Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology.

BACKGROUND: Reserpine is a popular drug in the equine industry for long-term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. OBJECTIVES: To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. STUDY DESIGN: Experimental controlled study. METHODS: The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC-MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B2 were performed on platelets exposed to varying concentrations of reserpine (0.01-10 ng/mL), aspirin (negative control) and saline (unexposed control). RESULTS: Oral reserpine administration demonstrated low plasma concentrations with a Cmax of 0.2 ± 0.06 ng/mL and a prolonged half-life of 23.6 ± 6.24 h. Simulations over a dose range of 2-8 µg/kg predicted Cmax at steady state between 0.06-0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin-exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B2 in the platelet suspension supernatant. MAIN LIMITATIONS: This study used a small number of horses and only in vitro platelet experiments. CONCLUSIONS: Oral reserpine demonstrates low plasma concentrations and a prolonged half-life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re-uptake which primes platelets for activation and thromboxane B2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.

Recruitment to randomised trials: strategies for trial enrollment and participation study. The STEPS study.

OBJECTIVES: To identify factors associated with good and poor recruitment to multicentre trials. DATA SOURCES: Part A: database of trials started in or after 1994 and were due to end before 2003 held by the Medical Research Council and Health Technology Assessment Programmes. Part B: interviews with people playing a wide range of roles within four trials that their funders identified as 'exemplars'. Part C: a large multicentre trial (the CRASH trial) of treatment for head injury. REVIEW METHODS: The study used a number of different perspectives ('multiple lenses'), and three components. Part A: an epidemiological review of a cohort of trials. Part B: case studies of trials that appeared to have particularly interesting lessons for recruitment. Part C: a single, in-depth case study to examine the feasibility of applying a business-orientated analytical framework as a reference model in future trials. RESULTS: In the 114 trials found in Part A, less than one-third recruited their original target within the time originally specified, and around one-third had extensions. Factors observed more often in trials that recruited successfully were: having a dedicated trial manager, being a cancer or drug trial, and having interventions only available inside the trial. The most commonly reported strategies to improve recruitment were newsletters and mailshots, but it was not possible to assess whether they were causally linked to changes in recruitment. The analyses in Part B suggested that successful trials were those addressing clinically important questions at a timely point. The investigators were held in high esteem by the interviewees, and the trials were firmly grounded in existing clinical practices, so that the trial processes were not alien to clinical collaborators, and the results could be easily applicable to future practice. The interviewees considered that the needs of patients were well served by participation in the trials. Clinical collaborators particularly appreciated clear delineation of roles, which released them from much of the workload associated with trial participation. There was a strong feeling from interviewees that they were proud to be part of a successful team. This pride fed into further success. Good groundwork and excellent communications across many levels of complex trial structures were considered to be extremely important, including training components for learning about trial interventions and processes, and team building. All four trials had faced recruitment problems, and extra insights into the working of trials were afforded by strategies invoked to address them. The process of the case study in Part C was able to draw attention to a body of research and practice in a different discipline (academic business studies). It generated a reference model derived from a combination of business theory and work within CRASH. This enabled identification of weaker managerial components within CRASH, and initiatives to strengthen them. Although it is not clear, even within CRASH, whether the initiatives that follow from developing and applying the model will be effective in increasing recruitment or other aspects of the success of the trial, the reference model could provide a template, with potential for those managing other trials to use or adapt it, especially at foundation stages. The model derived from this project could also be used as a diagnostic tool if trials have difficulties and hence as a basis for deciding what type of remedial action to take. It may also be useful for auditing the progress of trials, such as during external review. CONCLUSIONS: While not producing sufficiently definitive results to make strong recommendations, the work here suggests that future trials should consider the different needs at different phases in the life of trials, and place greater emphasis on 'conduct' (the process of actually doing trials). This implies learning lessons from successful trialists and trial managers, with better training for issues relating to trial conduct. The complexity of large trials means that unanticipated difficulties are highly likely at some time in every trial. Part B suggested that successful trials were those flexible and robust enough to adapt to unexpected issues. Arguably, the trialists should also expect agility from funders within a proactive approach to monitoring ongoing trials. Further research into different recruitment patterns (including 'failures') may help to clarify whether the patterns seen in the 'exemplar' trials differ or are similar. The reference model from Part C needs to be further considered in other similar and different trials to assess its robustness. These and other strategies aimed at increasing recruitment and making trials more successful need to be formally evaluated for their effectiveness in a range of trials.

Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.

BACKGROUND: Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures. METHODS: In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures. FINDINGS: 698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups. INTERPRETATION: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.

Improving survival following AIDS in Australia, 1991-1996. National HIV Surveillance Committee.

OBJECTIVE: To describe the pattern of survival following AIDS. DESIGN: National surveillance for AIDS diagnoses. METHODS: AIDS cases in adults/adolescents (aged 13 years or older at AIDS diagnosis) and deaths following AIDS were notified to the national HIV surveillance centre by the diagnosing doctor through State/Territory health authorities. The date of last medical contact for each case living with AIDS was updated annually. RESULTS: By 30 June 1999, 4814 AIDS cases, diagnosed in Australia in 1991-1996, and 3193 deaths following AIDS had been notified to the National AIDS Registry. Median survival following AIDS was 17.7 months. Survival following AIDS increased from 16.0 months in 1991 to 27.7 months in 1996. Factors independently associated with improved survival were year of AIDS diagnosis, late HIV diagnosis, CD4+ cell count greater than 50 x 10(6) cells/l, age of less than 45 years and presentation with Pneumocystis carinii pneumonia only or Kaposi's sarcoma only. The risk of death declined over time when the initial AIDS-defining illness was Pneumocystis carinii pneumonia only [adjusted hazard ratio (AHR) = 0.91, P < 0.0005]; other opportunistic infections (AHR, 0.88; P < 0.0005); Kaposi's sarcoma only (AHR, 0.92; P = 0.025); and central nervous system conditions (HIV encephalopathy, cryptococcosis, toxoplasmosis) (AHR, 0.92; P = 0.012). No time trend was observed for survival following diagnoses of non-Hodgkin's lymphoma or other multiple illnesses. CONCLUSIONS: Survival following AIDS has improved in Australia, especially among cases diagnosed in 1995 and 1996. Temporal improvements in survival following AIDS were coincident with the introduction of combination antiretroviral treatment for HIV infection and suggest that treatment is effective in limiting disease progression among people with advanced HIV infection.

The role of initial AIDS-defining illness in survival following AIDS.

OBJECTIVE: To examine the role of initial AIDS-defining illness in survival following AIDS and survival trends over time. DESIGN: States and Territory Health Departments notified new diagnoses of AIDS to the National AIDS Registry. Information on vital status and date of last medical contact was sought annually. METHODS: Survival was calculated for all adult and adolescent AIDS cases (n = 3204) in Australia diagnosed until 1 November 1991 and reported to the National AIDS Registry by 31 March 1994. The Cox regression method was used to identify independent predictors for survival. RESULTS: Age < 50 years, a CD4+ cell count > or = 100 x 10(6)/l and an initial diagnosis of Kaposi's sarcoma were independently associated with longer survival (P < 0.05). Acquisition of HIV through blood transfusion and the AIDS-defining illness non-Hodgkin's lymphoma were significantly associated with shorter survival. Survival improved substantially from 1986 to 1987, but did not improve further thereafter. A further study of initial AIDS-defining illnesses in a subgroup of individuals, i.e., men aged < 50 years at diagnosis who acquired HIV infection through homosexual or bisexual contact and diagnosed after 1987, showed that Kaposi's sarcoma, Pneumocystis carinii pneumonia, oesophageal candidiasis and herpes simplex virus as initial AIDS-defining illnesses had a relatively better prognosis than other single illnesses. Furthermore, patients with multiple illnesses did not have a worse prognosis than patients with a single illness, provided all illnesses were those with a better prognosis. CONCLUSIONS: Initial AIDS-defining illness, as well as age at diagnosis, year of diagnosis, HIV exposure and CD4+ cell count at diagnosis, plays an important role in survival following AIDS in Australia.

Estimating the population impact in Australia of improved antiretroviral treatment for HIV infection.

