An unexpected cause of constipation and abdominal distension in COPD.

Question: A 62-year old man presented to our tertiary care hospital for a second opinion regarding end stage COPD GOLD 4D. He had a medical history of former alcohol use complicated by liver steatosis and former smoking. Upon admission the patient complained of constipation and abdominal distension. Physical examination showed diffuse hypertympanic percussion and diffuse abdominal pain upon palpation without signs of peritoneal irrita- tion. CRP, hemoglobin, lactate, liver enzymes, and serum creatinine were within limits of normal. Abdominal radiography showed dilatation of the colon transversum with intramural and intra-abdominal free air (Figure 1). Contrast-enhanced abdominal CT showed extensive intramural air in the right hemicolon (Figure 2). Answer: The findings are consistent with pneumatosis intestinalis (PI). Conservative management with oxygen, triple bronchodilator therapy, fasting, laxation and antibiotic therapy resulted in resolution of the clinical symptoms.

Long-term outcome and health-related quality of life in difficult-to-wean patients with and without ventilator dependency at ICU discharge: a retrospective cohort study.

BACKGROUND: Long-term outcome and quality of life (QOL) in patients requiring prolonged mechanical ventilation after failure to wean in the ICU is scarcely documented. We aimed to evaluate long-term survival and QOL in patients discharged from the ICU with a tracheostomy for difficult weaning, and with or without ventilator dependency at ICU discharge. METHODS: We retrospectively investigated post-ICU trajectories and survival in patients requiring tracheostomy for difficult weaning admitted to the medical ICU of a tertiary center between 1999 and 2013, discriminating between patients who were ventilator dependent or were weaned at ICU discharge. In 2014, a QOL assessment was done in survivors with the use of the Short Form Health Survey (SF-36) and the Severe Respiratory Insufficiency questionnaire. RESULTS: A total of 114 patients was included, of whom 59 were ventilator dependent and 55 were weaned at ICU discharge. One-year survival rates were 73 % and 69 %, respectively. Overall QOL scores for physical functioning were low, and not significantly different between patients ventilated and those weaned at ICU discharge; scores for social functioning and mental health were less below norm and similar between both groups. CONCLUSIONS: Long-term survival in patients discharged from the ICU with tracheostomy and ventilator dependency after failure to wean was not significantly different from that of patients with tracheostomy and weaned at ICU discharge. Despite the physical QOL scores being low in both groups, mental QOL was acceptable. Given the intrinsic limitations of this retrospective study, prospective and preferentially multicenter studies are required to confirm these preliminary results.

The effect of radical treatment and rehabilitation on muscle mass and strength: a randomized trial in stages I-III lung cancer patients.

OBJECTIVES: Little is known about the impact of an oncological treatment on muscle mass and strength in patients with lung cancer and the impact of a subsequent rehabilitation program. This study investigates the effect of radical treatment and post-treatment pulmonary rehabilitation on muscle mass and strength in patients with lung cancer and the relationship between muscle mass and strength. METHODS: Lung cancer patients, candidate for radical treatment, were randomly (2:1) allocated after radical treatment to either standard follow up (CON) or a 12-week rehabilitation training program (RT). Muscle mass was estimated by bioelectric impedance and CT-scan. Muscle strength was estimated by measuring quadriceps force (QF) with a hand held dynamometer. All variables were measured before (M1) and after radical treatment (M2), and at the earliest 12 weeks after randomization (M3). Data are presented as means with standard deviation. RESULTS: 45 lung cancer patients (age: 65 years (9)) participated in the study. At M2, both muscle cross sectional area (MCSA) and QF were significantly decreased (p<0.05). 28 patients were randomized. 13/18 RT and 9/10 CON patients ended the trial. At M3, RT-patients improved significantly their MCSA compared to CON-patients (ΔMCSA: 6 cm(2) (6) (p=0.003) vs. 1cm(2) (11) (p=0.8)). CONCLUSION: Muscle mass and strength: (1) are decreased at presentation in a substantial part of lung cancer patients; (2) are significantly negatively affected by radical treatment and (3) completely recover after a 12 week structured rehabilitation program, whereas a further decline was observed in CON-patients.

Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease.

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.

Endurance and Resistance Training in Radically Treated Respiratory Cancer patients: A Pilot Study.

Introduction. Respiratory cancer and its treatment are known to contribute to muscle weakness and functional impairment. Aim. To assess the effects of rehabilitation in patients with respiratory cancer. Methods. Radically treated respiratory cancer patients were included in a 12-week multidisciplinary rehabilitation program. Results. 16 patients (age: 61 ± 7 years; FEV(1): 57 ± 16% pred.) showed a reduced exercise tolerance (VO(2)max: 56 ± 15% pred.; 6 MWD: 67 ± 11% pred.), muscle force (PImax: 54 ± 22% pred.; QF: 67 ± 16% pred.), and quality of life (CRDQd: 17 ± 5 points; CRDQf: 16 ± 5 points). Exercise tolerance, muscle force, and quality of life improved significantly after rehabilitation. Conclusion. Radically treated patients with respiratory cancer have a decreased exercise capacity, muscle force, and quality of life. 12 weeks of rehabilitation leads to a significant improvement in exercise capacity, respiratory muscle force, and quality of life.

Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma.

