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1.  Long-Term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this health technology assessment was to determine the effectiveness, cost-effectiveness, and safety of long-term oxygen therapy (LTOT) for chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Oxygen therapy is used in patients with COPD with hypoxemia, or very low blood oxygen levels, because they may have difficulty obtaining sufficient oxygen from inspired air.
Technology
Long-term oxygen therapy is extended use of oxygen. Oxygen therapy is delivered as a gas from an oxygen source. Different oxygen sources are: 1) oxygen concentrators, electrical units delivering oxygen converted from room air; 2) liquid oxygen systems, which deliver gaseous oxygen stored as liquid in a tank; and 3) oxygen cylinders, which contain compressed gaseous oxygen. All are available in portable versions. Oxygen is breathed in through a nasal cannula or through a mask covering the mouth and nose. The treating clinician determines the flow rate, duration of use, method of administration, and oxygen source according to individual patient needs. Two landmark randomized controlled trials (RCTs) of patients with COPD established the role of LTOT in COPD. Questions regarding the use of LTOT, however, still remain.
Research Question
What is the effectiveness, cost-effectiveness, and safety of LTOT compared with no LTOT in patients with COPD, who are stratified by severity of hypoxemia?
Research Methods
Literature Search
Search Strategy
A literature search was performed on September 8, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Library, and INAHTA for studies published from January 1, 2007 to September 8, 2010.
A single clinical epidemiologist reviewed the abstracts, obtained full-text articles for studies meeting the eligibility criteria, and examined reference lists for additional relevant studies not identified through the literature search. A second clinical epidemiologist and then a group of epidemiologists reviewed articles with an unknown eligibility until consensus was established.
Inclusion Criteria
patients with mild, moderate, or severe hypoxemia;
English-language articles published between January 1, 2007 and September 8, 2010;
journal articles reporting on effectiveness, cost-effectiveness, or safety for the comparison of interest;
clearly described study design and methods;
health technology assessments, systematic reviews, RCTs, or prospective cohort observational studies;
any type of observational study for the evaluation of safety.
Exclusion Criteria
no hypoxemia
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
studies comparing different oxygen therapy regimens
studies on nocturnal oxygen therapy
studies on short-burst, palliative, or ambulatory oxygen (supplemental oxygen during exercise or activities of daily living)
Outcomes of Interest
mortality/survival
hospitalizations
readmissions
forced expiratory volume in 1 second (FEV1)
forced vital capacity (FVC)
FEV1/FVC
pulmonary hypertension
arterial partial pressure of oxygen (PaO2)
arterial partial pressure of carbon dioxide (PaCO2)
end-exercise dyspnea score
endurance time
health-related quality of life
Note: Outcomes of interest were formulated according to existing studies, with arterial pressure of oxygen and carbon dioxide as surrogate outcomes.
Summary of Findings
Conclusions
Based on low quality of evidence, LTOT (~ 15 hours/day) decreases all-cause mortality in patients with COPD who have severe hypoxemia (PaO2 ~ 50 mm Hg) and heart failure.
The effect for all-cause mortality had borderline statistical significance when the control group was no LTOT: one study.
Based on low quality of evidence, there is no beneficial effect of LTOT on all-cause mortality at 3 and 7 years in patients with COPD who have mild-to-moderate hypoxemia (PaO2 ~ 59-65 mm Hg)1
Based on very low quality of evidence, there is some suggestion that LTOT may have a beneficial effect over time on FEV1 and PaCO2 in patients with COPD who have severe hypoxemia and heart failure: improved methods are needed.
Based on very low quality of evidence, there is no beneficial effect of LTOT on lung function or exercise factors in patients with COPD who have mild-to-moderate hypoxemia, whether survivors or nonsurvivors are assessed.
Based on low to very low quality of evidence, LTOT does not prevent readmissions in patients with COPD who have severe hypoxemia. Limited data suggest LTOT increases the risk of hospitalizations.
Limited work has been performed evaluating the safety of LTOT by severity of hypoxemia.
Based on low to very low quality of evidence, LTOT may have a beneficial effect over time on health-related quality of life in patients with COPD who have severe hypoxemia. Limited work using disease-specific instruments has been performed.
Ethical constraints of not providing LTOT to eligible patients with COPD prohibit future studies from examining LTOT outcomes in an ideal way.
PMCID: PMC3384376  PMID: 23074435
2.  Physiotherapy Rehabilitation After Total Knee or Hip Replacement 
Executive Summary
Objective
The objective of this health technology policy analysis was to determine, where, how, and when physiotherapy services are best delivered to optimize functional outcomes for patients after they undergo primary (first-time) total hip replacement or total knee replacement, and to determine the Ontario-specific economic impact of the best delivery strategy. The objectives of the systematic review were as follows:
To determine the effectiveness of inpatient physiotherapy after discharge from an acute care hospital compared with outpatient physiotherapy delivered in either a clinic-based or home-based setting for primary total joint replacement patients
To determine the effectiveness of outpatient physiotherapy delivered by a physiotherapist in either a clinic-based or home-based setting in addition to a home exercise program compared with a home exercise program alone for primary total joint replacement patients
To determine the effectiveness of preoperative exercise for people who are scheduled to receive primary total knee or hip replacement surgery
Clinical Need
Total hip replacements and total knee replacements are among the most commonly performed surgical procedures in Ontario. Physiotherapy rehabilitation after first-time total hip or knee replacement surgery is accepted as the standard and essential treatment. The aim is to maximize a person’s functionality and independence and minimize complications such as hip dislocation (for hip replacements), wound infection, deep vein thrombosis, and pulmonary embolism.
The Therapy
The physiotherapy rehabilitation routine has 4 components: therapeutic exercise, transfer training, gait training, and instruction in the activities of daily living. Physiotherapy rehabilitation for people who have had total joint replacement surgery varies in where, how, and when it is delivered. In Ontario, after discharge from an acute care hospital, people who have had a primary total knee or hip replacement may receive inpatient or outpatient physiotherapy. Inpatient physiotherapy is delivered in a rehabilitation hospital or specialized hospital unit. Outpatient physiotherapy is done either in an outpatient clinic (clinic-based) or in the person’s home (home-based). Home-based physiotherapy may include practising an exercise program at home with or without supplemental support from a physiotherapist.
Finally, physiotherapy rehabilitation may be administered at several points after surgery, including immediately postoperatively (within the first 5 days) and in the early recovery period (within the first 3 months) after discharge. There is a growing interest in whether physiotherapy should start before surgery. A variety of practises exist, and evidence regarding the optimal pre- and post-acute course of rehabilitation to obtain the best outcomes is needed.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy, which included searching the databases of Ovid MEDLINE, CINHAL, EMBASE, Cochrane Database of Systematic Reviews, and PEDro from 1995 to 2005. English-language articles including systematic reviews, randomized controlled trials (RCTs), non-RCTs, and studies with a sample size of greater than 10 patients were included. Studies had to include patients undergoing primary total hip or total knee replacement, aged 18 years of age or older, and they had to have investigated one of the following comparisons: inpatient rehabilitation versus outpatient (clinic- or home-based therapy) rehabilitation, land-based post-acute care physiotherapy delivered by a physiotherapist compared with patient self-administered exercise and a land-based exercise program before surgery. The primary outcome was postoperative physical functioning. Secondary outcomes included the patient’s assessment of therapeutic effect (overall improvement), perceived pain intensity, health services utilization, treatment side effects, and adverse events
The quality of the methods of the included studies was assessed using the criteria outlined in the Cochrane Musculoskeletal Injuries Group Quality Assessment Tool. After this, a summary of the biases threatening study validity was determined. Four methodological biases were considered: selection bias, performance bias, attrition bias, and detection bias. A meta-analysis was conducted when adequate data were available from 2 or more studies and where there was no statistical or clinical heterogeneity among studies. The GRADE system was used to summarize the overall quality of evidence.
Summary of Findings
The search yielded 422 citations; of these, 12 were included in the review including 10 primary studies (9 RCTs, 1 non-RCT) and 2 systematic reviews.
The Medical Advisory Secretariat review included 2 primary studies (N = 334) that examined the effectiveness of an inpatient physiotherapy rehabilitation program compared with an outpatient home-based physiotherapy program on functional outcomes after total knee or hip replacement surgery. One study, available only as an abstract, found no difference in functional outcome at 1 year after surgery (TKR or THR) between the treatments. The other study was an observational study that found that patients who are younger than 71 years of age on average, who do not live alone, and who do not have comorbid illnesses recover adequate function with outpatient home-based physiotherapy. However results were only measured up to 3 months after surgery, and the outcome measure they used is not considered the best one for physical functioning.
Three primary studies (N = 360) were reviewed that tested the effectiveness of outpatient home-based or clinic-based physiotherapy in addition to a self-administered home exercise program, compared with a self-administered exercise program only or in addition to using another therapy (phone calls or continuous passive movement), on postoperative physical functioning after primary TKR surgery. Two of the studies reported no difference in change from baseline in flexion range of motion between those patients receiving outpatient or home-based physiotherapy and doing a home exercise program compared with patients who did a home exercise program only with or without continuous passive movement. The other study reported no difference in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores between patients receiving clinic-based physiotherapy and practising a home exercise program and those who received monitoring phone calls and did a home exercise program after TKR surgery.
The Medical Advisory Secretariat reviewed two systematic reviews evaluating the effects of preoperative exercise on postoperative physical functioning. One concluded that preoperative exercise is not effective in improving functional recovery or pain after TKR and any effects after THR could not be adequately determined. The other concluded that there was inconclusive evidence to determine the benefits of preoperative exercise on functional recovery after TKR. Because 2 primary studies were added to the published literature since the publication of these systematic reviews the Medical Advisory Secretariat revisited the question of effectiveness of a preoperative exercise program for patients scheduled for TKR ad THR surgery.