OBJECTIVE: To estimate the reduction in AIDS incidence, if any, which has occurred in Australia following the availability of new combination antiretroviral treatments from 1995. DESIGN: Analyses were based on national surveillance data. METHODS: Back-projection analyses based on quarterly AIDS counts to the end of 1994 were used to estimate the numbers of AIDS diagnoses which would have occurred if new treatments had not reduced the rate of progression to AIDS. Estimates of the reduction in AIDS diagnoses between 1995 and 1998 were made by subtracting the observed delay-adjusted AIDS counts from the predicted AIDS incidence. RESULTS: AIDS incidence between 1995 and 1998 was estimated to have been reduced by 1093 cases (33%) following the availability of new antiretroviral treatments (95% confidence interval 831 (25%) to 1425 (43%) cases). The majority of this reduction in AIDS incidence was estimated to have occurred during 1997 (434 cases) and 1998 (427 cases). CONCLUSIONS: AIDS incidence in Australia has declined since 1995 coincidental with introduction of new antiretroviral treatments. In particular, the more rapid decline in AIDS incidence since mid-1996 coincided with the availability and widespread uptake of combinations including protease inhibitors.

Decreasing rates of Kaposi's sarcoma and non-Hodgkin's lymphoma in the era of potent combination anti-retroviral therapy.

OBJECTIVE: To describe the changing incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) in people with HIV in Australia during the time period of introduction of potent combination anti-retroviral therapy. DESIGN: A national, population-based linkage study of cancer and HIV registration data. METHODS: We calculated person-year rates of KS and NHL in people after reporting of HIV diagnosis. Trends in cancer incidence rates were examined, based on four time periods defined by the availability of specific anti-retroviral therapies. RESULTS: Linkage identified 206 cases of KS and 235 cases of NHL in 8108 people reported with HIV infection. There was an increasing trend in NHL incidence rates over the four time periods (P for trend, 0.012), but incidence for the period since the availability of the new therapies was significantly lower than that for the period immediately prior (incidence rate ratio 0.58; 95% confidence interval, 0.36-0.92). Incidence of KS had been decreasing prior to the new therapies and declined further since their widespread use (P for trend, 0.045). CONCLUSIONS: Population-based incidence rates of AIDS related KS and NHL have decreased since the widespread use of potent anti-retroviral therapies in Australia. NHL incidence decreased less than KS, and NHL is now the most common AIDS-associated cancer in Australia.

The pattern of diagnosed HIV infection in Australia, 1984-1992.

OBJECTIVE: To describe the pattern of newly diagnosed HIV infection in Australia, between 1984 and 1992. METHODS: State and Territory health authorities reported cases of newly diagnosed HIV infection to the national HIV surveillance centre. Information sought on each case included the State or Territory of diagnosis, the case identifying number, the sex, date of birth and postcode of residence of the person with newly diagnosed HIV infection, the source of exposure to HIV and the date of specimen collection for the diagnosis of infection. RESULTS: By the end of December 1992, a total of 16,765 cases of newly diagnosed HIV infection had been reported in Australia. The annual number of cases declined between 1985 and 1992. Most diagnoses were among males, and exposure to HIV was attributed to male homosexual contact for more than 80% of cases for which information on exposure to HIV was available. Cases of HIV infection attributed to heterosexual contact represented an increasing proportion of the annual number of diagnoses over the period 1985-1992, among both men and women. CONCLUSION: National surveillance for newly diagnosed HIV infection has complemented national surveillance for diagnoses of AIDS as a key mechanism for monitoring the course of the HIV epidemic in Australia. The pattern of newly diagnosed HIV infection was similar to the pattern of AIDS diagnoses, with the overwhelming majority of diagnoses of infection being in adult males whose exposure to HIV was attributed to homosexual contact. Limitations of HIV surveillance include the lack of information on HIV testing patterns, incomplete information on HIV exposure histories and duplication of reported diagnoses.

Sodium, lithium-countertransport and blood pressure control by nutritional intervention in 'mild' hypertension.

