p < 0.05). Relative to normothermic animals, hypothermia reduced cerebral embolization by 37% under an elevated CO2 condition (p < 0.05), but not under hypocarbic conditions. Similarly, regardless of temperature, fewer emboli were delivered to the eye in hypocarbic animals (p < 0.05), but hypothermia did not reduce ocular embolization., Conclusions: Cerebral embolization is determined by both temperature and PaCO2 at the time of embolization. In CPB practice, reductions in temperature and/or PaCO2 during periods of embolic risk may reduce brain injury.

Background: The Quality of Reporting of Meta-analyses (QUOROM) conference was convened to address standards for improving the quality of reporting of meta-analyses of clinical randomised controlled trials (RCTs)., Methods: The QUOROM group consisted of 30 clinical epidemiologists, clinicians, statisticians, editors, and researchers. In conference, the group was asked to identify items they thought should be included in a checklist of standards. Whenever possible, checklist items were guided by research evidence suggesting that failure to adhere to the item proposed could lead to biased results. A modified Delphi technique was used in assessing candidate items., Findings: The conference resulted in the QUOROM statement, a checklist, and a flow diagram. The checklist describes our preferred way to present the abstract, introduction, methods, results, and discussion sections of a report of a meta-analysis. It is organised into 21 headings and subheadings regarding searches, selection, validity assessment, data abstraction, study characteristics, and quantitative data synthesis, and in the results with "trial flow", study characteristics, and quantitative data synthesis; research documentation was identified for eight of the 18 items. The flow diagram provides information about both the numbers of RCTs identified, included, and excluded and the reasons for exclusion of trials., Interpretation: We hope this report will generate further thought about ways to improve the quality of reports of meta-analyses of RCTs and that interested readers, reviewers, researchers, and editors will use the QUOROM statement and generate ideas for its improvement.

The objective of this study was to compare the impact of closed- versus open-ended question formats on the completeness and accuracy of demographic data collected in a mailed survey questionnaire. We surveyed general internists in five Canadian provinces to determine their career satisfaction. We randomized respondents to receive versions of the questionnaire in which 16 demographic questions were presented in a closed-ended or open-ended format. Two questions required respondents to make a relatively simple computation (ensuring that three or four categories of response added to 100%). The response rate was 1007/1192 physicians (80.0%). The proportion of respondents with no missing data for all 16 questions was 44.7% for open-ended and 67.0% for closed-ended formats (P < 0.001). The odds of having missing items remained higher for open-ended response options after adjusting for a number of respondent characteristics (2.67, 95% confidence interval 2.01 to 3.55). For the two questions requiring computations focused on professional activity and income, there were more missing data (P = 0.02, 0.02, respectively) but fewer inaccurate responses (P = 0.009, 0.20, respectively) for the open-ended compared to the closed-ended format. Investigators can achieve higher response rates for demographic items using closed format response options, but at the risk of increasing inaccuracy in response to questions requiring computation.

Background: In patients with apparently operable non-small cell lung cancer (NSCLC), clinicians often omit investigation for M disease in asymptomatic patients. Previous investigations have not specified in detail what is meant by "symptomatic," and this could differ between surgeons. We have investigated the extent to which surgeons' criteria differ for presence of symptoms., Methods: Participating surgeons from seven centers, enrolled patients they judged "asymptomatic" in a randomized trial of investigational strategies for NSCLC. Patients completed a structured questionnaire describing symptoms of the central nervous system (CNS). In 685 patients, we documented CNS symptom recurrence after resectional surgery over 1 year of follow-up., Results: Two centers enrolled only patients without even the mildest symptoms. Three centers took an intermediate approach, occasionally classifying patients with mild symptoms as "asymptomatic" and thus enrolling them in the trial. Two centers classified an appreciable number of patients with minimal symptoms, and occasionally with more than minimal symptoms, as "asymptomatic." Patients with even mild CNS symptoms were more likely to subsequently present with CNS metastases., Conclusions: Thoracic surgeons differ in their ideas of what may constitute the symptoms of M disease. Patients with structured questionnaire results that suggest symptoms of CNS disease are more likely to have CNS symptom recurrence after resectional surgery.

