A dose-specific meta-analysis of lipid changes in randomized controlled trials of atorvastatin and simvastatin.

BACKGROUND: The available statins exhibit differences in the potency with which they alter serum lipid levels. OBJECTIVE: Meta-analyses were conducted to assess the relative potency of atorvastatin and simvastatin (the 2 most commonly prescribed statins) across all possible dose combinations in terms of changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C). METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, National Health Service (NHS) Centre for Reviews and Dissemination database, NHS Economic Evaluation Database, and Database of Abstracts of Reviews of Effects were searched for randomized, head-to-head trials of atorvastatin and simvastatin in patients aged >or=18 years with elevated levels of serum TC and LDL-C. Reference lists of the identified articles, letters, and editorials also were reviewed. The manufacturers of atorvastatin and simvastatin products were contacted for relevant unpublished data. All studies were reviewed and rated for quality by 2 independent reviewers. The maximum quality score was 4 points; trials with a score of <2 points were considered to be of poor quality and were excluded from analysis. Dose comparisons were abstracted in pairs from each trial. Meta-analyses were conducted on the fixed-dose pairs for each lipid parameter. Weighted mean differences in the change in TC, LDL-C, TG, and HDL-C were estimated using the Der Simonian and Laird random-effects model. RESULTS: Seventeen published trials and 1 unpublished study were included in the meta-analyses. Atorvastatin treatment was associated with significantly greater reductions in TC, LDL-C, and TG in the majority of dose comparisons with simvastatin. The potency of atorvastatin and simvastatin was comparable at dose ratios between 1:2 and 1:4. Higher doses of simvastatin were more effective in increasing HDL-C levels than atorvastatin, with no apparent dose-equivalence point. The HDL-C advantage of simvastatin was greatest when simvastatin 80 mg was compared with atorvastatin 80 mg (weighted mean difference, -4.35%; 95% CI, -5.64 to -3.08, P < 0.001). CONCLUSIONS: In these meta-analyses, atorvastatin was 2 to 4 times as potent as simvastatin in reducing TC, LDL-C, and TG, indicating that the dose equivalence of atorvastatin and simvastatin lay between 1:2 and 1:4. In contrast, simvastatin was more effective than atorvastatin in increasing HDL-C, but without any indication of a point of dose equivalence.

Development of a quality use of medicines coding system to rate clinical pharmacists' medication review recommendations.

OBJECTIVE: To develop a 'quality use of medicines' coding system for the assessment of pharmacists' medication reviews and to apply it to an appropriate cohort. METHOD: A 'quality use of medicines' coding system was developed based on findings in the literature. These codes were then applied to 216 (111 intervention, 105 control) veterans' medication profiles by an independent clinical pharmacist who was supported by a clinical pharmacologist with the aim to assess the appropriateness of pharmacy interventions. The profiles were provided for veterans participating in a randomised, controlled trial in private hospitals evaluating the effect of medication review and discharge counselling. The reliability of the coding was tested by two independent clinical pharmacists in a random sample of 23 veterans from the study population. MAIN OUTCOME MEASURE: Interrater reliability was assessed by applying Cohen's kappa score on aggregated codes. RESULTS: The coding system based on the literature consisted of 19 codes. The results from the three clinical pharmacists suggested that the original coding system had two major problems: (a) a lack of discrimination for certain recommendations e.g. adverse drug reactions, toxicity and mortality may be seen as variations in degree of a single effect and (b) certain codes e.g. essential therapy were in low prevalence. The interrater reliability for an aggregation of all codes into positive, negative and clinically non-significant codes ranged from 0.49-0.58 (good to fair). The interrater reliability increased to 0.72-0.79 (excellent) when all negative codes were excluded. Analysis of the sample of 216 profiles showed that the most prevalent recommendations from the clinical pharmacists were a positive impact in reducing adverse responses (31.9%), an improvement in good clinical pharmacy practice (25.5%) and a positive impact in reducing drug toxicity (11.1%). Most medications were assigned the clinically non-significant code (96.6%). In fact, the interventions led to a statistically significant difference in pharmacist recommendations in the categories; adverse response, toxicity and good clinical pharmacy practice measured by the quality use of medicine coding system. CONCLUSION: It was possible to use the quality use of medicine coding system to rate the quality and potential health impact of pharmacists' medication reviews, and the system did pick up differences between intervention and control patients. The interrater reliability for the summarised coding system was fair, but a larger sample of medication regimens is needed to assess the non-summarised quality use of medicines coding system.