Erythrocyte membrane cation transport was measured in 167 adults completing the fourth year of a randomized controlled trial testing the efficacy of nutrition intervention for treatment of 'mild' hypertension. Intervention objectives consisted of weight loss, moderate sodium restriction, and reduction of alcohol intake. The mean sodium-stimulated lithium-countertransport (LCT) for 35 participants able to maintain normotensive blood pressures for 4 years by nutritional means alone was 0.29 mmol/l cells per h compared with 0.38 for the 48 subjects requiring represcription of drugs (P less than 0.01). Weight loss from baseline to year 4 was inversely related to LCT among those who were overweight at baseline (P less than 0.05); reported alcohol intakes were positively related to LCT (P less than 0.05). These findings suggest that blood pressure control by nutrition intervention in 'mild' hypertensives is associated with levels of LCT characteristic of normotension. Higher mean LCT in those requiring represcription of drugs was related to lower serum potassium and higher serum triglyceride levels in this subgroup.

Sodium-lithium countertransport and systolic blood pressure response to exercise.

This study examined the relationship between erythrocyte sodium-stimulated lithium countertransport (Na-Li CT) and systolic blood pressure (SBP) response to exercise in 22 white normotensive men (mean age 40.6 years) completing a submaximal (85% of target heart rate) graded exercise tolerance test. These men were assessed to be at risk of hypertension on the basis of a high normal diastolic blood pressure (DBP; 80-89 mmHg), being overweight and having a rapid resting pulse rate. Na-Li CT was positively and significantly associated with the maximal SBP reached during exercise (P less than 0.01) and the lowest SBP achieved during post-exercise supine rest (P less than 0.01). The relationship with resting blood pressure was not significant. Standing DBP was the only resting blood pressure measurement significantly associated with Na-Li CT (P less than 0.05). We found an association between Na-Li CT, a membrane sodium transport system associated with blood pressure and hypertension, and the maximal SBP reached during exercise, a blood pressure measurement predictive of future hypertension, in people with normotensive resting blood pressure. This suggests that altered membrane sodium transport may occur before the establishment of hypertension, and supports the possibility that Na-Li CT may be a risk factor for this disease.

Separate and joint effects of marine oil and simvastatin in patients with combined hyperlipidemia.

Marine oil plus simvastatin is an effective therapy for improving serum triglycerides, non-high-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in patients with combined hyperlipidemia. Concurrent administration does not attenuate the individual effects of either marine oil or simvastatin on the serum lipid profile.

A retrospective study of nosocomial pneumonia at a long-term care facility.

BACKGROUND: Results of a passive surveillance system (pneumonia confirmed by x-ray examination) suggested that in 1989 a total of 187 cases of nosocomial pneumonia had occurred at the Canandaigua Veterans Administration Medical Center among 250 long-term care patients. METHODS: A retrospective study was undertaken to validate cases and to enumerate risk factors. A chart review showed that 136 of 187 cases (72%) met predetermined criteria for nosocomial pneumonia. RESULTS: Three nursing units characterized as at high risk had a pneumonia rate of 1.90 per 1000 patient days, as compared with a rate of 0.70 cases per 1000 patient days on the two other units. There were no differences in age, mean white blood cell count, or clinical symptoms between high- and average-risk patients. Two thirds of all patients had a history of chronic aspiration. High-risk patients were more likely to be confined to bed, to have a debilitating neurologic disease, and to require tube feedings. Twenty percent of patients on high-risk units died of nosocomial pneumonia or with nosocomial pneumonia as a contributory factor. CONCLUSIONS: Facility-associated pneumonia is an important cause of morbidity and mortality in long-term care facilities.

The iodine-staining properties and fine structure of some mammalian and invertebrate glycogens.

Glycogens from mammalian and invertebrate sources have been compared by measuring the iodine-staining spectra of the debranched polymers and the debranched beta-amylase limit dextrins. From the results, it is concluded that, whereas the interior chains of each group of glycogen are very similar, the exterior chains of the mammalian glycogens generally contain a small number of longer chains which are not found in the invertebrate glycogens.

Estimation of cumulative HIV incidence in Australia, based on national case reporting.