Objective: To evaluate the clinical utility of bronchoscopy with protected brush catheter (PBC) and BAL for patients with ventilator-associated pneumonia (VAP)., Design: Prospective cohort study., Setting: Ten tertiary care ICUs in Canada., Patients: Ninety-two mechanically ventilated patients with a clinical suspicion of VAP who underwent bronchoscopy were compared with 49 patients with a clinical suspicion of pneumonia who did not., Interventions: None., Measurements and Results: We compared antibiotic use, duration of mechanical ventilation, ICU stay, and mortality. In addition, for patients who received bronchoscopy, we administered a questionnaire (before and after bronchoscopy) to evaluate the effect of PBC or BAL on (1) physician perception of the probability of VAP, (2) physician confidence in the diagnosis of VAP, and (3) changes to antibiotic management. After bronchoscopy results became available, from the physician's perspective, the diagnosis of VAP was deemed much less likely (p < 0.001), confidence in the diagnosis increased (p = 0.03), and level of comfort with the management plan increased (p = 0.02). Following the results of invasive diagnostic tests, in the group that underwent bronchoscopy, patients were receiving fewer antibiotics (31/92 vs 9/49, p = 0.05) and more patients had treatment with all their antibiotics discontinued (18/92 vs 3/49, p = 0.04) compared with the group that did not undergo bronchoscopy. Duration of mechanical ventilation and ICU stay were similar between the two groups, but mortality was lower in the group that underwent bronchoscopy with PBC or BAL (18.5% vs 34.7%, p = 0.03)., Conclusions: Invasive diagnostic testing may increase physician confidence in the diagnosis and management of VAP and allows for greater ability to limit or discontinue antibiotic treatment. Whether performing PBC or BAL affects clinically important outcomes requires further study.

During cardiopulmonary bypass, haemodilution is standard practice and is accompanied by increases in cerebral blood flow (CBF). We investigated if changes in cerebral vascular resistance (CVR) during cardiopulmonary bypass-haemodilution are dependent on nitric oxide synthase. The cerebral response to haemodilution in nine dogs treated with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), was compared with a control group (n = 8). Both groups underwent serial isovolaemic haemodilution (target packed cell volumes 0.39, 0.26, 0.19 and 0.14) using 6% dextran 70. CBF, CVR and cerebral metabolic rate for oxygen (CMRO2) were measured. While initial CVR was different in the two groups, haemodilution-dependent reductions in CVR were equivalent and the curves describing the packed cell volume-CVR relationship were parallel in control and nitric oxide synthase inhibition groups. Our data indicate that nitric oxide synthase does not play a primary role in the cerebral response to haemodilution.

Objective: To critically appraise and summarize the trials examining the addition of continuous positive airway pressure (CPAP) or noninvasive positive pressure ventilation (NPPV) to standard therapy on hospital mortality, need for endotracheal intubation, and predischarge left ventricular function in patients admitted to the hospital with cardiogenic pulmonary edema with gas exchange abnormalities., Data Sources: We searched MEDLINE (1983 to June 1997) and bibliographies of all selected articles and review articles. We also reviewed the abstracts from the proceedings of relevant meetings from 1985 to 1997., Study Selection: (1) POPULATION: patients presenting to hospital with cardiogenic pulmonary edema; (2) intervention: one of the following three: (a) the use of CPAP and standard medical therapy vs standard medical therapy alone; (b) the use of NPPV and standard medical therapy vs standard medical therapy alone; and (c) the use of NPPV and standard therapy vs CPAP and standard therapy; (3) outcome: hospital survival, need for endotracheal intubation, or predischarge left ventricular dysfunction; and (4) study design: randomized controlled trial (RCT); if there were fewer than two RCTs, other study designs were included., Data Extraction: Two authors independently extracted data and evaluated the methodologic quality of the studies., Data Synthesis: CPAP was associated with a decrease in need for intubation (risk difference, -26%, 95% confidence intervals, -13 to -38%) and a trend to a decrease in hospital mortality (risk difference, -6.6%; +3 to -16%) compared with standard therapy alone. There was insufficient evidence to comment on the effectiveness of NPPV either compared with standard therapy or CPAP and standard therapy. Evidence was also lacking on the potential for either intervention to cause harm., Conclusions: A modest amount of favorable experimental evidence exists to support the use of CPAP in patients with cardiogenic pulmonary edema. CPAP appears to decrease intubation rates and data suggest a trend toward a decrease in mortality, although the potential for harm has not been excluded. The role of NPPV in this setting requires further study before it can be widely recommended.