The Medical Advisory Secretariat also reviewed 3 primary studies (N = 184) that tested the effectiveness of preoperative exercise beginning 4-6 weeks before surgery on postoperative outcomes after primary TKR surgery. All 3 studies reported negative findings with regard to the effectiveness of preoperative exercise to improve physical functioning after TKR surgery. However, 2 failed to show an effect of the preoperative exercise program before surgery in those patients receiving preoperative exercise. The third study did not measure functional outcome immediately before surgery in the preoperative exercise treatment group; therefore the study’s authors could not document an effect of the preoperative exercise program before surgery. Regarding health services utilization, 2 of the studies did not find significant differences in either the length of the acute care hospital stay or the inpatient rehabilitation care setting between patients treated with a preoperative exercise program and those not treated. The third study did not measure health services utilization.
These results must be interpreted within the limitations and the biases of each study. Negative results do not necessarily support a lack of treatment effect but may be attributed to a type II statistical error.
Finally, the Medical Advisory Secretariat reviewed 2 primary studies (N = 136) that examined the effectiveness of preoperative exercise on postoperative functional outcomes after primary THR surgery. One study did not support the effectiveness of an exercise program beginning 8 weeks before surgery. However, results from the other did support the effectiveness of an exercise program 8 weeks before primary THR surgery on pain and functional outcomes 1 week before and 3 weeks after surgery.
Conclusions
Based on the evidence, the Medical Advisory Secretariat reached the following conclusions with respect to physiotherapy rehabilitation and physical functioning 1 year after primary TKR or THR surgery:
There is high-quality evidence from 1 large RCT to support the use of home-based physiotherapy instead of inpatient physiotherapy after primary THR or TKR surgery.
There is low-to-moderate quality evidence from 1 large RCT to support the conclusion that receiving a monitoring phone call from a physiotherapist and practising home exercises is comparable to receiving clinic-based physiotherapy and practising home exercises for people who have had primary TKR surgery. However, results may not be generalizable to those who have had THR surgery.
There is moderate evidence to suggest that an exercise program beginning 4 to 6 weeks before primary TKR surgery is not effective.
There is moderate evidence to support the effectiveness of an exercise program beginning 8 weeks before surgery to improve physical functioning 3 weeks after THR surgery.
PMCID: PMC3382414  PMID: 23074477
3.  Lung Function and Incidence of Chronic Obstructive Pulmonary Disease after Improved Cooking Fuels and Kitchen Ventilation: A 9-Year Prospective Cohort Study 
PLoS Medicine  2014;11(3):e1001621.
Pixin Ran, Nanshan Zhong, and colleagues report that cleaner cooking fuels and improved ventilation were associated with better lung function and reduced COPD among a cohort of villagers in Southern China.
Please see later in the article for the Editors' Summary
Background
Biomass smoke is associated with the risk of chronic obstructive pulmonary disease (COPD), but few studies have elaborated approaches to reduce the risk of COPD from biomass burning. The purpose of this study was to determine whether improved cooking fuels and ventilation have effects on pulmonary function and the incidence of COPD.
Methods and Findings
A 9-y prospective cohort study was conducted among 996 eligible participants aged at least 40 y from November 1, 2002, through November 30, 2011, in 12 villages in southern China. Interventions were implemented starting in 2002 to improve kitchen ventilation (by providing support and instruction for improving biomass stoves or installing exhaust fans) and to promote the use of clean fuels (i.e., biogas) instead of biomass for cooking (by providing support and instruction for installing household biogas digesters); questionnaire interviews and spirometry tests were performed in 2005, 2008, and 2011. That the interventions improved air quality was confirmed via measurements of indoor air pollutants (i.e., SO2, CO, CO2, NO2, and particulate matter with an aerodynamic diameter of 10 µm or less) in a randomly selected subset of the participants' homes. Annual declines in lung function and COPD incidence were compared between those who took up one, both, or neither of the interventions.
Use of clean fuels and improved ventilation were associated with a reduced decline in forced expiratory volume in 1 s (FEV1): decline in FEV1 was reduced by 12 ml/y (95% CI, 4 to 20 ml/y) and 13 ml/y (95% CI, 4 to 23 ml/y) in those who used clean fuels and improved ventilation, respectively, compared to those who took up neither intervention, after adjustment for confounders. The combined improvements of use of clean fuels and improved ventilation had the greatest favorable effects on the decline in FEV1, with a slowing of 16 ml/y (95% CI, 9 to 23 ml/y). The longer the duration of improved fuel use and ventilation, the greater the benefits in slowing the decline of FEV1 (p<0.05). The reduction in the risk of COPD was unequivocal after the fuel and ventilation improvements, with an odds ratio of 0.28 (95% CI, 0.11 to 0.73) for both improvements.
Conclusions
Replacing biomass with biogas for cooking and improving kitchen ventilation are associated with a reduced decline in FEV1 and risk of COPD.
Trial Registration
Chinese Clinical Trial Register ChiCTR-OCH-12002398
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Nearly 3 billion people in developing countries heat their homes and cook by burning biomass—wood, crop waste, and animal dung—in open fires and leaky stoves. Burning biomass this way releases pollutants into the home that impair lung function and that are responsible for more than a million deaths from chronic obstructive pulmonary disease (COPD) every year. COPD is a group of diseases that interfere with breathing. Normally, air is breathed in through the nose or mouth and travels down the windpipe into two bronchial tubes (airways) in the lungs. These tubes branch into smaller tubes (bronchioles) that end in bunches of tiny air sacs (alveoli). Oxygen in the air passes through the thin walls of these sacs into small blood vessels and is taken to the heart for circulation round the body. The two main types of COPD—chronic bronchitis (long-term irritation and swelling of the bronchial tubes) and emphysema (damage to the walls of the alveoli)—make it hard for people to breathe. Most people with COPD have both chronic bronchitis and emphysema, both of which are caused by long-term exposure to cigarette smoke, indoor air pollution, and other lung irritants. Symptoms of COPD include breathlessness during exercise and a persistent cough that produces large amounts of phlegm (mucus). There is no cure for COPD, but drugs and oxygen therapy can relieve its symptoms, and avoiding lung irritants can slow disease progression.
Why Was This Study Done?
Exposure to indoor air pollution has been associated with impaired lung function and COPD in several studies. However, few studies have assessed the long-term effects on lung function and on the incidence of COPD (the proportion of a population that develops COPD each year) of replacing biomass with biogas (a clean fuel produced by bacterial digestion of biodegradable materials) for cooking and heating, or of improving kitchen ventilation during cooking. Here, the researchers undertook a nine-year prospective cohort study in rural southern China to investigate whether these interventions are associated with any effects on lung function and on the incidence of COPD. A prospective cohort study enrolls a group of people, determines their characteristics at baseline, and follows them over time to see whether specific characteristic are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers offered nearly 1,000 people living in 12 villages in southern China access to biogas and to improved kitchen ventilation. All the participants, who adopted these interventions according to personal preferences, completed a questionnaire about their smoking habits and occupational exposure to pollutants and had their lung function measured using a spirometry test at the start and end of the study. Some participants also completed a questionnaire and had their lung function measured three and six years into the study. Finally, the researchers measured levels of indoor air pollution in a randomly selected subset of homes at the end of the study to confirm that the interventions had reduced indoor air pollution. Compared with non-use, the use of clean fuels and of improved ventilation were both associated with a reduction in the decline in lung function over time after adjusting for known characteristics that affect lung function, such as smoking. The use of both interventions reduced the decline in lung function more markedly than either intervention alone, and the benefits of using the interventions increased with length of use. Notably, the combined use of both interventions reduced the risk of COPD occurrence among the study participants.
What Do These Findings Mean?
These findings suggest that, among people living in rural southern China, the combined interventions of use of biogas instead of biomass and improved kitchen ventilation were associated with a reduced decline in lung function over time and with a reduced risk of COPD. Because participants were not randomly allocated to intervention groups, the people who adopted the interventions may have shared other unknown characteristics (confounders) that affected their lung function (for example, having a healthier lifestyle). Thus, it is not possible to conclude that either intervention actually caused a reduction in the decline in lung function. Nevertheless, these findings suggest that the use of biogas as a substitute for biomass for cooking and heating and improvements in kitchen ventilation might lead to a reduction in the global burden of COPD associated with biomass smoke.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001621.
The US National Heart, Lung, and Blood Institute provides detailed information for the public about COPD
The US Centers for Disease Control and Prevention provides information about COPD and links to other resources (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about COPD, personal stories, and links to other resources
The British Lung Foundation, a not-for-profit organization, provides information about COPD in several languages
The Global Initiative for Chronic Obstructive Lung Disease works to improve prevention and treatment of COPD around the world
The World Health Organization provides information about all aspects of indoor air pollution and health (in English, French, and Spanish)
MedlinePlus provides links to other information about COPD (in English and Spanish)
doi:10.1371/journal.pmed.1001621
PMCID: PMC3965383  PMID: 24667834
4.  Evaluation of a novel method to assess corticosteroid responsiveness in chronic obstructive pulmonary disease 
Annals of Thoracic Medicine  2010;5(4):232-237.
BACKGROUND:
Some patients with chronic obstructive pulmonary disease (COPD) may benefit from oral steroid therapy. These steroid-responsive patients are diagnosed based on laboratory spirometry. We hypothesize that daily, home-based spirometry is a better tool.
METHODS:
Thirty patients with COPD underwent a single-blinded study, with a crossover design. They received 2 weeks of placebo followed by 2 weeks of prednisone therapy (40 mg/day). Laboratory spirometry was done at the beginning and end of the study and daily home-based spirometry was done twice a day.
