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Background and objectives: Diagnosis and assessment of treatment effect in chronic obstructive pulmonary disease (COPD) have relied primarily on the examination of a complex set of symptoms and the use of spirometry. However, these methods require long periods of assessment to determine whether patients show clinically relevant improvements after intervention. We therefore wanted to determine how existing clinical and laboratory measures change with COPD severity and identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect. Methods: Using standard COPD keywords and terms, we searched PubMed, ISI Web of Science, and Cochrane Review databases for retrospective and prospective clinical studies published since 1966. We identified 652 studies (nZ146,255) from 1978 to September 2003 based on the availability of spirometric and demographic data, investigation of possible markers, absence of acute exacerbations and comorbidities, and the withdrawal of standard COPD medication. Central tendencies and dispersions of subject baseline measures were collected according to study sample size, smoking status, and mild, moderate and severe COPD stages. A fixed effect meta-analysis was then conducted on each measure at various disease stages. Results: Arterial oxygen tension, sputum neutrophils and IL-8, and serum TNF-a and C-Reactive Protein showed a trend toward separation between COPD stages. Other measures such as pack-years and St George’s Respiratory Questionnaire only distinguished between disease and disease-free states. Conclusions: We observed little separation between disease stages for many measures used in COPD diagnosis and clinical trials. This demonstrates the poor sensitivity of such endpoints to define a patient’s clinical status and to quantify treatment effect. Therefore, we recommend that longitudinal studies and disease modelling be the primary methods for assessing whether potential markers of disease progression can be used for COPD diagnosis and clinical trials. q 2005 Elsevier Ltd. All rights reserved.

To test the efficacy of a combination of selective pre- and post-surgical local anesthetic infiltrations of the knee, compared with standard intra-articular injection at the end of surgery alone, to reduce postoperative opioid requirements following arthroscopic cruciate ligament reconstruction (ACLR).In a double-blind, randomized, controlled trial, we studied 23 patients (ASA I or II) scheduled for elective ACLR under general anesthesia. The treatment group (n = 12) received infiltrations with bupivacaine 0.25% with epinephrine 1:200,000 presurgically (10 ml into the portals, 10 ml at the medial tibial incision site, 10 ml at the lateral femoral incision site, and 10 ml intra-articularly) and postsurgically (5 ml at the medial tibial incision and 10 ml at the lateral femoral incision). The control group (n = 11) received infiltrations with saline 0.9% in the same manner. All patients received a standard intra-articular local anesthetic instillation of the knee (25 ml of bupivacaine 0.25% with epinephrine 1:200,000) at the completion of surgery.Postoperative opioid requirements were lower in the treatment group (5.8 +/- 2.9 mg morphine equivalent) than in the control group ( 13.7 +/- 5.8 mg; P = 0.008). Treatment patients were ready for discharge approximately 30 min earlier than control patients (P = 0.046). There were no adverse events in the treatment group. In the control group, 2/11 patients vomited and a third experienced transient postoperative diaphoresis, dizziness and pallor.We conclude that a combination of selective pre- and post-surgical wound infiltration with bupivacaine 0.25% provides superior analgesia compared with a standard post-surgical intra-articular injection alone.

To determine the "real world" cost of sevoflurane compared with isoflurane in balanced general anesthesia for daycare arthroscopic menisectomy, we prospectively investigated perioperative drug requirement and expense as well as recovery time.Following intravenous induction, 40 consenting adult patients randomly received either sevoflurane- or isoflurane-based anesthesia with a standardized gas inflow rate of 3 l x min. Recovery was assessed in the postanesthetic recovery room (PARR) in a double-blind manner at 15 min intervals using the Aldrete scoring system until patients met discharge criteria.Patient demographics, anesthetic duration, volatile potency and adjunct drug requirements were similar in the two groups. Total perioperative drug cost per patient was CAN$38.10+/-10.13 (mean +/- SD) for the sevoflurane group and $23.87+/-6.59 for the isoflurane group (P0.01). Although the nonvolatile drug cost was comparable between the two groups, the volatile drug cost per patient was $19.40+/-8.80 for sevoflurane and $4.50+/-1.90 for isoflurane (P0.01). This four-fold sevoflurane-to-isoflurane cost difference was the product of two ratios, both based on the volume of liquid anesthetic: the ratio of consumption, 2.1; and the ratio of institutional price, 2.1. Intraoperative hemodynamic response, time until discharge from the PARR and incidences of postoperative nausea and vomiting did not significantly differ between the two groups.When used to maintain equipotent balanced general anesthesia for daycare arthroscopic menisectomy, volatile consumption and cost were greater for sevoflurane compared with isoflurane. Nonvolatile perioperative drug cost and recovery times were similar, however, in the two groups.