Background: Few meta-analyses of randomised trials assess the quality of the studies included. Yet there is increasing evidence that trial quality can affect estimates of intervention efficacy. We investigated whether different methods of quality assessment provide different estimates of intervention efficacy evaluated in randomised controlled trials (RCTs)., Methods: We randomly selected 11 meta-analyses that involved 127 RCTs on the efficacy of interventions used for circulatory and digestive diseases, mental health, and pregnancy and childbirth. We replicated all the meta-analyses using published data from the primary studies. The quality of reporting of all 127 clinical trials was assessed by means of component and scale approaches. To explore the effects of quality on the quantitative results, we examined the effects of different methods of incorporating quality scores (sensitivity analysis and quality weights) on the results of the meta-analyses., Findings: The quality of trials was low. Masked assessments provided significantly higher scores than unmasked assessments (mean 2.74 [SD 1.10] vs 2.55 [1.20]). Low-quality trials (score < or = 2), compared with high-quality trials (score > 2), were associated with an increased estimate of benefit of 34% (ratio of odds ratios [ROR] 0.66 [95% CI 0.52-0.83]). Trials that used inadequate allocation concealment, compared with those that used adequate methods, were also associated with an increased estimate of benefit (37%; ROR=0.63 [0.45-0.88]). The average treatment benefit was 39% (odds ratio [OR] 0.61 [0.57-0.65]) for all trials, 52% (OR 0.48 [0.43-0.54]) for low-quality trials, and 29% (OR 0.71 [0.65-0.77]) for high-quality trials. Use of all the trial scores as quality weights reduced the effects to 35% (OR 0.65 [0.59-0.71]) and resulted in the least statistical heterogeneity., Interpretation: Studies of low methodological quality in which the estimate of quality is incorporated into the meta-analyses can alter the interpretation of the benefit of intervention, whether a scale or component approach is used in the assessment of trial quality.

Background: The management of blood pressure during cardiopulmonary bypass varies widely. This may be particularly relevant with the trend to warmer bypass temperatures and an older patient population. Therefore, we examined the minimal perfusion pressure that maintains cerebral oxygen delivery during cardiopulmonary bypass at 33 degrees C., Methods: Ten dogs were placed on bypass and body temperature was reduced to 33 degrees C (alpha-stat pH management). At six randomly ordered mean arterial blood pressures (35, 40, 45, 50, 60, and 70 mm Hg), cerebral blood flow, oxygen delivery, and metabolic rate were determined., Results: Cerebral oxygen delivery was stable if the mean arterial pressure was greater than or equal to 60 mm Hg. If mean arterial pressure was less than or equal to 50 mm Hg, cerebral oxygen delivery decreased, and at less than 45 mm Hg cerebral ischemia was seen., Conclusions: In a dog without vascular disease, the brain becomes perfusion pressure-dependent at a mean arterial pressure of approximately 50 mm Hg. There is no leftward shift of the cerebral autoregulatory curve during bypass at 33 degrees C. Greater support of mean arterial pressure during "tepid" cardiopulmonary bypass is indicated in the current adult surgical population that is older and has vascular comorbidity.