RESULTS:
Analysis of variance model was used. The variability of the median day-to-day forced expiratory volume in 1 s (FEV1) was 72.5 mL (25th percentile of 40 mL and 75th percentile of 130 mL). The daily FEV1 variation was 70 mL (25th percentile of 50 mL and 75th percentile of 100 mL). The overall laboratory FEV1 variability was larger after the steroid course (P < 0.001), but not clinically significant. The variability was not significant postplacebo treatment compared with the baseline values. For home-based spirometry, steroid treatment was not significantly different. The majority (97%) completed more than 80% of the measurements. Ninety percent of the performed tests were considered acceptable. Only 53% of the tests were considered accurate. Overall both laboratory and home-based measurements did not show significant association between airway responsiveness and dyspnea or exercise capacity.
CONCLUSION:
Twice-daily home measurements of FEV1 might be better than the conventional approach to identify steroid responsive COPD patients. However, this finding was only statistically but not clinically significant. Therefore, we would not recommend this approach to identify COPD patients with steroid responsiveness.
doi:10.4103/1817-1737.69114
PMCID: PMC2954378  PMID: 20981184
COPD; corticosteroids; home spirometry; responsiveness; variability
5.  Location and Duration of Treatment of Cystic Fibrosis Respiratory Exacerbations Do Not Affect Outcomes 
Rationale: Individuals with cystic fibrosis (CF) are subject to recurrent respiratory infections (exacerbations) that often require intravenous antibiotic treatment and may result in permanent loss of lung function. The optimal means of delivering therapy remains unclear.
Objectives: To determine whether duration or venue of intravenous antibiotic administration affect lung function.
Methods: Data were retrospectively collected on 1,535 subjects recruited by the US CF Twin and Sibling Study from US CF care centers between 2000 and 2007.
Measurements and Main Results: Long-term decline in FEV1 after exacerbation was observed regardless of whether antibiotics were administered in the hospital (mean, −3.3 percentage points [95% confidence interval, −3.9 to −2.6]; n = 602 courses of therapy) or at home (mean, −3.5 percentage points [95% confidence interval, −4.5 to −2.5]; n = 232 courses of therapy); this decline was not different by venue using t tests (P = 0.69) or regression (P = 0.91). No difference in intervals between courses of antibiotics was observed between hospital (median, 119 d [interquartile range, 166]; n = 602) and home (median, 98 d [interquartile range, 155]; n = 232) (P = 0.29). Patients with greater drops in FEV1 with exacerbations had worse long-term decline even if lung function initially recovered with treatment (P < 0.001). Examination of FEV1 measures obtained during treatment for exacerbations indicated that improvement in FEV1 plateaus after 7–10 days of therapy.
Conclusions: Intravenous antibiotic therapy for CF respiratory exacerbations administered in the hospital and in the home was found to be equivalent in terms of long-term FEV1 change and interval between courses of antibiotics. Optimal duration of therapy (7–10 d) may be shorter than current practice. Large prospective studies are needed to answer these essential questions for CF respiratory management.
doi:10.1164/rccm.201001-0057OC
PMCID: PMC3001256  PMID: 20581166
cystic fibrosis; FEV1; exacerbation; antibiotic; outcome
6.  Exercise Protocol for the Treatment of Rotator Cuff Impingement Syndrome 
Journal of Athletic Training  2010;45(5):483-485.
Abstract
Reference/Citation:
Kuhn JE. Exercise in the treatment of rotator cuff impingement: a systematic review and a synthesized evidence-based rehabilitation protocol. J Shoulder Elbow Surg. 2009;18(1):138–160.
Clinical Question:
What is the role of exercise in the treatment of rotator cuff impingement syndrome (RCIS), and what evidence-based exercises can be synthesized into a criterion-standard exercise rehabilitation protocol?
Data Sources:
Investigations were identified by PubMed, Ovid, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, and Database of Abstracts of Reviews of Effects. The search terms included shoulder, impingement, rotator cuff, rehabilitation, physical therapy, physiotherapy, and exercise. Additional searches were performed with bibliographies of retrieved studies.
Study Selection:
To qualify for inclusion, studies had to be level 1 or level 2 (randomized controlled trials); had to compare rehabilitation interventions, such as exercise or manual therapy, with other treatments or placebo; had to include validated outcome measures of pain, function, or disability; and had to be limited to individuals with diagnosed impingement syndrome. Impingement syndrome was determined by a positive impingement sign per Neer or Hawkins criteria, or both. Articles were excluded if they addressed other shoulder conditions (eg, calcific tendinosis, full-thickness rotator cuff tears, adhesive capsulitis, osteoarthritis), addressed postoperative management, were retrospective studies or case series, or used other outcome measures.
Data Extraction:
An evidence-based journal club of 9 faculty members and fellows reviewed the articles and extracted and tabulated the data. Individual outcomes for pain, range of motion (ROM), strength, and function were organized. Intragroup and between-groups outcomes were assessed for the effectiveness of treatment, and statistical outcomes were recorded when available. Clinical importance was determined when statistical value was P < .05 and the effect size or difference between treatments was 20% or more. Sixa major categories were created to organize the components of the physical therapy programs used in each study: ROM, flexibility and stretching, strengthening techniques, therapist-driven manual therapy, modalities, and schedule. Components from these categories were used to create a synthesized physical therapy program.
Main Results:
The searches identified 80 studies, of which 11 met the inclusion criteria. In 5 studies, the diagnosis of RCIS was confirmed using an impingement test consisting of lidocaine injected into the subacromial space and elimination of pain with the impingement sign. Randomization methods were used in 6 studies, and blinded, independent examiners were involved in follow-up data collection in only 3 studies. Validated outcome measures were used in all studies. Follow-up was very good in 10 studies and was less than 90% in only 1 study. The specific exercise programs varied among studies. However, general treatment principles were identified among the different studies and included frequency, ROM, stretching or flexibility, strengthening, manual therapy (joint and/or soft tissue mobilizations), modalities, and others.
The findings indicated that exercise improves outcomes of pain, strength, ROM impairments, and function in patients with impingement syndrome. In 10 studies, investigators reported improvements in pain with supervised exercise, home exercise, exercise associated with manual therapy, and exercise after subacromial decompression. Of the 6 studies in which researchers compared pre-exercise pain with postexercise pain, 5 demonstrated that exercise produced statistically significant and clinically important reductions in pain. Two studies demonstrated improvements in pain when comparing exercise and control groups. In 1 study, investigators evaluated bracing without exercise and found no difference in pain between the brace and exercise groups. Investigators evaluated exercise combined with manual therapy in 3 studies and demonstrated improvement in pain relief in each study and improvement in strength in 1 study. In most studies, exercise also was shown to improve function. The improvement in function was statistically significant in 4 studies and clinically meaningful in 2 of these studies. In 2 studies, researchers compared supervised exercise with a home exercise program and found that function improved in both groups but was not different between groups. This finding might have resulted from a type II statistical error. In 4 studies, researchers did not find differences between acromioplasty with exercise and exercise alone for pain alone or for outcomes of pain and function.
Conclusions:
Findings indicated that exercise is beneficial for reducing pain and improving function in individuals with RCIS. The effects of exercise might be augmented with implementation of manual therapy. In addition, supervised exercise might not be more effective than a home exercise program. Many articles had methodologic concerns and provided limited descriptions of specific exercises, which made comparing types of exercise among studies difficult. Based on the results, Kuhn generated a physical therapy protocol using evidence-based exercise that could be used by clinicians treating individuals with impingement syndrome. This evidence-based protocol can serve as the criterion standard to reduce variables in future cohort and comparative studies to help find better treatments for patients with this disorder.
doi:10.4085/1062-6050-45.5.483
PMCID: PMC2938321  PMID: 20831395
function; subacromial impingement; rehabilitation
7.  The clinical and integrated management of COPD. An official document of AIMAR (Interdisciplinary Association for Research in Lung Disease), AIPO (Italian Association of Hospital Pulmonologists), SIMER (Italian Society of Respiratory Medicine), SIMG (Italian Society of General Medicine) 
COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD "a preventable and treatable disease". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 < 60% predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2 < 88%) or PaO2 values between 56 and 59 mmHg (SO2 < 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit > 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with "severe" or "very severe" COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneously published in Sarcoidosis Vasc Diffuse Lung Dis 2014, 31(Suppl. 1);3-21.
doi:10.1186/2049-6958-9-25
PMCID: PMC4107539  PMID: 25057359
COPD; Integrated care; Management
8.  Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients with Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to compare hospital-at-home care with inpatient hospital care for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) who present to the emergency department (ED).
Clinical Need: Condition and Target Population
Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease is a disease state characterized by airflow limitation that is not fully reversible. This airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. The natural history of COPD involves periods of acute-onset worsening of symptoms, particularly increased breathlessness, cough, and/or sputum, that go beyond normal day-to-day variations; these are known as acute exacerbations.
Two-thirds of COPD exacerbations are caused by an infection of the tracheobronchial tree or by air pollution; the cause in the remaining cases is unknown. On average, patients with moderate to severe COPD experience 2 or 3 exacerbations each year.
Exacerbations have an important impact on patients and on the health care system. For the patient, exacerbations result in decreased quality of life, potentially permanent losses of lung function, and an increased risk of mortality. For the health care system, exacerbations of COPD are a leading cause of ED visits and hospitalizations, particularly in winter.
Technology
Hospital-at-home programs offer an alternative for patients who present to the ED with an exacerbation of COPD and require hospital admission for their treatment. Hospital-at-home programs provide patients with visits in their home by medical professionals (typically specialist nurses) who monitor the patients, alter patients’ treatment plans if needed, and in some programs, provide additional care such as pulmonary rehabilitation, patient and caregiver education, and smoking cessation counselling.