It has been recognised that the Australian National HIV Database may contain multiple reports for some individuals, mainly because of incomplete or inaccurate recording of name codes. The number of distinct individuals diagnosed with human immunodeficiency virus (HIV) was estimated from the dates of birth of cases of HIV infection reported to the database. There were 18,787 cases of HIV infection diagnosed by the end of 1994 and reported to the database by the end of April 1995. Based on the reported dates of birth, the total number of individuals was estimated to lie in the range 13,600 to 15,300. Corresponding analyses by state (or territory) estimated the total number of individuals diagnosed with HIV to lie in the ranges 8360 to 9760 in New South Wales, 1490 to 1540 in Queensland, 3010 to 3180 in Victoria and 1530 to 1600 in other states and territories combined. It was estimated that 5 per cent of individuals were diagnosed with HIV infection in more than one state. Allowing for people with HIV infection who have not yet been tested for HIV antibody and reported, the total number of people to have acquired HIV in Australia by the end of 1994 was estimated to lie in the range 15,500 to 17,700. This is consistent with back-projection estimates.

Demographic pattern of AIDS in Australia, 1991 to 1993. The National HIV Surveillance Committee.

Population-based acquired immune deficiency syndrome (AIDS) incidence in Australia in 1991-1993 was ascertained. The National Centre in HIV Epidemiology and Clinical Research obtained information on AIDS cases from notification by doctors of AIDS diagnoses through the Department of Health in each state and territory. Information on the Australian population, broken down by sex, age group, country of birth and geographic area of residence was obtained from the Australian Bureau of Statistics. To the end of February 1995, 2341 cases of AIDS were reported as having been diagnosed in Australia during 1991-1993. Of these, 96 per cent were in males, of whom over 72 per cent were in the age group 25-44 years. Geographic concentration of AIDS cases was observed: over 55 per cent of cases were in New South Wales (NSW) and these were concentrated in inner Sydney, in particular, in two metropolitan health areas: Eastern Sydney and Central Sydney. Age-standardised average annual incidence per 100,000 population was 8.9 for males, 0.4 for females and 4.6 overall. This incidence varied widely when the population was subdivided by Local Government Area, especially in NSW, where incidence for males varied from 0.0 to 204.4. The highest average annual incidence per 100,000 population by country of birth was recorded for people born in North America, which was almost four times higher than that for people born in Australia. Although AIDS cases diagnosed in 1991-1993 were concentrated on the metropolitan area of capital cities, cases also occurred in rural areas.

The clinical effect of correction of vitamin E depletion in cystic fibrosis.

Thirty patients with cystic fibrosis, 24 of whom had longstanding low serum vitamin E, were treated with 50 mg alpha-tocopherol acetate per day for periods of 18-24 months. None of the patients received haematinics during the study period. Throughout the period of study the overall clinical state of the patients did not alter significantly. The serum vitamin E level increased in all patients, but to a variable degree which was not related to the severity of steatorrhoea. A range of nutritional parameters, including anthropometry, vitamin levels, essential elements, haemoglobin and albumin, as well as dietary intake and faecal fat excretion, were assessed at the beginning and end of the study. Haemoglobin was the only parameter to change significantly from 13.14 to 13.47 g/100 ml. Twenty one of the 30 patients showed some increase in haemoglobin values and this increase could not be related to clinical state, fat absorption or dietary intake but was related to the improved vitamin E status.

Soft drink consumption in Pacific Island countries and territories: a review of trade data.

INTRODUCTION: Pacific Islands Countries and Territories (PICTs) have some of the highest rates of obesity and diabetes in the world. Research has demonstrated a strong link between sugar-sweetened beverage (SSB) consumption and subsequent risk of overweight, obesity, dental caries and type II diabetes. To address the impact of SSBs on noncommunicable diseases, it is crucial to understand the level of SSB consumption in PICTs. METHODS: The volume of soft drinks imported and exported was requested from PICTs to estimate the litres of soft drink consumption per head of population. Analysis was confined to PICTs who did not produce their own soft drinks because production data was limited. The Harmonised Commodity Description and Coding System (HS) category 22.02 was used which includes both diet and sugar-sweetened soft drinks. The trade data estimates were then compared with school survey data to explore how the data sources corresponded given the strengths and weaknesses of each. RESULTS: Soft drink import volumes were a feasible way of estimating total soft drink consumption in PICTs and look at trends over time. Seven out of eleven non-producing PICTs contacted were able to provide volume of soft drinks imported. In 2011, estimates of soft drink consumption per person were 84L in Palau, 47L in the Commonwealth of the Northern Mariana Islands (CNMI), 41L in Niue, 31L in Tonga, 22L in Federates States of Micronesia, 8L in Tuvalu and 1L in Kiribati. CONCLUSIONS: Trade data is a feasible way of monitoring soft drink consumption and may be useful to evaluate the impact of changes in government policy on importation of soft drinks. Data quality could be maximised by including export data, adjusting for visitor numbers and cross-checking exports from corresponding countries. To monitor SSB consumption, a wider range of categories could be included such as categories for sugar-sweetened juice and sweetened-milk drinks.

