A pilot phase II randomized, cross-over, double-blinded, controlled efficacy study of octreotide versus hyoscine hydrobromide for control of noisy breathing at the end-of-life. Non-pharmacological intervention for breathlessness in lung cancer. A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Multicentre randomised controlled trial of nursing intervention for breathlessness in patients with lung cancer. High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669]. Randomised controlled trial of the effectiveness of a respiratory health worker in reducing impairment, disability, and handicap due to chronic airflow limitation. The effects of a cognitive behavioural intervention in asthmatic patients. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Can a standardized acupuncture technique palliate disabling breathlessness: a single-blind, placebo-controlled crossover study.
Noisy breathing at the end of life (noisy breathing ("NB") occurs in up to 90% of people. Interventions have not been systematically evaluated. There has been clinical observation coupled with a proposed mechanism of effect that supports a role for octreotide in management of NB. The aim of this phase II study was to assess ten completed participants for the feasibility of an adequately powered phase III study. This randomized, double-blind, crossover pilot trial recruited participants from an inpatient palliative unit. Participants while well and their proxies simultaneously provided written informed consent. If NB were encountered, people were randomized to 200 mcg octreotide or 400 mcg hyoscine hydrobromide subcutaneously. If subsequent treatment was needed, the other medication was administered. A five point categorical scale documented the nurses' assessment of secretions over six hours. Eighty participants were consented of whom 10 (3 females, 7 males; median age 79, all with advanced cancer) received medication, five in each arm. There was no difference in the median time to administration of the second medication (3 hours). Two participants in each arm had a 2 category reduction of intensity after the second medication. Although feasible to consent and study this population in a way that respects autonomy and dignity even in the terminal hours of life, this pilot study suggests reconsideration of the pharmacological interventions (choice of agents, dosing, timing of dosing and pharmacokinetic profiles), standardizing of non-pharmacological care; and ways to measure directly family distress before further randomized studies for this symptom. To evaluate the effect of non-pharmacological intervention for breathlessness in lung cancer on breathlessness ratings and patient functioning.
                Randomised controlled pilot study.
                A nurse led clinic in a specialist cancer centre.
                20 patients with advanced small cell and non-small cell lung cancer.
                Weekly sessions with a nurse research practitioner over 3-6 weeks using counselling, breathing re-training, relaxation and teaching coping and adaptation strategies.
                Visual analogue scale ratings of breathlessness, distress caused by breathlessness, functional capacity, ability to perform activities of daily living and the Hospital Anxiety and Depression Scale.
                Improvements in median scores on all measures were observed in the intervention group with the exception of depression, compared with the control group where median scores were static or worsened. Distress from breathlessness was improved by a median of 53%, breathlessness at worst by 35% and functional capacity by 21%. In contrast, distress in the control group worsened by a median of 10%. Significant improvements compared with the control group were observed in breathlessness at best (p < 0.02), breathlessness at worst (p < 0.05), distress caused by breathlessness (p < 0.01), functional capacity (p < 0.02) and ability to perform activities of daily living (p < 0.03) but were not observed for anxiety or depression.
                Lung cancer patients suffering from breathlessness benefited from this rehabilitative approach to breathlessness management and strategies employed in this pilot study warrant further multicentre research. Macmillan nurses and palliative care teams are recommended to explore the potential of adopting similar approaches. To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency.
                A multi-centre, randomized, double-blind, placebo-controlled clinical study.
                Thirty-one hospitals in six European countries.
                One hundred two patients with ARDS.
                Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 microg/kg per h, rising over 24 h to a maximum dose of 1.8 microg/kg per h.
                Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23).
                TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation. To evaluate the effectiveness of nursing intervention for breathlessness in patients with lung cancer.
                Patients diagnosed with lung cancer participated in a multicentre randomised controlled trial where they either attended a nursing clinic offering intervention for their breathlessness or received best supportive care. The intervention consisted of a range of strategies combining breathing control, activity pacing, relaxation techniques, and psychosocial support. Best supportive care involved receiving standard management and treatment available for breathlessness, and breathing assessments. Participants completed a range of self assessment questionnaires at baseline, 4 weeks, and 8 weeks.
                Nursing clinics within 6 hospital settings in the United Kingdom.
                119 patients diagnosed with small cell or non-small cell lung cancer or with mesothelioma who had completed first line treatment for their disease and reported breathlessness.
                Visual analogue scales measuring distress due to breathlessness, breathlessness at best and worst, WHO performance status scale, hospital anxiety and depression scale, and Rotterdam symptom checklist.
                The intervention group improved significantly at 8 weeks in 5 of the 11 items assessed: breathlessness at best, WHO performance status, levels of depression, and two Rotterdam symptom checklist measures (physical symptom distress and breathlessness) and showed slight improvement in 3 of the remaining 6 items.
                Most patients who completed the study had a poor prognosis, and breathlessness was typically a symptom of their deteriorating condition. Patients who attended nursing clinics and received the breathlessness intervention experienced improvements in breathlessness, performance status, and physical and emotional states relative to control patients. To compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted.