There are 2 types of hospital-at-home programs: admission avoidance and early discharge hospital-at-home. In the former, admission avoidance hospital-at-home, after patients are assessed in the ED, they are prescribed the necessary medications and additional care needed (e.g., oxygen therapy) and then sent home where they receive regular visits from a medical professional. In early discharge hospital-at-home, after being assessed in the ED, patients are admitted to the hospital where they receive the initial phase of their treatment. These patients are discharged into a hospital-at-home program before the exacerbation has resolved. In both cases, once the exacerbation has resolved, the patient is discharged from the hospital-at-home program and no longer receives visits in his/her home.
In the models that exist to date, hospital-at-home programs differ from other home care programs because they deal with higher acuity patients who require higher acuity care, and because hospitals retain the medical and legal responsibility for patients. Furthermore, patients requiring home care services may require such services for long periods of time or indefinitely, whereas patients in hospital-at-home programs require and receive the services for a short period of time only.
Hospital-at-home care is not appropriate for all patients with acute exacerbations of COPD. Ineligible patients include: those with mild exacerbations that can be managed without admission to hospital; those who require admission to hospital; and those who cannot be safely treated in a hospital-at-home program either for medical reasons and/or because of a lack of, or poor, social support at home.
The proposed possible benefits of hospital-at-home for treatment of exacerbations of COPD include: decreased utilization of health care resources by avoiding hospital admission and/or reducing length of stay in hospital; decreased costs; increased health-related quality of life for patients and caregivers when treated at home; and reduced risk of hospital-acquired infections in this susceptible patient population.
Ontario Context
No hospital-at-home programs for the treatment of acute exacerbations of COPD were identified in Ontario. Patients requiring acute care for their exacerbations are treated in hospitals.
Research Question
What is the effectiveness, cost-effectiveness, and safety of hospital-at-home care compared with inpatient hospital care of acute exacerbations of COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on August 5, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 1990, to August 5, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
English language full-text reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies including patients with COPD as well as patients with other conditions, if results are reported for COPD patients separately;
studies performed in patients with acute exacerbations of COPD who present to the ED;
studies published between January 1, 1990, and August 5, 2010;
studies comparing hospital-at-home and inpatient hospital care for patients with acute exacerbations of COPD;
studies that include at least 1 of the outcomes of interest (listed below).
Cochrane Collaboration reviews have defined hospital-at-home programs as those that provide patients with active treatment for their acute exacerbation in their home by medical professionals for a limited period of time (in this case, until the resolution of the exacerbation). If a hospital-at-home program had not been available, these patients would have been admitted to hospital for their treatment.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
Outcomes of Interest
Patient/clinical outcomes
mortality
lung function (forced expiratory volume in 1 second)
health-related quality of life
patient or caregiver preference
patient or caregiver satisfaction with care
complications
Health system outcomes
hospital readmissions
length of stay in hospital and hospital-at-home
ED visits
transfer to long-term care
days to readmission
eligibility for hospital-at-home
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1; otherwise, results were summarized descriptively. Data from RCTs were analyzed using intention-to-treat protocols. In addition, a sensitivity analysis was done assigning all missing data/withdrawals to the event. P values less than 0.05 were considered significant. A priori subgroup analyses were planned for the acuity of hospital-at-home program, type of hospital-at-home program (early discharge or admission avoidance), and severity of the patients’ COPD. Additional subgroup analyses were conducted as needed based on the identified literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed, taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Fourteen studies met the inclusion criteria and were included in this review: 1 health technology assessment, 5 systematic reviews, and 7 RCTs.
The following conclusions are based on low to very low quality of evidence. The reviewed evidence was based on RCTs that were inadequately powered to observe differences between hospital-at-home and inpatient hospital care for most outcomes, so there is a strong possibility of type II error. Given the low to very low quality of evidence, these conclusions must be considered with caution.
Approximately 21% to 37% of patients with acute exacerbations of COPD who present to the ED may be eligible for hospital-at-home care.
Of the patients who are eligible for care, some may refuse to participate in hospital-at-home care.
Eligibility for hospital-at-home care may be increased depending on the design of the hospital-at-home program, such as the size of the geographical service area for hospital-at-home and the hours of operation for patient assessment and entry into hospital-at-home.
Hospital-at-home care for acute exacerbations of COPD was associated with a nonsignificant reduction in the risk of mortality and hospital readmissions compared with inpatient hospital care during 2- to 6-month follow-up.
Limited, very low quality evidence suggests that hospital readmissions are delayed in patients who received hospital-at-home care compared with those who received inpatient hospital care (mean additional days before readmission comparing hospital-at-home to inpatient hospital care ranged from 4 to 38 days).
There is insufficient evidence to determine whether hospital-at-home care, compared with inpatient hospital care, is associated with improved lung function.
The majority of studies did not find significant differences between hospital-at-home and inpatient hospital care for a variety of health-related quality of life measures at follow-up. However, follow-up may have been too late to observe an impact of hospital-at-home care on quality of life.
A conclusion about the impact of hospital-at-home care on length of stay for the initial exacerbation (defined as days in hospital or days in hospital plus hospital-at-home care for inpatient hospital and hospital-at-home, respectively) could not be determined because of limited and inconsistent evidence.
Patient and caregiver satisfaction with care is high for both hospital-at-home and inpatient hospital care.
PMCID: PMC3384361  PMID: 23074420
9.  Small Bowel Transplant 
EXECUTIVE SUMMARY
Objective
The Medical Advisory Secretariat undertook a review of the evidence on the effectiveness and cost-effectiveness of small bowel transplant in the treatment of intestinal failure.
Small Bowel Transplantation
Intestinal failure is the loss of absorptive capacity of the small intestine that results in an inability to meet the nutrient and fluid requirements of the body via the enteral route. Patients with intestinal failure usually receive nutrients intravenously, a procedure known as parenteral nutrition. However, long-term parenteral nutrition is associated with complications including liver failure and loss of venous access due to recurrent infections.
Small bowel transplant is the transplantation of a cadaveric intestinal allograft for the purpose of restoring intestinal function in patients with irreversible intestinal failure. The transplant may involve the small intestine alone (isolated small bowel ISB), the small intestine and the liver (SB-L) when there is irreversible liver failure, or multiple organs including the small bowel (multivisceral MV or cluster). Although living related donor transplant is being investigated at a limited number of centres, cadaveric donors have been used in most small bowel transplants.
The actual transplant procedure takes approximately 12-18 hours. After intestinal transplant, the patient is generally placed on prophylactic antibiotic medication and immunosuppressive regimen that, in the majority of cases, would include tacrolimus, corticosteroids and an induction agent. Close monitoring for infection and rejection are essential for early treatment.
Medical Advisory Secretariat Review
The Medical Advisory Secretariat undertook a review of 35 reports from 9 case series and 1 international registry. Sample size of the individual studies ranged from 9 to 155.
As of May 2001, 651 patients had received small bowel transplant procedures worldwide. According to information from the Canadian Organ Replacement Register, a total of 27 small bowel transplants were performed in Canada from 1988 to 2002.
Patient Outcomes
The experience in small bowel transplant is still limited. International data showed that during the last decade, patient survival and graft survival rates from SBT have improved, mainly because of improved immunosuppression therapy and earlier detection and treatment of infection and rejection. The Intestinal Transplant Registry reported 1-year actuarial patient survival rates of 69% for isolated small bowel transplant, 66% for small bowel-liver transplant, and 63% for multivisceral transplant, and a graft survival rate of 55% for ISB and 63% for SB-L and MV. The range of 1-year patient survival rates reported ranged from 33%-87%. Reported 1-year graft survival rates ranged from 46-71%.
Regression analysis performed by the International Transplant Registry in 1997 indicated that centres that have performed at least 10 small bowel transplants had better patient and graft survival rates than centres that performed less than 10 transplants. However, analysis of the data up to May 2001 suggests that the critical mass of 10 transplants no longer holds true for transplants after 1995, and that good results can be achieved at any multiorgan transplant program with moderate patient volumes.
The largest Centre reported an overall 1-year patient and graft survival rate of 72% and 64% respectively, and 5-year patient and graft survival of 48% and 40% respectively. The overall 1-year patient survival rate reported for Ontario pediatric small bowel transplants was 61% with the highest survival rate of 83% for ISB.
The majority (70% or higher) of surviving small bowel transplant recipients was able to wean from parenteral nutrition and meet all caloric needs enterally. Some may need enteral or parenteral supplementation during periods of illness. Growth and weight gain in children after ISB were reported by two studies while two other studies reported a decrease in growth velocity with no catch-up growth.
The quality of life after SBT was reported to be comparable to that of patients on home enteral nutrition. A study found that while the parents of pediatric SBT recipients reported significant limitations in the physical and psychological well being of the children compared with normal school children, the pediatric SBT recipients themselves reported a quality of life similar to other school children.
Survival was found to be better in transplants performed since 1991. Patient survival was associated with the type of organ transplanted with better survival in isolated small bowel recipients.
Adverse Events
Despite improvement in patient and graft survival rates, small bowel transplant is still associated with significant mortality and morbidity.
Infection with subsequent sepsis is the leading cause of death (51.3%). Bacterial, fungal and viral infections have all been reported. The most common viral infections are cytomegalorvirus (18-40%) and Epstein-Barr virus. The latter often led to ß-cell post-transplant lymphoproliferative disease.
Graft rejection is the second leading cause of death after SBT (10.4%) and is responsible for 57% of graft removal. Acute rejection rates ranged from 51% to 83% in the major programs. Most of the acute rejection episodes were mild and responded to steroids and OKT3. Antilymphocyte therapy was needed in up to 27% of patients. Isolated small bowel allograft and positive lymphocytotoxic cross-match were found to be risk factors for acute rejection.