Background Patients with chronic obstructive pulmonary disease (COPD) can experience 'exacerbations' of their conditions. An exacerbation is an event defined in terms of subjective descriptors or symptoms, namely dyspnoea, cough and sputum that worsen sufficiently to warrant a change in medical management. There is a need for reliable markers that reflect the pathological mechanisms that underlie exacerbation severity and that can be used as a surrogate to assess treatment effects in clinical studies. Little is known as to how existing study variables and suggested markers change in both the stable and exacerbation phases of COPD. In an attempt to find the best surrogates for exacerbations, we have reviewed the literature to identify which of these markers change in a consistent manner with the severity of the exacerbation event. Methods We have searched standard databases between 1966 to July 2004 using major keywords and terms. Studies that provided demographics, spirometry, potential markers, and clear eligibility criteria were included in this study. Central tendencies and dispersions for all the variables and markers reported and collected by us were first tabulated according to sample size and ATS/ERS 2004 Exacerbation Severity Levels I to III criteria. Due to the possible similarity of patients in Levels II and III, the data was also redefined into categories of exacerbations, namely out-patient (Level I) and in-patient (Levels II & III combined). For both approaches, we performed a fixed effect meta-analysis on each of the reported variables. Results We included a total of 268 studies reported between 1979 to July 2004. These studies investigated 142,407 patients with COPD. Arterial carbon dioxide tension and breathing rate were statistically different between all levels of exacerbation severity and between in out- and in-patient settings. Most other measures showed weak relationships with either level or setting, or they had insufficient data to permit meta-analysis. Conclusion Arterial carbon dioxide and breathing rate varied in a consistent manner with exacerbation severity and patient setting. Many other measures showed weak correlations that should be further explored in future longitudinal studies or assessed using suggested mathematical modelling techniques.

OBJECTIVE To provide evidence for the clinical efficacy of changes in urinary pH on the pain associated with interstitial cystitis (IC). PATIENTS AND METHODS A prospective, randomized, double-blind cross-over study was conducted with 26 women with IC between 2000 and 2002, consisting of cross-over instillations of urine at physiological pH (5.0), and neutral buffered pH (NaH2PO4 buffered to pH 7.5). The outcome measured was the subjective symptom of pain assessed using a visual analogue scale at baseline, after the initial instillation of solution, at washout, and after the crossover instillation. Data were analysed using repeated-measures analysis of variance. RESULTS There was no statistically significant difference between the mean (sd) change from baseline pain scores after instilling neutral buffered solution, at 0.50 (2.78), and acidic solution, at 0.33 (3.43) (P = 0.85). Secondary outcomes were analysed, including baseline variability and treatment-order effects; neither were significantly different between the groups. CONCLUSIONS There was no statistically significant difference in subjective pain scores on instilling urine at physiological pH or sodium-phosphate buffered saline in these patients with IC. Further work is required to define the role, if any, of urinary pH in the pathophysiology and treatment of IC.