An organizational field approach to resource environments in healthcare: comparing entries of hospitals and home health agencies in the San Francisco Bay region.

OBJECTIVE: To draw together insights from three perspectives (health economics, organizational ecology, and institutional theory) in order to clarify the factors that influence entries of providers into healthcare markets. A model centered on the concept of an organizational field is advanced as the level of analysis best suited to examining the assortment and interdependence of organizational populations and the institutional forces that shape this co-evolution. In particular, the model argues that: (1) different populations of healthcare providers partition fiscal, geographic, and demographic resource environments in order to ameliorate competition and introduce service complementarities; and (2) competitive barriers to entry within populations of providers vary systematically with regulatory regimens. DATA SOURCES: County-level entries of hospitals and home health agencies in the San Francisco Bay Area using data from the American Hospital Association (1945-1991) and California's Office of Statewide Health Planning and Development (1976-1991). Characteristics of the resource environment are derived from the Area Resource File (ARF) and selected government censuses. METHODS OF ANALYSIS: A comparative design is applied to contrast influences on hospital and home health agency entries during the post-World War II period. Empirical estimates are obtained using Poisson and negative binomial regression models. RESULTS: Hospital and HHA markets are partitioned primarily by the age and education of consumers and, to a lesser extent, by urbanization levels and public funding expenditures. Such resource partitioning allows independent HHAs to exist comfortably in concentrated hospital markets. For both hospitals and HHAs, the barriers to entry once generated by oligopolistic concentration have declined noticeably with the market-oriented reforms of the past 15 years. CONCLUSION: A field-level perspective demonstrates that characteristics of local resource environments interact with interdependencies of provider populations and broader regulatory regimes to affect significantly the types of provider organizations likely to enter a given healthcare market.

The differential regulation of the circulating levels of the insulin-like growth factors and their binding proteins (IGFBP) 1, 2 and 3 after elective abdominal surgery.