Post-transplant lymphoproliferative disease occurred in 21% of SBT recipients and accounted for 7% of post-transplant mortality. The frequency was higher in pediatric recipients (31%) and in adults receiving composite visceral allografts (25%). The allograft itself is often involved in post-transplant lymphoproliferative disease. The reported incidence of host versus graft disease varied widely among centers (0% - 14%).
Surgical complications were reported to occur in 85% of SB-L transplants and 25% of ISB transplants. Reoperations were required in 45% - 66% of patients in a large series and the most common reason for reoperation was intra-abdominal abscess.
The median cost of intestinal transplant in the US was reported to be approximately $275,000US (approximately CDN$429,000) per case. A US study concluded that based on the US cost of home parenteral nutrition, small bowel transplant could be cost-effective by the second year after the transplant.
Conclusion
There is evidence that small bowel transplant can prolong the life of some patients with irreversible intestinal failure who can no longer continue to be managed by parenteral nutrition therapy. Both patient survival and graft survival rates have improved with time. However, small bowel transplant is still associated with significant mortality and morbidity. The outcomes are inferior to those of total parenteral nutrition. Evidence suggests that this procedure should only be used when total parenteral nutrition is no longer feasible.
PMCID: PMC3387750  PMID: 23074441
10.  Mobile-phone-based home exercise training program decreases systemic inflammation in COPD: a pilot study 
BMC Pulmonary Medicine  2014;14:142.
Background
Moderate-intensity exercise training improves skeletal muscle aerobic capacity and increased oxidative enzyme activity, as well as exercise tolerance in COPD patients.
Methods
To investigate whether the home-based exercise training program can reduce inflammatory biomarkers in patients with COPD, twelve patients using mobile phone assistance and 14 with free walk were assessed by incremental shuttle walk test (ISWT), spirometry, strength of limb muscles, and serum C-reactive protein (CRP) and inflammatory cytokines.
Results
Patients in the mobile phone group improved their ISWT walking distance, with decrease in serum CRP after 2 months, and sustained at 6 months. Patients in the control group had no improvement. Serum IL-8 in the mobile phone group was significantly reduced at 2, 3 and 6 months after doing home exercise training compared to baseline. IL-6 and TNF-α were significantly elevated at 3 and 6 months in control group, while there were no changes in mobile phone group. The strength of limb muscles was significantly greater compared to baseline at 3 and 6 months in the mobile phone group.
Conclusions
A mobile-phone-based system can provide an efficient home endurance exercise training program with improved exercise capacity, strength of limb muscles and a decrease in serum CRP and IL-8 in COPD patients. Decreased systemic inflammation may contribute to these clinical benefits. (Clinical trial registration No.: NCT01631019)
doi:10.1186/1471-2466-14-142
PMCID: PMC4236722  PMID: 25175787
Chronic obstructive pulmonary disease; Pulmonary rehabilitation; Mobile phone; Biomarker; Interleukin-8
11.  The short and long term effects of exercise training in non-cystic fibrosis bronchiectasis – a randomised controlled trial 
Respiratory Research  2014;15(1):44.
Background
Exercise training is recommended for non-cystic fibrosis (CF) bronchiectasis, but the long-term effects are unclear. This randomised controlled trial aimed to determine the effects of exercise training and review of airway clearance therapy (ACT) on exercise capacity, health related quality of life (HRQOL) and the incidence of acute exacerbations in people with non-CF bronchiectasis.
Methods
Participants were randomly allocated to 8 weeks of supervised exercise training and review of ACT, or control. Primary outcomes of exercise capacity and HRQOL (Chronic respiratory disease questionnaire) and secondary outcomes of cough-related QOL (Leicester cough questionnaire) and psychological symptoms (Hospital anxiety and depression scale) were measured at baseline, following completion of the intervention period and at 6 and 12 months follow up. Secondary outcomes of the exacerbation rate and time to first exacerbation were analysed over 12 months.
Results
Eighty-five participants (mean FEV1 74% predicted; median Modified Medical Research Council Dyspnoea grade of 1 (IQR [1–3]) were included. Exercise training increased the incremental shuttle walk distance (mean difference to control 62 m, 95% CI 24 to 101 m) and the 6-minute walking distance (mean difference to control 41 m, 95% CI 19 to 63 m), but these improvements were not sustained at 6 or 12 months. Exercise training reduced dyspnoea (p = 0.009) and fatigue (p = 0.01) but did not impact on cough-related QOL or mood. Exercise training reduced the frequency of acute exacerbations (median 1[IQR 1–3]) compared to the control group (2[1–3]) over 12 months follow up (p = 0.012), with a longer time to first exacerbation with exercise training of 8 months (95% CI 7 to 9 months) compared to the control group (6 months [95% CI 5 to 7 months], p = 0.047).
Conclusions
Exercise training in bronchiectasis is associated with short term improvement in exercise capacity, dyspnoea and fatigue and fewer exacerbations over 12 months.
Trial registry
ClinicalTrials.gov (NCT00885521).
doi:10.1186/1465-9921-15-44
PMCID: PMC3996132  PMID: 24731015
Bronchiectasis; Exercise training; Quality of life; Exercise capacity; Acute exacerbations
12.  Lung volume reduction surgery for the treatment of severe emphysema: a study in a single Canadian institution 
Canadian Journal of Surgery  2000;43(5):369-376.
Objective
To evaluate lung volume reduction surgery (LVRS) and its effectiveness in improving pulmonary function, exercise capacity and quality of life in a population of emphysema patients referred to and screened in a single centre.
Design
A prospective case series.
Setting
A Canadian tertiary care hospital.
Patients
Patients with severe emphysema, significant dyspnea and impaired exercise capacity interfering with quality of life.
Interventions
Bilateral LVRS was performed through a median sternotomy.
Main outcome measures
Pulmonary function tests (preoperative forced expiratory volume in the first second [FEV1], residual volume [RV]), 6-minute walk (6MW) distance, quality of life (Medical Outcomes Study 36-item short-form health survey) and degree of dyspnea (Medical Research Council of Great Britain dyspnea scale and the baseline and transitional dyspnea indices) were assessed before LVRS and at 6 and 12 months after.
Results
Fifty-seven patients were assessed for LVRS, of whom 10 were selected for surgery. Homogeneous distribution of disease was the most common reason for exclusion. Of the 10 patients operated upon, 1 died of acute cor pulmonale on the fourth postoperative day and 1 died of recurrent exacerbations of chronic obstructive pulmonary disease and chronic respiratory failure at 315 days postoperatively. In the surviving patients, the mean preoperative FEV1 increased from 0.70 L before surgery to 0.90 L at 1 year, with a mean relative increase of 33.4%. The mean RV decreased from 5.57 L to 4.10 L, with a mean relative decrease of 27.6%. The 6MW distance increased from 302.7 m to 356.9 m at 1 year, with a mean relative increase of 21.6%. Quality of life and degree of dyspnea were improved significantly at 1 year after LVRS. Of the 5 patients on oxygen at home before surgery, 4 were able to reduce their requirements but not to discontinue oxygen.
Conclusions
LVRS is an effective palliative treatment for dyspnea and poor exercise tolerance in highly selected patients. Although the duration of palliation is unknown, our results show that improvements in pulmonary function, exercise, quality of life and degree of dyspnea are preserved over the first year. Only a minority of the patients screened were eligible for surgery. The 2 deaths in our series emphasize the need for even further delineation of selection criteria.
PMCID: PMC3695144  PMID: 11045096
13.  Pulmonary Rehabilitation for Patients With Chronic Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based review was to determine the effectiveness and cost-effectiveness of pulmonary rehabilitation in the management of chronic obstructive pulmonary disease (COPD).
Technology
Pulmonary rehabilitation refers to a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy. Exercise training is the cornerstone of pulmonary rehabilitation programs, though they may also include components such as patient education and psychological support. Pulmonary rehabilitation is recommended as the standard of care in the treatment and rehabilitation of patients with COPD who remain symptomatic despite treatment with bronchodilators.
For the purpose of this review, the Medical Advisory Secretariat focused on pulmonary rehabilitation programs as defined by the Cochrane Collaboration—that is, any inpatient, outpatient, or home-based rehabilitation program lasting at least 4 weeks that includes exercise therapy with or without any form of education and/or psychological support delivered to patients with exercise limitations attributable to COPD.
Research Questions
What is the effectiveness and cost-effectiveness of pulmonary rehabilitation compared with usual care (UC) for patients with stable COPD?
Does early pulmonary rehabilitation (within 1 month of hospital discharge) in patients who had an acute exacerbation of COPD improve outcomes compared with UC (or no rehabilitation)?
Do maintenance or postrehabilitation programs for patients with COPD who have completed a pulmonary rehabilitation program improve outcomes compared with UC?
Research Methods
Literature Search
Search Strategy
For Research Questions 1and 2, a literature search was performed on August 10, 2010 for studies published from January 1, 2004 to July 31, 2010. For Research Question 3, a literature search was performed on February 3, 2011 for studies published from January 1, 2000 to February 3, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
Research questions 1 and 2:
published between January 1, 2004 and July 31, 2010
randomized controlled trials, systematic reviews, and meta-analyses
COPD study population
studies comparing pulmonary rehabilitation with UC (no pulmonary rehabilitation)
duration of pulmonary rehabilitation program ≥ 6 weeks
pulmonary rehabilitation program had to include at minimum exercise training
Research question 3:
published between January 1, 2000 and February 3, 2011
randomized controlled trials, systematic reviews, and meta-analyses
COPD study population
studies comparing a maintenance or postrehabilitation program with UC (standard follow-up)
duration of pulmonary rehabilitation program ≥ 6 weeks
initial pulmonary rehabilitation program had to include at minimum exercise training
Exclusion Criteria
Research questions 1, 2, and 3:
grey literature
duplicate publications
non-English language publications
study population ≤ 18 years of age
studies conducted in a palliative population
studies that did not report primary outcome of interest
Additional exclusion criteria for research question 3:
studies with ≤ 2 sessions/visits per month
Outcomes of Interest
The primary outcomes of interest for the stable COPD population were exercise capacity and health-related quality of life (HRQOL). For the COPD population following an exacerbation, the primary outcomes of interest were hospital readmissions and HRQOL. The primary outcomes of interest for the COPD population undertaking maintenance programs were functional exercise capacity and HRQOL.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Research Question 1: Effect of Pulmonary Rehabilitation on Outcomes in Stable COPD
Seventeen randomized controlled trials met the inclusion criteria and were included in this review.