Background: Risk factors for death after heart transplantation (Tx) are frequently documented from multicenter registries. Although this information is helpful, it reflects a whole range of experiences and results, and may not translate to a particular center. This study was performed to (1) evaluate pre-Tx factors affecting mortality in a single-center experience, and (2) compare these factors with risk factors obtained from multicenter registry reports., Methods: Review of our transplant database between January 1984 and December 1995 identified 405 adults who received a primary heart Tx. Multiple factors were analyzed, including demographics, Tx era, cytomegalovirus status, United Network for Organ Sharing status of recipient, presence of pulmonary hypertension, previous cardiac operations, mechanical ventilation or circulatory support, ischemia time, number of rejection episodes, and preoperative flow cytometry crossmatching., Results: One- and 5-year survival rates were 87.8% and 73.4%, respectively (Kaplan-Meier). Contrary to multicenter registry reports, our data indicate that reoperative procedures, left ventricular assist device support, increasing donor and recipient age, and ischemia time up to 4.2 hours are not risk factors for death after Tx. Likewise, mode of donor death is not a risk factor affecting outcome. Significant risk factors for mortality identified by multivariate analysis included early transplant era (1984 to 1989; p = 0.002), female donor (p = 0.042), cytomegalovirus-seropositive donor (p = 0.048), high pulmonary vascular resistance (p = 0.018), and intraaortic balloon pump support (p = 0.03). It also identified a positive B-cell flow cytometry crossmatch (p = 0.015) to be a risk factor with univariate analysis., Conclusions: Our data identify a group of recipients, reportedly at high risk in multicenter registries, who are not at increased risk of death after Tx. This information supports the growing experience with older donors and recipients and with bridged transplants, and has allowed us to expand our donor pool. These prognostic factors at evaluation allow more liberal selection of patients and donors for transplantation.

Objective: To evaluate the effect of heparin on thrombus formation and infection associated with use of central venous and pulmonary artery catheters., Data Sources: We used MEDLINE, EMBASE, citation review of relevant primary and review articles, personal files, and contact with expert informants., Study Selection: Fourteen randomized controlled trials evaluating prophylactic doses of heparin or heparin bonding were included., Data Extraction: In duplicate, independently, we abstracted data on the population, intervention, outcome, and methodologic quality., Data Synthesis: Prophylactic heparin decreases catheter-related venous thrombosis (relative risk [RR], 0.43; 95% confidence interval [CI], 0.23, 0.78) and bacterial colonization (RR, 0.18; 95% CI, 0.06, 0.60) of central venous catheters and may decrease catheter-related bacteremia (RR, 0.26; 95% CI, 0.07, 1.03). Heparin bonding decreases the risk of pulmonary artery catheter clot formation within 24 h (RR, 0.08; 95% CI, 0.02, 0.37)., Conclusions: Heparin administration effectively reduces thrombus formation and may reduce catheter-related infections in patients who have central venous and pulmonary artery catheters in place. Cost-effectiveness comparisons of unfractionated heparin, low molecular weight heparin, and warfarin are needed.

Background: Patients bridged to transplantation (TX) with the implantable left ventricular assist device (LVAD) may be at increased risk for the development of panel-reactive antibodies (PRA) during support., Methods: To investigate that, we evaluated 60 patients who received the HeartMate LVAD at our institution, of whom 53 had PRA results available for analysis. T lymphocyte PRA levels were examined before LVAD, at the peak PRA level during LVAD support (PEAK), and just before TX. A PRA level more than 10% was considered indicative of sensitization against HLA antigens., Results: The only factor that had a significant effect on PRA levels before LVAD was patient's sex (1.3% for men versus 7.4% for women; p = 0.005). During LVAD support, peak PRA levels increased significantly and the sex-associated differences were no longer evident (33.3% men, 34.3% women; not significant). At the time of TX, PRAs decreased to 10.9% (men) and 7.0% (women) (not significant). We examined the influence of blood products received before TX on PRA levels. Patients who received less than the median number of total units (median). When examined by the type of blood product, only the number of platelet transfusions significantly increased the peak PRA (median: 46.9%; p = 0.03). Patients who received blood that was leukocyte-depleted tended to have lower TX PRA levels (2.9%) compared with those who did not (13.9%, p = 0.18). Forty-two patients were successfully bridged to TX, with three early and two late deaths after TX. Whereas 39 patients received transplants without intervention, 3 were treated by plasmapheresis with a 77% reduction in their HLA antibody levels at TX as measured by flow cytometry., Conclusions: Patients with the implantable LVAD are at significant risk for the development of anti-HLA antibodies during support. Although this sensitization is often transient, intervention using plasmapheresis may be useful for some patients.

