Gary H. Mills

The Persistent Exclusion of Older Patients From Ongoing Clinical Trials Regarding Heart Failure

BACKGROUND Much clinical research of relevance to elderly patients examines individuals who are younger than those who have the disease in question. A good example is heart failure. Therefore, we investigated the extent of exclusion of older individuals in ongoing clinical trials regarding heart failure. METHODS In the context of the Increasing the PaRticipation of the ElDerly in Clinical Trials (PREDICT) study, data from ongoing clinical trials regarding heart failure were extracted from the World Health Organization Clinical Trials Registry Platform on December 1, 2008. Main outcome measures were the proportion of trials excluding patients by an arbitrary upper age limit or by other exclusion criteria that might indirectly cause limited recruitment of older individuals. We classified exclusion criteria into 2 categories: justified or poorly justified. RESULTS Among 251 trials investigating treatments for heart failure, 64 (25.5%) excluded patients by an arbitrary upper age limit. Such exclusion was significantly more common in trials conducted in the European Union than in the United States (31/96 [32.3%] vs 17/105 [16.2%]; P = .007) and in drug trials sponsored by public institutions vs those by private entities (21/59 [35.6%] vs 5/36 [13.9%]; P = .02). Overall, 109 trials (43.4%) on heart failure had 1 or more poorly justified exclusion criteria that could limit the inclusion of older individuals. A similar proportion of clinical trials with poorly justified exclusion criteria was found in pharmacologic and nonpharmacologic trials. CONCLUSION Despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.

Sleep disruption in critically ill patients--pharmacological considerations.

Sleep disturbances are common in critically ill patients and contribute to morbidity. Environmental factors, patient care activities and acute illness are all potential causes of disrupted sleep. Additionally, it is important to consider drug therapy as a contributing factor to this adverse experience, which patients perceive as particularly stressful. Sedative and analgesic combinations used to facilitate mechanical ventilation are among the most sleep disruptive drugs. Cardiovascular, gastric protection, anti‐asthma, anti‐infective, antidepressant and anticonvulsant drugs have also been reported to cause a variety of sleep disorders. Withdrawal reactions to prescribed and occasionally recreational drugs should also be considered as possible triggers for sleep disruption. Tricyclic antidepressants and benzodiazepines are commonly prescribed in the treatment of sleep disorders, but have problems with decreasing slow wave and rapid eye movement sleep phases. Newer non‐benzodiazepine hypnotics offer little practical advantage. Melatonin and atypical antipsychotics require further investigation before their routine use can be recommended.

Clinical review: Sleep measurement in critical care patients: research and clinical implications

Sleep disturbances are common in critically ill patients and have been characterised by numerous studies using polysomnography. Issues regarding patient populations, monitoring duration and timing (nocturnal versus continuous), as well as practical problems encountered in critical care studies using polysomnography are considered with regard to future interventional studies on sleep. Polysomnography is the gold standard in objectively measuring the quality and quantity of sleep. However, it is difficult to undertake, particularly in patients recovering from critical illness in an acute-care area. Therefore, other objective (actigraphy and bispectral index) and subjective (nurse or patient assessment) methods have been used in other critical care studies. Each of these techniques has its own particular advantages and disadvantages. We use data from an interventional study to compare agreement between four of these alternative techniques in the measurement of nocturnal sleep quantity. Recommendations for further developments in sleep monitoring techniques for research and clinical application are made. Also, methodological problems in studies validating various sleep measurement techniques are explored.Trial registration Current Controlled Trials ISRCTN47578325.

Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach

Please cite this paper as: Kiely D, Condliffe R, Webster V, Mills G, Wrench I, Gandhi S, Selby K, Armstrong I, Martin L, Howarth E, Bu’Lock F, Stewart P, Elliot C. Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach. BJOG 2010;117:565–574.

MRI of Helium-3 Gas in Healthy Lungs: Posture Related Variations of Alveolar Size

To probe the variation of alveolar size in healthy lung tissue as a function of posture using diffusion‐weighted helium‐3 hyperpolarized gas imaging.

Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study.

AbstractBackground: There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co-morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study. Objective: The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials. Methods: A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK. Results: There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61–83%) and polypharmacy (63–85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration. Conclusions: Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people.

The use of iloprost in early pregnancy in patients with pulmonary arterial hypertension

In patients with pulmonary hypertension, pregnancy is associated with a high risk of maternal death. Such patients are counselled to avoid pregnancy, or if it occurs, are offered early interruption. Some patients, however, decide to continue with their pregnancy and others may present with symptoms for the first time whilst pregnant. Pulmonary vasodilator therapy provides a treatment option for these high-risk patients. The present study describes three patients with pulmonary arterial hypertension of various aetiologies who were treated with the prostacyclin analogue iloprost during pregnancy, and the post-partum period. Nebulised iloprost commenced as early as 8 weeks of gestation and patients were admitted to hospital between 24–36 weeks of gestation. All pregnancies were completed with a duration of between 25–36 weeks and all deliveries were by caesarean section under local anaesthetic. All patients delivered children free from congenital abnormalities, and there was no post-partum maternal or infant mortality. In conclusion, although pregnancy is strongly advised against in those with pulmonary hypertension, the current authors have achieved a successful outcome for mother and foetus with a multidisciplinary approach and targeted pulmonary vascular therapy.

Implications of ICU triage decisions on patient mortality: a cost-effectiveness analysis

IntroductionIntensive care is generally regarded as expensive, and as a result beds are limited. This has raised serious questions about rationing when there are insufficient beds for all those referred. However, the evidence for the cost effectiveness of intensive care is weak and the work that does exist usually assumes that those who are not admitted do not survive, which is not always the case. Randomised studies of the effectiveness of intensive care are difficult to justify on ethical grounds; therefore, this observational study examined the cost effectiveness of ICU admission by comparing patients who were accepted into ICU after ICU triage to those who were not accepted, while attempting to adjust such comparison for confounding factors.MethodsThis multi-centre observational cohort study involved 11 hospitals in 7 EU countries and was designed to assess the cost effectiveness of admission to intensive care after ICU triage. A total of 7,659 consecutive patients referred to the intensive care unit (ICU) were divided into those accepted for admission and those not accepted. The two groups were compared in terms of cost and mortality using multilevel regression models to account for differences across centres, and after adjusting for age, Karnofsky score and indication for ICU admission. The analyses were also stratified by categories of Simplified Acute Physiology Score (SAPS) II predicted mortality (< 5%, 5% to 40% and >40%). Cost effectiveness was evaluated as cost per life saved and cost per life-year saved.ResultsAdmission to ICU produced a relative reduction in mortality risk, expressed as odds ratio, of 0.70 (0.52 to 0.94) at 28 days. When stratified by predicted mortality, the odds ratio was 1.49 (0.79 to 2.81), 0.7 (0.51 to 0.97) and 0.55 (0.37 to 0.83) for <5%, 5% to 40% and >40% predicted mortality, respectively. Average cost per life saved for all patients was

Rapid lung volumetry using ultrafast dynamic magnetic resonance imaging during forced vital capacity maneuver: correlation with spirometry

103,771 (€82,358) and cost per life-year saved was

MR imaging of the lungs with hyperpolarized helium-3 gas transported by air

7,065 (€5,607). These figures decreased substantially for patients with predicted mortality higher than 40%,