The following conclusions are based on moderate quality of evidence.
Pulmonary rehabilitation including at least 4 weeks of exercise training leads to clinically and statistically significant improvements in HRQOL in patients with COPD.1
Pulmonary rehabilitation also leads to a clinically and statistically significant improvement in functional exercise capacity2 (weighted mean difference, 54.83 m; 95% confidence interval, 35.63–74.03; P < 0.001).
Research Question 2: Effect of Pulmonary Rehabilitation on Outcomes Following an Acute Exacerbation of COPD
Five randomized controlled trials met the inclusion criteria and are included in this review. The following conclusion is based on moderate quality of evidence.
Pulmonary rehabilitation (within 1 month of hospital discharge) after acute exacerbation significantly reduces hospital readmissions (relative risk, 0.50; 95% confidence interval, 0.33–0.77; P = 0.001) and leads to a statistically and clinically significant improvement in HRQOL.3
Research Question 3: Effect of Pulmonary Rehabilitation Maintenance Programs on COPD Outcomes
Three randomized controlled trials met the inclusion criteria and are included in this review. The conclusions are based on a low quality of evidence and must therefore be considered with caution.
Maintenance programs have a nonsignificant effect on HRQOL and hospitalizations.
Maintenance programs have a statistically but not clinically significant effect on exercise capacity (P = 0.01). When subgrouped by intensity and quality of study, maintenance programs have a statistically and marginally clinically significant effect on exercise capacity.
PMCID: PMC3384375  PMID: 23074434
14.  Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis 
Thorax  1997;52(11):987-993.
BACKGROUND: Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis. METHODS: Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti- pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms. RESULTS: Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study. CONCLUSIONS: Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored. 



PMCID: PMC1758447  PMID: 9487348
15.  Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations 
Respiratory Research  2010;11(1):137.
Background
Cystic Fibrosis (CF) is a life-shortening genetic disease in which ~80% of deaths result from loss of lung function linked to inflammation due to chronic bacterial infection (principally Pseudomonas aeruginosa). Pulmonary exacerbations (intermittent episodes during which symptoms of lung infection increase and lung function decreases) can cause substantial resource utilization, morbidity, and irreversible loss of lung function. Intravenous antibiotic treatment to reduce exacerbation symptoms is standard management practice. However, no prospective studies have identified an optimal antibiotic treatment duration and this lack of objective data has been identified as an area of concern and interest.
Methods
We have retrospectively analyzed pulmonary function response data (as forced expiratory volume in one second; FEV1) from a previous blinded controlled CF exacerbation management study of intravenous ceftazidime/tobramycin and meropenem/tobramycin in which spirometry was conducted daily to assess the time course of pulmonary function response.
Results
Ninety-five patients in the study received antibiotics for at least 4 days and were included in our analyses. Patients received antibiotics for an average of 12.6 days (median = 13, SD = 3.2 days), with a range of 4 to 27 days. No significant differences were observed in mean or median treatment durations as functions of either treatment group or baseline lung disease stage. Average time from initiation of antibiotic treatment to highest observed FEV1 was 8.7 days (median = 10, SD = 4.0 days), with a range of zero to 19 days. Patients were treated an average of 3.9 days beyond the day of peak FEV1 (median = 3, SD = 3.8 days), with 89 patients (93.7%) experiencing their peak FEV1 improvement within 13 days. There were no differences in mean or median times to peak FEV1 as a function of treatment group, although the magnitude of FEV1 improvement differed between groups.
Conclusions
Our results suggest that antibiotic response to exacerbation as assessed by pulmonary function is essentially complete within 2 weeks of treatment initiation and relatively independent of the magnitude of pulmonary function response observed.
doi:10.1186/1465-9921-11-137
PMCID: PMC2959026  PMID: 20925941
16.  Alternatives to inpatient mental health care for children and young people 
Background
Current policy in the UK and elsewhere places emphasis on the provision of mental health services in the least restrictive setting, whilst also recognising that some children will require inpatient care. As a result, there are a range of mental health services to manage young people with serious mental health problems who are at risk of being admitted to an inpatient unit in community or outpatient settings.
Objectives
1. To assess the effectiveness, acceptability and cost of mental health services that provide an alternative to inpatient care for children and young people.
2. To identify the range and prevalence of different models of service that seek to avoid inpatient care for children and young people.
Search methods
Our search included the Cochrane Effective Practice and Organisation of Care Group Specialised Register (2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, issue 4), MEDLINE (1966 to 2007), EMBASE (1982 to 2006), the British Nursing Index (1994 to 2006), RCN database (1985 to 1996), CINAHL (1982 to 2006) and PsycInfo (1972 to 2007).
Selection criteria
Randomised controlled trials of mental health services providing specialist care, beyond the scope of generic outpatient provision, as an alternative to inpatient mental health care, for children or adolescents aged from five to 18 years who have a serious mental health condition requiring specialist services beyond the capacity of generic outpatient provision. The control group received mental health services in an inpatient or equivalent setting.
Data collection and analysis
Two authors independently extracted data and assessed study quality. We grouped studies according to the intervention type but did not pool data because of differences in the interventions and measures of outcome. Where data were available we calculated confidence intervals (CIs) for differences between groups at follow up. We also calculated standardised mean differences (SMDs) and 95% CIs for each outcome in terms of mean change from baseline to follow up using the follow-up SDs. We calculated SMDs (taking into account the direction of change and the scoring of each instrument) so that negative SMDs indicate results that favour treatment and positive SMDs favour the control group.
Main results
We included seven randomised controlled trials (recruiting a total of 799 participants) evaluating four distinct models of care: multi-systemic therapy (MST) at home, specialist outpatient service, intensive home treatment and intensive home-based crisis intervention (‘Homebuilders’ model for crisis intervention). Young people receiving home-based MST experienced some improved functioning in terms of externalising symptoms and they spent fewer days out of school and out-of-home placement. At short term follow up the control group had a greater improvement in terms of adaptability and cohesion; this was not sustained at four months follow up. There were small, significant patient improvements reported in both groups in the trial evaluating the intensive home-based crisis intervention using the ‘Homebuilders’ model. No differences at follow up were reported in the two trials evaluating intensive home treatment, or in the trials evaluating specialist outpatient services.
Authors’ conclusions
The quality of the evidence base currently provides very little guidance for the development of services. If randomised controlled trials are not feasible then consideration should be given to alternative study designs, such as prospective systems of audit conducted across several centres, as this has the potential to improve the current level of evidence. These studies should include baseline measurement at admission along with demographic data, and outcomes measured using a few standardised robust instruments.
doi:10.1002/14651858.CD006410.pub2
PMCID: PMC4014676  PMID: 19370634
17.  Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial 
Trials  2012;13:156.
Background
Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis.
Methods
We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported.
Discussion
Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886.
doi:10.1186/1745-6215-13-156
PMCID: PMC3488323  PMID: 22937736
Amoxicillin-clavulanic acid; Azithromycin; Bronchiectasis; Placebo; Pulmonary exacerbations; Randomised controlled trial
18.  Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma 
The European respiratory journal  2009;34(5):1052-1059.
This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (FeNO) and no bronchodilator responsiveness (BDR <12%)) is uncommon in paediatric DA.
We report on 102 children, mean±SD age 11.6±2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR and FeNO before and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial.
Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02–0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13–26.07) and high baseline forced expiratory volume in 1 s (FEV1) (OR 1.08, 95% CI 1.02–1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had <12% BDR. FeNO data was available in 70 patients, of whom 53 (75%) had normal FeNO. Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV1 (OR 0.93, 95% CI 0.90–0.97).
Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.
doi:10.1183/09031936.00186508
PMCID: PMC3471127  PMID: 19541710
Corticosteroid responsiveness; difficult asthma; eosinophil; nitric oxide; paediatric asthma
19.  Treatment of Infections in Young Infants in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis of Frontline Health Worker Diagnosis and Antibiotic Access 
PLoS Medicine  2014;11(10):e1001741.
Anne C. C. Lee and colleagues assess the factors affecting access to treatment for neonatal and infant infections in low- and middle-income countries by conducting a systematic review and meta-analysis of frontline health worker diagnosis and access to antibiotics.
Please see later in the article for the Editors' Summary
Background
Inadequate illness recognition and access to antibiotics contribute to high case fatality from infections in young infants (<2 months) in low- and middle-income countries (LMICs). We aimed to address three questions regarding access to treatment for young infant infections in LMICs: (1) Can frontline health workers accurately diagnose possible bacterial infection (pBI)?; (2) How available and affordable are antibiotics?; (3) How often are antibiotics procured without a prescription?
Methods and Findings
We searched PubMed, Embase, WHO/Health Action International (HAI), databases, service provision assessments (SPAs), Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and grey literature with no date restriction until May 2014. Data were identified from 37 published studies, 46 HAI national surveys, and eight SPAs. For study question 1, meta-analysis showed that clinical sign-based algorithms predicted bacterial infection in young infants with high sensitivity (87%, 95% CI 82%–91%) and lower specificity (62%, 95% CI 48%–75%) (six studies, n = 14,254). Frontline health workers diagnosed pBI in young infants with an average sensitivity of 82% (95% CI 76%–88%) and specificity of 69% (95% CI 54%–83%) (eight studies, n = 11,857) compared to physicians. For question 2, first-line injectable agents (ampicillin, gentamicin, and penicillin) had low variable availability in first-level health facilities in Africa and South Asia. Oral amoxicillin and cotrimoxazole were widely available at low cost in most regions. For question 3, no studies on young infants were identified, however 25% of pediatric antibiotic purchases in LMICs were obtained without a prescription (11 studies, 95% CI 18%–34%), with lower rates among infants <1 year. Study limitations included potential selection bias and lack of neonatal-specific data.