All therapeutic decisions involve some trade-off between therapeutic benefits and risks; a new therapy may be associated with greater efficacy but also a greater risk of adverse effects. In making treatment decisions clinicians must examine the clinical evidence regarding the magnitudes of benefit and risk and the precision with which they have been estimated. Ideally this requires a systemic assessment of the quality of the research and the strength of the evidence. We examine how the concept of number needed to treat can be used to improve the current presentation of clinical trials data of efficacy and side-effects to give clinicians a more clinically meaningful and quantitative measure of benefit-risk trade-offs. We propose a benefit-risk ratio that quantifies for a new therapy how many therapeutic (efficacy) events will be achieved for each adverse event incurred. We show how data from a clinical trial with a single binary measure of efficacy and a single adverse event of concern can be used to provide point estimates and confidence intervals for the benefit-risk ratio. The approach is illustrated using data from the GUSTO trial comparing tissue plasminogen activator and streptokinase in the management of patients with acute myocardial infarction.

Background: Determination of cerebral blood flow and oxygenation is a means of evaluating our cardiopulmonary bypass (CPB) practice. Because much of CPB is hypothermic, our measurement technique must be valid over a range of temperatures. In this study we evaluate the validity of N2O washin for measurement of cerebral blood flow and oxygenation at three temperatures., Methods: Cerebral blood flow and oxygenation were measured in 7 dogs undergoing CPB at 37 degrees, 32 degrees, and 27 degrees C using simultaneous direct (sagittal sinus outflow) and indirect (nitrous oxide washin) techniques. Animals underwent CPB with a whole blood prime and alpha-stat pH management., Results: In the absence of hemodilution, cerebral blood flow and oxygenation were reduced by approximately 38% and 55% at 32 degrees C and 27 degrees C, respectively, by both techniques. Direct and indirect methods showed an excellent correlation (R = 0.87) during CPB between 27.5 degrees C and 37.8 degrees C (21 paired measurements)., Conclusions: This investigation demonstrates that the correlation between a direct measure of global cerebral blood flow and that obtained by the N2O saturation method is excellent during CPB over the range of common CPB temperatures.

Considerable effort is often expended to adjudicate outcomes in clinical trials, but little has been written on the administration of the adjudication process and its possible impact on study results. As a case study, we describe the function and performance of an adjudication committee in a large randomized trial of two diagnostic approaches to potentially operable lung cancer. Up to five independent adjudicators independently determined two primary outcomes: tumor status at death or at final follow-up and the cause of death. Patients for whom there was any disagreement were discussed in committee until a consensus was achieved. We describe the pattern of agreement among the adjudicators and with the final consensus result. Additionally, we model the adjudication process and predict the results if a smaller committee had been used. We found that reducing the number of adjudicators from five to two or three would probably have changed the consensus outcome in less than 10% of cases. Correspondingly, the effect on the final study results (comparing primary outcomes in both randomized arms) would have been altered very little. Even using a single adjudicator would not have affected the results substantially. About 90 minutes of person-time per patient was required for activities directly related to the adjudication process, or approximately 6 months of full time work for the entire study. This level of effort could be substantially reduced by using fewer adjudicators with little impact on the results. Thus, we suggest that when high observer agreement is demonstrated or anticipated, adjudication committees should consist of no more than three members. Further work is needed to evaluate if smaller committees are adequate to detect small but important treatment effects or if they compromise validity when the level of adjudicator agreement is lower.