To compare the measured "real world" perioperative drug cost and recovery associated with desflurane- and isoflurane-based anesthesia in short (less than one hour) ambulatory surgery.We conducted a prospective, randomized, blinded trial with patients undergoing arthroscopic meniscectomy under general anesthesia. Following iv induction, patients received either isoflurane (group I; n = 25) or desflurane (group D; n = 20) for maintenance. The primary outcome variable was total perioperative drug cost per patient in Canadian dollars. Secondary outcome variables included volatile agent consumption and cost, adjuvant anesthetic and postanesthesia care unit (PACU) drug cost, readiness for PACU discharge, and incidence of adverse events.Total perioperative drug cost per patient was 14.58 +/- 6.83 Canadian dollars (mean +/- standard deviation) for group I, and 21.47 +/- 5.18 Canadian dollars for group D (P0.001). Isoflurane consumption per patient was 6.0 +/- 3.0 mL compared to 18.6 +/- 7.7 mL for desflurane (P0.0001); corresponding costs were 0.83 +/- 0.42 Canadian dollars vs 7.61 +/- 3.15 Canadian dollars (P0.0001). There were no differences in adjuvant anesthetic or PACU drug cost. All but one patient from each group were deemed ready for PACU discharge at 15 min postoperatively (Aldrete scoreor= 9). One patient in group D experienced postoperative nausea. No other adverse events were noted.Measured total perioperative drug cost for a short ambulatory procedure (less than one hour) under general anesthesia was higher when desflurane rather than isoflurane was used for maintenance, essentially due to volatile agent cost. Desflurane use did not translate into faster PACU discharge under "real world" conditions.

To test the hypothesis that the addition of a preincisional femoral 3-in-1 block to intra-articular instillation with ropivacaine 0.2% at the end of surgery improves postoperative pain control in patients undergoing arthroscopic anterior cruciate ligament reconstruction (ACLR) under general anesthesia.In a prospective, randomized, placebo-controlled, double-blind trial, we studied 44 patients scheduled for inpatient ACLR. Prior to incision, the treatment group (n = 22) received a femoral 3-in-1 block with 40 ml ropivacaine 0.2%, augmented by infiltrations of the lateral and anteromedial incisions with 20 ml ropivacaine 0.2% at the end of the procedure. The control group (n = 22) received saline 0.9% instead of ropivacaine. All patients received an intra-articular instillation with 30 ml ropivacaine 0.2% at the end of surgery. The primary efficacy variable was 24 hr morphine consumption postoperatively standardized by weight, administered intravenously via a patient-controlled analgesia (PCA) pump.There was no difference between both groups in 24 hr PCA morphine consumption postoperatively (control, 0.45 +/- 0.44 [mean +/- SD] mg x kg(-1); treatment, 0.37 +/- 0.50 mg x kg(-1); p = 0.55). No difference was found in postoperative visual analog scale pain scores, adverse events, or vital signs. In the treatment group, R = 10/22 patients did not require postoperative morphine compared with R = 6/22 in the control group (P = 0.35).We found no effect of a femoral 3-in-1 block with ropivacaine 0.2% on postoperative analgesic consumption, compared to intra-articular instillation with ropivacaine 0.2% alone, in patients undergoing ACLR under general anesthesia.

Methods The safety of RPL554 0.003 and 0.009 mg/kg was evaluated in 18 healthy males (age 18-41 years; weight 58-90 kg; height 168-196 cm; BMI 18-29 kg/m) in a randomised, double-blind study. For each dose group, 6 subjects inhaled RPL554 and 3 placebo. Study medication was administered by a calibrated electronic nebuliser and oronasal mask. Subsequently, RPL554 0.009 and 0.018 mg/kg were evaluated in 6 asthmatic males (22-29 years; 58-98 kg; 174-198 cm; BMI 19-27 kg/m, FEV1 75-118% pred.) using an open, adaptive design to select an effective dose. This dose (0.018 mg/kg) was further evaluated in a randomised, double-blind, placebo-controlled, cross-over study in 10 allergic asthmatics (20-50 years; 67-112 kg; 171-191 cm; BMI 21-33 kg/m, FEV1 82-112% pred.; baseline PC20(methacholine=MCh) 0.07-1.49 mg/ml; not on controller medication) to assess its bronchodilator effects and bronchoprotective activity against methacholine (MCh) challenge.