OBJECTIVES: Patients undergoing abdominal surgery often suffer from morbidity associated with increased protein catabolism. Therapeutic recombinant human insulin-like growth factor (rhIGF)-I has been proposed as a means of reversing this process. As IGFBPs modulate the bioavailability of the IGFs, we have studied the changes in the circulating levels of these peptides during surgery. DESIGN: Patients undergoing elective intestinal surgery were recruited prospectively. Blood samples were taken before, during and after surgery. Standard anaesthetic techniques were used. METHODS: Twelve adults (aged 30-70 years; 9 female, 3 male) undergoing surgery were studied. Serum was taken before premedication (preop), end of surgery (end surg), 2 h, 6 h post surgery, on days 1-4, 7, 10 and 14, and on recovery at 6 weeks. MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, insulin and C-peptide were measured by radioimmunoassay. IGFBP profiles were also assessed by Western ligand blot (WLB). Samples taken preop and at 2 days were separated by fast-phase liquid chromatography (FPLC) using a Superose 12 column under neutral conditions (pH 7.4), and the fractions were analysed subsequently by WLB and immunoblot using a specific IGFBP-3 antiserum. RESULTS: IGF-I fell rapidly during surgery from 170 +/- 21 (preop) to 133 +/- 14 micrograms/l (end surg) (P < 0.05). The magnitude of this fall could not be explained by haemodilution. IGF-I levels then fell further to a nadir of 103 +/- 10 micrograms/l at day 4 (P < 0.05). IGF-II fell from 580 +/- 46 (preop) to 397 +/- 38 micrograms/l (day 2). Both IGF-I and IGF-II recovered to preop levels at 6 weeks (205 +/- 14 micrograms/l and 623 +/- 30 micrograms/l respectively). IGFBP-3 levels fell similarly from 4.46 +/- 0.45 to 3.2 +/- 0.3 mg/l (end surg) and to a nadir of 2.66 +/- 0.19 mg/l at day 2. There was a close correlation between IGFBP-3 levels and the sum of IGF-I and IGF-II levels before surgery (r = 0.9, P < 0.01) and this was maintained throughout the post-operative period (mean correlation coefficient of 0.86 +/- 0.02, P < 0.05). On days 2 and 3 there was a small but significant increase in the ratio between serum IGF-I and IGFBP-3 levels compared with the preop ratio (P < 0.05 and < 0.005, respectively). WLB demonstrated almost complete absence of IGFBP-3 by day 2. This discrepancy between RIA and WLB analysis of IGFBP-3 suggested the presence of IGFBP-3 protease activity between days 1 and 4. This was confirmed by WLB and immunoblot analyses of samples taken 2 days after surgery. The decrease in IGFBP-3 on WLB was shown to be associated with an increase in the proteolytically cleaved fragments of IGFBP-3. These fragments following FPLC were detected in the high molecular weight fractions, suggesting that the fragments were still able to form the high molecular weight IGFBP-3/ALS complex which is thought to form only when IGF is bound by IGFBP-3. IGFBP-1 levels rose during surgery (mean duration of surgery was 125 minute) from 18 +/- 3 (preop) to 51 +/- 12 micrograms/l (end surg) (P < 0.05). This rise in IGFBP-1 paralleled increases in insulin from 7.3 +/- 1.0 to 20.8 +/- 7.5 mU/l and glucose from 4.6 +/- 0.3 to 8.7 +/- 1.2 mmol/l. IGFBP-1 levels then fell to basal values by 6 hours. IGFBP-2, in contrast, fell slightly during surgery from 636 +/- 14 to 599 +/- 96 mg/l and then returned to basal levels by 6 hours. CONCLUSION: After major surgery there are complex and diverse changes in the IGFs and IGFBPs. The effect of these changes on IGF bioavailability may significantly affect the therapeutic potential of IGF-I in this setting.

Alfentanil suppresses coughing and agitation during emergence from isoflurane anesthesia.

STUDY OBJECTIVE: To evaluate the effectiveness of alfentanil in suppressing coughing and agitation during emergence from isoflurane anesthesia. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Operating rooms at a university medical center. PATIENTS: 34 healthy ASA physical status I and II adult patients scheduled to undergo oral surgical procedures. INTERVENTIONS: During emergence from anesthesia, patients received either alfentanil 15 micrograms/kg (in 10 ml) or saline (10 ml) when the end-tidal isoflurane concentration reached 0.3%. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables were measured at one-minute intervals following administration of the study medication. A blinded observer recorded the time for patients to spontaneously open their eyes and to follow commands after discontinuing the isoflurane. The occurrence of coughing and agitation prior to extubation was noted. Patients in the alfentanil treatment group exhibited a reduced incidence of coughing prior to extubation (6% vs. 83%, respectively) and a longer time interval until the onset of spontaneous movements (21.1 +/- 2.6 min vs. 14.6 +/- 1.7 min, respectively). The interval between the onset of movement and orientation was shorter in the alfentanil-treated patients, resulting in similar extubation times for both groups. Alfentanil administration was also associated with lower heart rate, systolic diastolic, and mean arterial pressure values during the emergence period. CONCLUSION: Alfentanil decreased coughing, agitation, and cardiovascular stimulation during emergence from isoflurane anesthesia without prolonging the time of extubation.

Oxygen supply failure revisited.

This is a report of a previously undescribed cause of oxygen supply failure during anesthesia, resulting from a worn main switch on a Narkomed 2A anesthesia machine (North American Dräger Information Systems, Telford, PA). The implications of this incident are discussed.

Anaesthesia for procedures on the larynx and pharynx. The use of the Bullard laryngoscope in conjunction with high frequency jet ventilation.