Conclusions
Trained frontline health workers may screen for pBI in young infants with relatively high sensitivity and lower specificity. Availability of first-line injectable antibiotics appears low in many health facilities in Africa and Asia. Improved data and advocacy are needed to increase the availability and appropriate utilization of antibiotics for young infant infections in LMICs.
Review Registration
PROSPERO International prospective register of systematic reviews (CRD42013004586).
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Neonatal mortality—death that occurs during the first 28 days of life—accounts for nearly half of all the deaths that occur in children before they reach their fifth birthday. Worldwide, nearly 3 million neonatal deaths occur every year. Three bacterial infections—sepsis (infection of the bloodstream), pneumonia (infection of the lungs), and meningitis (infection of the brain's protective covering)—are responsible for nearly a quarter of all neonatal deaths. Babies born in low- and middle-income countries (LMICs) are at particularly high risk of developing neonatal bacterial infections because the risk factors for these infections, which include maternal infections and unhygienic delivery care, are more common in LMICs than in high-income countries. Babies born in LMICs are also at a high risk of dying from bacterial infections because access to appropriate medical care and antibiotics is often poor.
Why Was This Study Done?
To reduce neonatal deaths from bacterial infections in LMICs, health care experts need to identify the factors that limit access to medical care and antibiotics in these countries. Are babies dying because health care providers fail to diagnose neonatal bacterial infections, because antibiotics are not available in first-line health facilities, or for some other reason? In this systematic review and meta-analysis, the researchers investigate access to treatment for neonatal bacterial infections in LMICs by first asking whether frontline health workers in LMICs can accurately diagnose bacterial infections in neonates and young infants (babies less than 2 months old). Next, they ask whether antibiotics for treating neonatal infections are available and affordable in LMICs. Finally, they ask how often antibiotics are procured for young children (children up to the age of 5 years) without a prescription. A systematic review uses pre-defined criteria to identify all the research on a given topic; meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 37 published studies, 46 surveys of drug availability and affordability in LMICs (Health Access International databases), and eight surveys of the capacity of health facilities in LMICs to provide quality health care services (service provision assessments) that met their inclusion criteria. Meta-analysis of six studies indicated that a combination of simple clinical signs for the diagnosis of bacterial infection in children predicted very severe disease in young infants with a sensitivity of 87% and a specificity of 62% (“sensitivity” indicates the percentage of true positives detected by a test; “specificity” indicates the percentage of healthy people that a test correctly identifies as healthy) compared to a physician's diagnosis with laboratory testing. Meta-analysis of eight studies indicated that frontline health workers (for example, community health workers) diagnosed very severe disease (including possible bacterial infection) in young infants with a sensitivity of 82% and a specificity of 69% compared to trained physicians. The national surveys analyzed indicated that first-level (primary) health facilities in Africa and South Asia had low, variable stocks of recommended first-line injectable antibiotics and that the cost of these drugs was high. By contrast, some oral antibiotics were widely available at low cost in most regions. Finally, meta-analysis of 11 studies indicated that, in LMICs, 25% of antibiotic purchases for the treatment of young children were obtained without a prescription.
What Do These Findings Mean?
These findings suggest that trained frontline health workers should be able to identify most young infants who have possible bacterial infections in LMICs but may also diagnose bacterial infections in many young infants who are not infected. This may lead to the inappropriate use of antibiotics and facilitate the emergence of antibiotic resistance. These findings also show that the availability and affordability of first-line injectable antibiotics is low in many health facilities in Africa and Asia. The lack of neonatal-specific data on illness recognition, antibiotic formulations and availability, and other aspects of this systematic review and meta-analysis are likely to limit the accuracy of these findings. Nevertheless, the researchers suggest that, to decrease the neonatal death toll in LMICs, governments, policymakers, and the pharmaceutical industry need to work together to improve the diagnosis of neonatal bacterial infections and to increase the availability, affordability, and appropriate use of antibiotics for the treatment of these infections.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001741.
WHO provides information on global efforts to reduce global child mortality and on ending preventable neonatal deaths (available in several languages)
The United Nations Children's Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on global efforts to reduce child mortality , and its Childinfo website provides detailed statistics about neonatal survival and health; its “Committing to Child Survival: A Promise Renewed” webpage includes links to its 2013 progress report and to videos about ending preventable child deaths
The WHO has published a report entitled UN Commission on Life Saving Commodities for Women and Children
The Healthy Newborn Network (NHH) is an online community of more than 80 partner organizations that addresses critical knowledge gaps in newborn health; its website includes information on neonatal infections in LMICs
Kidshealth, a resource provided by the not-for-profit Nemours Foundation, has information for parents on neonatal infections (in English and Spanish)
The MedlinePlus Encyclopedia has a page on neonatal sepsis (in English and Spanish)
A personal story about fatal neonatal bacterial meningitis is available on the website of Meningitis UK, a not-for-profit organization; the site also includes a survivor story
doi:10.1371/journal.pmed.1001741
PMCID: PMC4196753  PMID: 25314011
20.  Continuous-Infusion Antipseudomonal Beta-Lactam Therapy in Patients With Cystic Fibrosis 
Pharmacy and Therapeutics  2011;36(11):723-763.
Objective:
We sought to evaluate the pharmacokinetics, efficacy, safety, stability, pharmacoeconomics, and quality-of-life effects of continuous-infusion antipseudomonal beta-lactam therapy in patients with cystic fibrosis (CF).
Data Sources:
Literature retrieval was accessed through Medline (from 1950 to December 2010) using the following terms: cystic fibrosis; beta-lactams or piperacillin or ticarcillin or cefepime or ceftazidime or doripenem or meropenem or imipenem/cilastin or aztreonam; continuous infusion or constant infusion; drug stability; economics, pharmaceutical; and quality of life. In addition, reference citations from identified publications were reviewed.
Study Selection and Data Extraction:
We evaluated all articles in English identified from the data sources.
Data Synthesis:
Patients with CF often harbor colonies of multidrug-resistant organisms, increasing the risk of suboptimal dosing and failure to meet the time above the minimum inhibitory concentration (T > MIC) pharmacodynamic targets. The pharmacokinetics of continuous-infusion antipseudomonal beta-lactam therapy in CF maintains serum concentrations above the MIC of susceptible strains and is more likely than intermittent infusion to achieve optimal T > MIC targets for some intermediate and resistant strains of Pseudomonas aeruginosa.
Three noncomparative and four comparative studies have assessed the efficacy and safety of continuous-infusion antipseudomonal beta-lactam therapy during CF pulmonary exacerbations. Ceftazidime, the most extensively studied antibiotic for continuous infusion in CF, has been shown to improve forced expiratory volume in 1 second (FEV1), to improve forced vital capacity (FVC), and to extend the time between pulmonary exacerbations. Continuous-infusion cefepime has been studied in a small number of patients, and a trend toward improved pulmonary function has been observed.
Continuous-infusion antipseudomonal beta-lactam therapy appears to be well tolerated, although most of the data pertain to ceftazidime. Because continuous infusion may necessitate that patients wear a portable pump in close proximity to the body, the stability of the antibiotic at body temperature must be considered. Several beta-lactams have good stability at body temperature (piperacillin/tazobactam, ticarcillin/clavulanate, and aztreonam) or acceptable if the medication cartridge is changed twice daily (cefepime and doripenem), whereas other beta-lactams have acceptable 24-hour stability only at lower temperatures (cefepime, ceftazidime, doripenem, and meropenem). Although no pharmacoeconomic studies have evaluated the cost–benefit of continuous infusion versus intermittent infusion in patients with CF, the potential medication cost reduction appears to be considerable. There is little information regarding the impact of continuous infusion on quality of life in patients with CF.
Conclusion:
Efficacy and safety studies suggest that ceftazidime, administered as a continuous infusion for the treatment of CF pulmonary exacerbations, is safe and effective; has the potential to reduce the costs of treatment; and is preferred to intermittent infusion among patients treated at home. Continuous-infusion ceftazidime may therefore be an alternative to traditional dosing on a case-by-case basis, such as for patients with multidrug-resistant isolates of P. aeruginosa. Treatment with continuous-infusion ceftazidime at home may be considered in such a case, assuming resources and support equivalent to the hospital setting can be ensured. Additional studies assessing the safety and efficacy of other antipseudomonal beta-lactams, when administered as a continuous infusion, during CF pulmonary exacerbations are needed.
PMCID: PMC3278169  PMID: 22346306
pulmonary; infectious disease; cystic fibrosis; continuous infusion; beta-lactam; monobactam; pulmonary exacerbation; intermittent infusion
21.  Asymptomatic bacteriuria, antibiotic use, and suspected urinary tract infections in four nursing homes 
BMC Geriatrics  2012;12:73.
Background
Urinary tract infections (UTIs) are the most commonly treated infection among nursing home residents. Even in the absence of specific (e.g., dysuria) or non-specific (e.g., fever) signs or symptoms, residents frequently receive an antibiotic for a suspected infection. This research investigates factors associated with the use of antibiotics to treat asymptomatic bacteriuria (ASB) among nursing home residents.
Methods
This was a cross-sectional study involving multi-level multivariate analyses of antibiotic prescription data for residents in four nursing homes in central Texas. Participants included all nursing home residents in these homes who, over a six-month period, received an antibiotic for a suspected UTI. We investigated what factors affected the likelihood that a resident receiving an antibiotic for a suspected UTI was asymptomatic.