Background: Respiratory rehabilitation is increasingly recognised as an important part of the management of patients with chronic obstructive pulmonary disease (COPD). The widespread application of such programmes should be preceded by evidence of directly attributable improvements in function. We assessed the effect of respiratory rehabilitation on exercise capacity and health-related quality of life (HRQL) in patients with COPD., Methods: We carried out a meta-analysis of randomised controlled trials of respiratory rehabilitation in patients with COPD that assessed functional or maximal exercise capacity, HRQL, or both. Respiratory rehabilitation was defined as exercise training (for at least 4 weeks) with or without education, psychological support, or both. The most commonly used measure for HRQL was the chronic respiratory questionnaire, in which responses were presented on a 7-point scale. The control groups received no rehabilitation. Within each trial and for each outcome an effect size was calculated; the effect sizes were then pooled by a random-effects model. The overall effect of treatment was compared with its minimum clinically important difference (MCID)--defined as the smallest difference perceived as important by the average patient., Findings: We included 14 trials. Significant improvements were found for all the outcomes. For two important features of HRQL, dyspnoea and mastery, the overall treatment effect was larger than the MCID: 1.0 (95% CI 0.6-1.5) and 0.8 (0.5-1.2), respectively, compared with an MCID of 0.5. For functional exercise capacity (6-min walk test), the overall effect was 55.7 m (27.8-92.8), and for maximum exercise capacity (incremental cycle ergometer test), 8.3 W (2.8-16.5). Functional exercise capacity showed heterogeneity that could not be explained by the sensitivity analyses., Interpretation: Respiratory rehabilitation relieves dyspnoea and improves the control over COPD. These improvements are clinically important. The value of the improvement in exercise capacity is not clear. Respiratory rehabilitation is an effective part of care in patients with COPD.

Background: The neurologic effects of warm heart operations is a subject of popular interest. The purpose of this study was to examine the adequacy of cerebral oxygenation during normothermic cardiopulmonary bypass and better define the relationship between hematocrit, temperature, and brain oxygen delivery., Methods: Cerebral blood flow, metabolic rate, and oxygen delivery were measured in 60 patients randomized to normothermic (37 degrees C) or hypothermic (27 degrees C) cardiopulmonary bypass. The nitrous oxide saturation technique of Kety and Schmidt was used for cerebral blood flow determinations. Both temperature groups underwent moderate (31%) hemodilution., Results: During normothermic cardiopulmonary bypass, cerebral blood flow increased secondary to hemodilution and decreased cerebral vascular resistance; a normal matching of oxygen demand and delivery was maintained. During hypothermic bypass, hemodilution and hypothermia had essentially equal, opposing effects on cerebral vascular resistance and blood flow. With hypothermia, brain oxygen demand and delivery were both reduced but not closely coupled., Conclusions: From the standpoint of global cerebral perfusion and oxygenation, our data support the practice of "warm" heart operations. It clarifies the marked influence of hematocrit on cerebral blood flow and delineates the interaction of temperature and hematocrit on cerebral oxygen delivery. It also suggests that additional investigation to better define "temperature-appropriate" hemodilution during cardiopulmonary bypass is indicated.

This study simultaneously compared the standard Kety-Schmidt and the modified xenon-133 (133Xe) clearance techniques for measuring cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) during cardiac operations. The validity of the CBF method is important because our management of the patient during cardiopulmonary bypass (CPB) is based, in part, on our understanding of the cerebral hemodynamics during CPB. In 20 patients undergoing coronary artery bypass grafting, CBF and CMRO2 were determined by both methods. Measurements were made before onset of CPB and once during CPB. Ten patients underwent CPB with systemic normothermia (37 degrees C) and 10 with systemic hypothermia (27 degrees C). Anesthesia consisted of fentanyl and midazolam. CPB pump flows were kept at 2.2 to 2.4 L.min-1.m-2 and alpha-stat pH management was used. Xenon-133 clearance significantly underestimated CBF and CMRO2 relative to the Kety-Schmidt technique before CPB and at both bypass temperatures. Values obtained by 133Xe clearance were approximately 50% of that measured by the Kety-Schmidt method. The modified 133Xe technique as typically used during cardiac operations does not appear to measure CBF accurately; this leads to corresponding errors in CMRO2 calculations. Determination of CMRO2 and cerebral autoregulatory function during cardiac operations appears to be more appropriate if based on the more direct Kety-Schmidt technique. Accordingly, our management of CPB with respect to cerebral perfusion as it has been determined by the modified 133Xe clearance method may require reassessment.