Twenty patients undergoing elective procedures on the larynx and pharynx were anaesthetised using a propofol infusion and a bolus of vecuronium. High frequency jet ventilation was employed via a 7 French gauge catheter, with a second catheter being used to measure expired carbon dioxide levels. The Bullard laryngoscope was compared with the Macintosh instrument both for visualising the larynx and subsequently inserting a catheter. One catheter was left in place until the patient was fully awake, and in one case this enabled gas exchange to be maintained in the presence of laryngospasm. Using the Bullard laryngoscope, intubation was possible in all 20 patients, in a mean time of 22 (6.8) s. Using the Macintosh laryngoscope only 16 patients could be intubated and this took significantly longer at 34 (18.3) s (p < 0.05). The Bullard laryngoscope and high frequency jet ventilation offer a reliable method of intubating and anaesthetising patients with upper airways pathology and further benefits may accrue in the recovery period.

Thyrotoxicosis presenting as a life threatening hypokalaemic paralysis: investigation of the Na/K pump in isolated leucocytes.

A 37-year-old Chinese man presented with the rapid onset of profound muscle weakness, and a serum potassium of 1.7 mmol/l. The intravenous infusion of undiluted potassium chloride (2 mmol/ml) through a central venous catheter resulted in rapid recovery. Further investigation revealed thyrotoxicosis. He was treated with carbimazole and subsequently remained well. We assessed Na/K pump activity in isolated leucocytes taken from the patient and found an exaggerated response to adrenaline which ceased after he became euthyroid.

New methods of dealing with the complications of panendoscopy.

A 70-year-old man with chronic obstructive airways disease was scheduled to undergo panendoscopy following a course of radiotherapy for carcinoma of the larynx. He was anaesthetized using a propofol infusion and high frequency jet ventilation (HFJV). The jet ventilation catheter was left in situ at the end of the procedure. This enabled oxygenation to be maintained in the presence of post-operative laryngospasm by re-attaching the jet ventilator. Subsequently he developed respiratory failure, and a Bullard laryngoscope was used to visualize the vocal folds despite oedema of the tumour which made direct laryngoscopy impossible. A catheter was passed through the biopsy channel of the Bullard, enabling HFJV to be commenced. A conventional endotracheal tube was then railroaded over the catheter to facilitate conventional ventilation.

Interhospital transfers by helicopter: the first 50 patients of the Careflight project.

An interhospital helicopter transfer service was set up using a dedicated helicopter fitted with medical equipment and staffed by anaesthetists. The system proved to be safe and practical. Fifty patients were referred from 38 hospitals throughout the UK, with 84% of transfers preplanned. Patients were transferred a mean distance of 118 miles (range 35-397 miles) and there was no deterioration during transfer as measured by pre and post transfer sickness scores. Twenty-eight per cent of cases could not have been practically transferred by conventional means. The death rate of 20% was lower than that reported for specially equipped and staffed land transfer systems, which may indicate less physiological deterioration in the critically ill compared to road transfer. Dedicated helicopter transfer resulted in a 50% survival rate in patients with a sickness score over 18, a group found not to survive after land transfer. There was no correlation between distance moved and outcome. A helicopter transfer system using suitable equipment and staff is a practical and safe method of moving critically ill patients between hospitals, and may be preferable to land transfer for distances in excess of 25 miles.

Comparison of calcium-modulated proteins from vertebrate brains.

Calmodulins have been purified from porcine, rabbit, rat, and chicken brains and their structural and functional properties compared to those of the bovine brain protein whose complete amino acid sequence has been elucidated. No major differences were detected in the amino acid compositions and tryptic peptide maps of these five proteins. All calmodulins lacked tryptophan and cysteine and contained 1 mol of N epsilon-trimethyllysine and histidine per mol of protein. Bovine, porcine, rabbit, rat, and chicken brain calmodulins comigrated on polyacrylamide gels run under a variety of conditions in the presence and absence of denaturants. All brain calmodulins gave identical profiles for the calcium-dependent activation of "activatable" bovine brain 3',5'-cyclic nucleotide phosphodiesterase. In addition, they formed calcium-dependent complexes with rabbit skeletal muscle troponin I and the electrophoretic mobilities of the complexes were identical with one another and similar to the corresponding complex between troponin I and troponin C. These studies more fully define what is a calmodulin, demonstrate that calmodulin is a relatively invariant constituent of vertebrate brain, and indicate that calmodulin structure and function have been highly conserved throughout vertebrate evolution.