Results
The most powerful predictor of antibiotic treatment for ASB was the presence of an indwelling urinary catheter. Over 80 percent of antibiotic prescriptions written for catheterized individuals were written for individuals with ASB. For those without a catheter, record reviews identified 204 antibiotic prescriptions among 151 residents treated for a suspected UTI. Almost 50% of these prescriptions were for residents with no documented UTI symptoms. Almost three-quarters of these antibiotics were ordered after laboratory results were available to clinicians. Multivariate analyses indicated that resident characteristics did not affect the likelihood that an antibiotic was prescribed for ASB. The only statistically significant factor was the identity of the nursing home in which a resident resided.
Conclusions
We confirm the findings of earlier research indicating frequent use of antibiotics for ASB in nursing homes, especially for residents with urinary catheters. In this sample of nursing home residents, half of the antibiotic prescriptions for a suspected UTI in residents without catheters occurred with no documented signs or symptoms of a UTI. Urine studies were performed in almost all suspected UTI cases in which an antibiotic was prescribed. Efforts to improve antibiotic stewardship in nursing homes must address clinical decision-making solely on the basis of diagnostic testing in the absence of signs or symptoms of a UTI.
doi:10.1186/1471-2318-12-73
PMCID: PMC3534219  PMID: 23176555
Nursing home; Antibiotic stewardship; Urinary tract infection; Asymptomatic bacteriuria; Antibiotics
22.  Indacaterol therapy in moderate-to-severe chronic obstructive pulmonary disease: findings from a single-center primary care cohort 
Background
Once-daily long-acting β2-agonists (LABAs) are an important treatment option, either alone or in combination with other inhaled long-acting bronchodilators in the management of chronic obstructive pulmonary disease (COPD).
Aims/objectives
To audit the effectiveness of indacaterol as maintenance therapy in patients with moderate-to-severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] stage II/III).
Methods
This was a single-center audit of a primary care COPD cohort comprising all patients treated with indacaterol following treatment escalation (as per National Institute for Health and Care Excellence guidelines) or failure with other therapies. The sample was restricted to patients treated for a minimum of 12 months with indacaterol, for whom preswitching and follow-up spirometry as well as exacerbation frequency data were available (GOLD spirometry guidelines). Pulmonary function was assessed by spirometry (recorded as forced expiratory volume in 1 second [FEV1] expressed as percentage predicted). Relevant self-reported qualitative information was recorded in descriptive terms for quality of life (QoL) assessment.
Results
A total of 15 patients met the audit inclusion criteria (66.6% male, mean age 64.9±7.7 years). COPD disease duration ranged from 1 to 22 years; 93% had GOLD stage II or III COPD. Follow-up ranged in duration from 12 to 27 months. Indacaterol was associated with a significant reduction in exacerbation frequency compared with the 12 months prior to initiation (P=0.02). In those patients who experienced three or more exacerbations/year, mean exacerbation rate fell from 5.43±1.07 to 2.43±0.2 after 12 months treatment with indacaterol (P=0.02). A reduction in dyspnea was noted in 53% of patients. Similarly, improvements in exercise tolerance and well-being were self-reported in 67% and 93%, respectively.
Conclusion
Indacaterol was found to be an effective LABA as an escalation or switch medication in patients with moderate-to-severe COPD. Indacaterol was effective both as monotherapy and in combination with a long-acting muscarinic antagonist. Switching to indacaterol from a LABA/inhaled corticosteroid fixed-combination inhaler significantly reduced the number of acute exacerbations and also improved self-reported QoL.
doi:10.2147/COPD.S53707
PMCID: PMC3862397  PMID: 24353411
chronic obstructive pulmonary disease; primary care; audit; indacaterol; bronchodilators; effectiveness
23.  Characterization of Lung Function Impairment in Adults with Bronchiectasis 
PLoS ONE  2014;9(11):e113373.
Background
Characteristics of lung function impairment in bronchiectasis is not fully understood.
Objectives
To determine the factors associated with lung function impairment and to compare changes in spirometry during bronchiectasis exacerbation and convalescence (1 week following 14-day antibiotic therapy).
Methods
We recruited 142 patients with steady-state bronchiectasis, of whom 44 with acute exacerbations in the follow-up were included in subgroup analyses. Baseline measurements consisted of chest high-resolution computed tomography (HRCT), sputum volume, purulence and bacteriology, spirometry and diffusing capacity. Spirometry, but not diffusing capacity, was examined during acute exacerbations and convalescence.
Results
In the final multivariate models, having bronchiectasis symptoms for 10 years or greater (OR = 4.75, 95%CI: 1.46–15.43, P = 0.01), sputum culture positive for Pseudomonas aeruginosa (OR = 4.93, 95%CI: 1.52–15.94, P<0.01) and HRCT total score being 12 or greater (OR = 7.77, 95%CI: 3.21–18.79, P<0.01) were the major variables associated with FEV1 being 50%pred or less; and the only variable associated with reduced DLCO was 4 or more bronchiectatic lobes (OR = 5.91, 95%CI: 2.20–17.23, P<0.01). Overall differences in FVC and FEV1 during exacerbations and convalescence were significant (P<0.05), whereas changes in other spirometric parameters were less notable. This applied even when stratified by the magnitude of FEV1 and DLCO reduction at baseline.
Conclusion
Significant lung function impairment should raise alert of chest HRCT abnormality and sputum culture positive for Pseudomonas aeruginosa, in patients with predominantly mild to moderate steady-state bronchiectasis. Acute exacerbations elicited reductions in FVC and FEV1. Changes of other spirometric parameters were less significant during exacerbations.
Trial Registration
ClinicalTrials.gov NCT01761214
doi:10.1371/journal.pone.0113373
PMCID: PMC4236163  PMID: 25405614
24.  Parent and Child Perceptions of a Self-Regulated, Home-Based Exercise Program for Children with Cystic Fibrosis 
Nursing research  2013;62(5):305-314.
Background
Despite recognized benefits, many children with cystic fibrosis (CF) do not consistently participate in physical activities. There is little empirical literature regarding the feelings and attitudes of children with CF toward exercise programs, parental roles in exercise, or factors influencing exercise experiences during research participation.
Objectives
To describe the exercise experiences of children with CF and their parents during participation in a six-month program of self-regulated, home-based exercise.
Methods
This qualitative descriptive study nested within a randomized controlled trial of a self-regulated, home-based exercise program used serial semi-structured interviews conducted individually at two and six months with 11 purposively selected children with CF and their parent(s).
Results
Six boys and five girls, ages 10–16, and parents (nine mothers, four fathers) participated in a total of 44 interviews. Five major thematic categories describing child and parent perceptions and experience of the bicycle exercise program were identified in the transcripts: (a) motivators; (b) barriers; (c) effort/work; (d) exercise routine; (e) sustaining exercise. Research participation, parent-family participation, health benefits, and the child’s personality traits were primary motivators. Competing activities, priorities and responsibilities were the major barriers to implementing the exercise program as prescribed. Motivation waned and the novelty wore off for several (approximately half) parent-child dyads, who planned to decrease or stop the exercise program after the study ended.
Discussion
We identified motivators and barriers to a self-regulated, home-based exercise program for children with CF that can be addressed in planning future exercise interventions to maximize the health benefits for children with CF and the feasibility and acceptability to the children and their families.
doi:10.1097/NNR.0b013e3182a03503
PMCID: PMC4053557  PMID: 23995464
Exercise; children; cystic fibrosis; chronic disease; qualitative research
25.  Long term benefits of rehabilitation at home on quality of life and exercise tolerance in patients with chronic obstructive pulmonary disease. 
Thorax  1995;50(8):824-828.
BACKGROUND--Pulmonary rehabilitation has been shown to have short term subjective and objective benefits for patients with chronic obstructive pulmonary disease (COPD). However, appropriately controlled studies have not previously been performed, nor have the benefits of different types of continuation programme for rehabilitation been investigated. Both these problems have been addressed in a single study of the long term effects of once monthly physiotherapy versus once weekly physiotherapy at home after a comprehensive home rehabilitation programme on quality of life and exercise tolerance in patients with COPD. METHODS--Thirty six patients with severe airways obstruction (mean SD) forced expiratory volume in one second (FEV1) 1.3(0.4) 1, FEV1/inspiratory vital capacity (IVC) 37.2(7.9)%) were studied. Twenty three patients followed a rehabilitation programme at home for 18 months consisting of physiotherapy and supervision by a nurse and general practitioner. During the first three months all 23 patients visited the physiotherapist twice a week for a 0.5 hour session. Thereafter, 11 patients (group A) received a session of physiotherapy once weekly while 12 patients (group B) received a session of physiotherapy once a month. The control group C (13 patients) received no rehabilitation at all. Quality of life was assessed by the Chronic Respiratory Questionnaire, exercise tolerance by the six minute walking distance, and lung function by FEV1 and IVC. Outcome measures were assessed at baseline and at three, six, 12, and 18 months. RESULTS--Long term improvements in quality of life were found in patients in groups A and B, but not in those in group C compared with baseline, but these only reached significance in group B at all time points. Patients in group B had a higher quality of life than those in group C only at three and 12 months. There was a decrease in both six minute walking distance (at 12 and 18 months) and IVC (at three, 12, and 18 months) in patients in group C compared with the baseline measurement. Between groups analysis showed no differences for six minute walking distance, FEV1, and IVC. CONCLUSIONS--This study is the first to show that rehabilitation at home for three months followed by once monthly physiotherapy sessions improves quality of life over 18 months. The change in quality of life was not associated with a change in exercise tolerance.
PMCID: PMC474891  PMID: 7570431

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