                Patients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up.
                The study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22-2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43-3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI.
                No significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI. A randomised controlled trial was undertaken to determine whether a respiratory health worker was effective in reducing the respiratory impairment, disability, and handicap experienced by patients with chronic airflow limitation attending a respiratory outpatient department. The 152 adults (aged 30-75 years) who participated had a prebronchodilator forced expiratory volume in one second (FEV1) below 60% predicted and no other disease. They were randomised to receive the care of a respiratory health worker or the normal services provided by the outpatient department. The respiratory health worker provided health education and symptom and treatment monitoring in liaison with primary care services. After one year there was little difference between the two groups in spirometric values (FEV1 and forced vital capacity before and after salbutamol 200 micrograms), disability (six minute walking distance and paced step test), and handicap (sickness impact profile, hospital anxiety and depression scale). Patients not looked after by the respiratory health worker were more likely to die (relative risk 2.9 (95% confidence limits 0.8, 10.2); when age and FEV1 were controlled for this risk increased to 5.5 (95% confidence limits 1.2, 24.5). Patients looked after by the respiratory health worker attended their general practitioner more frequently and were prescribed a greater range of drugs. This is the third study to have found limited measurable benefit in terms of morbidity from the intervention of a respiratory health worker. This may be due to the ability of such workers to keep frail patients alive. There is evidence that educational programmes may improve patient's compliance with asthma treatment and control symptoms. Whilst medical parameters have been thoroughly studied, few data are available concerning psychological intervention. The aim of our open pilot study was to verify whether any difference in perceived illness and response style to asthma existed in the patients enrolled in an Asthma Rehabilitation Group (ARG) and in a Control Group (CG). Forty consecutive asthmatics were randomly enrolled, all of whom were diagnosed, treated and followed-up according to the International Guidelines. Both groups underwent a psychological assessment at baseline and after one year. A battery of questionnaires was used to obtain data relating to baseline characteristics (anxiety, depression, psychophysiological disorders), emotional reactions to asthma attacks (panic-fear, etc,) and cognitive variables (external control, psychological stigma, internal beliefs, external chance, etc.) involved in the perceived illness. In addition, the Asthma Rehabilitation Group patients underwent an educational programme and a cognitive-behavioural intervention. In both groups, a reduction of anxiety and depression scores was observed, as well as a significant improvement of the medical parameters evaluated. Only the Asthma Rehabilitation Group reported lower scores on the Psychophysiological Questionnaire and on the External Control Subscale after 1 year. The Control Group reported higher score on the External Chance Scale. The data of our study seem to confirm the effectiveness of psychological intervention on the cognitive skills involved in the perception and management of asthma. Larger scale studies on this topic are suggested. To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed.
                Prospective, multicenter, randomized, double-blind, placebo-controlled study.
                Intensive care units of 30 academic, teaching, and community hospitals in the United States.
                Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization.
                Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm.
                Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm.
                From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome. The management of disabling breathlessness is poor, and a standardized form of acupuncture has been reported as offering benefit. This study was designed to evaluate the efficacy of standardized acupuncture treatment.
                A single-blind, randomized, crossover study.
                This study was carried out on a domiciliary basis in Southampton (UK).
                This study evaluated a standardized acupuncture technique vs an appropriately validated placebo/control (mock transcutaneous electrical nerve stimulation [TENS]) for disabling, nonmalignant breathlessness (largely COPD). The acupuncture was provided by an appropriately trained nurse acupuncturist. Each patient received six treatments in each phase of the study, with an intervening 2-week washout period.
                The primary outcome was worst breathlessness (visual analog scale, 0 to 100 mm), with the sample size based on an 80% power to detect a 10-mm difference between treatment means. Secondary outcomes included the St George's respiratory questionnaire score and treatment credibility.
                Thirty-six patients were entered into the study (33 with COPD), and 24 patients completed both treatment phases. The primary outcome improved significantly during the course of the study, but there were no significant treatment differences between acupuncture and the placebo/control of mock TENS for either primary or secondary outcomes. The placebo was shown to be a credible control. There was no evidence of a carryover effect from the first to second phase of the study.
                This standardized acupuncture technique does not show specific efficacy in disabling nonmalignant breathlessness, but those entered into the study did experience clinically significant benefit from both treatments.
In our original Cochrane review, we concluded that there was no evidence to show that any intervention, be it pharmacological or non-pharmacological, was superior to placebo in the treatment of noisy breathing. This conclusion has not changed. We acknowledge that in the face of heightened emotions when death is imminent, it is difficult for staff not to intervene. It is therefore likely that the current therapeutic options will continue to be used. However, patients need to be closely monitored for lack of therapeutic benefit and adverse effects while relatives need time, explanation and reassurance to relieve their fears and concerns. There remains a need for well-designed multi-centre studies with objective outcome measures which demonstrates the efficacy of intervention against placebo for this condition.