Developing a placebo-controlled trial in surgery: issues of design, acceptability and feasibility.

BACKGROUND: Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. METHODS: Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). RESULTS: There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. CONCLUSIONS: Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. TRIAL REGISTRATION NUMBER: The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007.

Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of the knee: a mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study).

OBJECTIVES: To ascertain the acceptability of a randomised controlled trial comparing arthroscopic lavage with a placebo-surgical procedure for the management of osteoarthritis of the knee; and to assess the practical feasibility of mounting such a multicentre placebo-controlled trial. DESIGN: Mixed methods study including: focus groups with surgeons and anaesthetists; focus groups and interviews with potential participants; interviews with chairpersons of UK Multicentre Research Ethics Committees (MRECs); surveys of surgeons and anaesthetists; and a two-centre, three-arm pilot. SETTING: UK secondary care. PARTICIPANTS: Members of the British Association of Surgeons of the Knee and members of the British Society of Orthopaedic Anaesthetists took part in the focus groups and surveys. Surgeons and anaesthetists from two regional centres in the UK also contributed to focus groups, as did patients from consultant lists in two UK regional centres, and members of Arthritis Care. Chairpersons of six UK MRECs were interviewed. Participants were eligible for the pilot if they were adults (18 years or older) with radiological evidence of osteoarthritis of the knee who might be considered for arthroscopic lavage, and were fit for general anaesthetic (defined by the American Society of Anaesthesiologists grades 1 and 2), and able to give informed consent. INTERVENTIONS: Participants in the pilot study were randomised to arthrosocopic lavage (with or without debridement at the clinical discretion of the surgeon); placebo surgery; or non-operative management with specialist reassessment. MAIN OUTCOME MEASURES: The acceptability and feasibility of mounting a placebo-controlled trial for the evaluation of knee arthroscopic lavage. RESULTS: There was broad acceptance across all stakeholder groups of the need to find out more about the effectiveness of arthroscopic lavage. Despite this there was variation in opinion within all the groups about how researchers should approach this and whether or not it would be acceptable to investigate using placebo surgery. Within the health professional groups, there tended to be a split between those who were strongly opposed to the inclusion of a placebo surgery arm and those who were more in favour. For prospective trial participants who had osteoarthritis of the knee, the acceptability of the trial was discussed from a more individual perspective - reflecting on their personal reasons for or against participating. The majority of this group said they would consider taking part. The pilot study showed that, in principle, a placebo-controlled trial could be conducted. It showed that patients were willing to participate in a trial which would involve a placebo-surgical arm and that it was possible to undertake placebo surgery successfully and to blind patients to their allocation - although once patients knew their allocation, some patients allocated to surgery became more concerned about the possibility of undergoing placebo surgery, and withdrew. The experience of the pilot, however, showed that, despite full MREC approval, the study required major discussion and negotiation before local clinical approvals could be obtained. The fact that ethics approval had been granted did not mean that clinicians would automatically accept that the process was ethical. CONCLUSIONS: The study showed that, in principle, a placebo-controlled trial of arthroscopic lavage could be conducted in the UK, albeit with difficulty. Against the background of falling use of arthroscopic lavage the decision was, therefore, taken not to proceed to full-scale trial for this procedure. The study showed that for some health professionals the use of placebo surgery can never be justified. It highlighted the importance of the surgeon-anaesthetist relationship in this context and how acceptance of the trial design by both parties is essential to successful participation. It also highlighted the importance of informed consent for trial participants and the strength and influence of individuals' ethical perspectives in addition to collective ethics provided by MRECs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02328576.