We compared the systemic and clinical effects of ciclesonide (CIC) and fluticasone propionate (FP) administered, in addition to CIC 160 microg x day(-1) and salmeterol 50 microg twice daily, in 32 patients with persistent asthma using a randomised double-blind, placebo-controlled, double-dummy, five-period crossover design. All patients exhibited a provocative concentration leading to a 20% decrease in forced expiratory volume in 1 s (PC(20)) methacholine <8 mg x mL(-1) and a PC(20) adenosine <60 mg x mL(-1). Primary outcome was 24-h serum cortisol suppression after 7 days. Secondary outcomes were changes in PC(20) methacholine and adenosine after 9 days. FP 500 microg x day(-1) and 1,000 microg x day(-1) significantly suppressed cortisol secretion versus placebo by -46.2 (95% confidence interval (CI) -83.8- -8.5) nmol x L(-1) and by -76.1 (95% CI -112.9- -39.3) nmol x L(-1), respectively. Neither dose of CIC (320 nor 640 microg x day(-1)) had a significant suppressive effect (-28.2 (95% CI -65.5-9.2) nmol x L(-1) and -37.3 (95% CI -74.7-0.0) nmol x L(-1), respectively). Differences between FP 1,000 microg x day(-1) and both CIC treatments were statistically significant (CIC 320 microg x day(-1): -48.0 (95% CI -84.8- -11.1) nmol x L(-1); CIC 640 microg x day(-1): -38.8 (95% CI -75.7- -1.9) nmol x L(-1)). Compared with placebo, the increase in PC(20) adenosine after the four treatments was small, but significant. Greater improvements in PC(20) adenosine were seen with FP 500 microg x day(-1) (1.8 (95% CI 1.0-2.6) doubling concentrations) compared with CIC 320 microg x day(-1) (0.9 (95% CI 0.1-1.7) doubling concentrations). No significant difference was seen between CIC 640 microg x day(-1) and FP 1,000 microg x day(-1). For a similar decrease in hyperresponsiveness, cortisol secretion was suppressed significantly with moderate-to-high doses of fluticasone propionate, but not with ciclesonide.

Primary care spirometry.

Primary care spirometry is a uniquely valuable tool in the evaluation of patients with respiratory symptoms, allowing the general practitioner to diagnose or exclude chronic obstructive pulmonary disease (COPD), sometimes to confirm asthma, to determine the efficacy of asthma treatment and to correctly stage patients with COPD. The use of spirometry for case finding in asymptomatic COPD patients might become an option, once early intervention studies have shown it to be beneficial in these patients. The diagnosis of airway obstruction requires accurate and reproducible spirometric measurements, which should comply with the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. Low acceptability of spirometric manoeuvres has been reported in primary care practices. This may hamper the validity of the results and affect clinical decision making. Training and refresher courses may produce and maintain good-quality testing, promote the use of spirometric results in clinical practice and enhance the quality of interpretation. Softening the stringent ATS/ERS criteria could enhance the acceptability rates of spirometry when used in a general practice. However, the implications of potential simplifications on the quality of the data and clinical decision making remain to be investigated. Hand-held office spirometers have been developed in recent years, with a global quality and user-friendliness that makes them acceptable for use in general practices. The precision of the forced vital capacity measurements could be improved in some of the available models.

Pulmonary rehabilitation in chronic obstructive pulmonary disease.

Pulmonary rehabilitation, a multidisciplinary and structured intervention for patients with chronic pulmonary diseases, has been shown to improve exercise tolerance, reduce dyspnea and improve health-related quality of life. Pulmonary rehabilitation appears to be cost-effective, since it reduces health care utilization. Exercise training represents the cornerstone of every pulmonary rehabilitation program. To obtain clinically relevant effects, training should closely supervised, of high intensity, lasting 30-45 min for at least 3 days/week. Patients should undertake a minimum of 20 sessions, but longer programs result in larger and more long-lasting effects. Education and self-management programs have been shown to result in a substantial reduction in hospital admissions. Nutritional intervention should be considered for patients who are underweight or those with body composition abnormalities. Patients reporting fear and anxiety may benefit from psychosocial support, and the integration of occupational therapy in a pulmonary rehabilitation program can improve independence in activity. Multidisciplinary pulmonary rehabilitation is preferably implemented in an outpatient hospital- or community-based setting. Inpatient programs are suited for patients with limited transportation capabilities or severe deconditioning. The most convincing effects of home-based rehabilitation are in maintaining the improvements obtained in an outpatient setting.

Indacaterol, a novel inhaled beta2-agonist, provides sustained 24-h bronchodilation in asthma.

The present study examined the bronchodilator and safety profiles of single-dose indacaterol in intermittent or persistent asthma. In the present double-blind crossover study, 42 patients were randomised to receive single doses of indacaterol (50, 100, 200 and 400 microg) or placebo via a hydrofluoroalkane pressurised metered-dose inhaler. The primary efficacy comparisons were the per cent changes in forced expiratory volume in one second (FEV(1 )) between indacaterol and placebo 30 min and 21 h post-dose. All doses resulted in prolonged bronchodilation, with indacaterol 200 and 400 microg meeting pre-specified efficacy criteria. The mean percentage increases in FEV(1) from placebo with indacaterol 200 and 400 microg were 7.6 and 14.9%, respectively, at 30 min, and 7.5 and 10.4%, respectively, at 21 h post-dose. At these doses, changes in mean FEV(1) relative to placebo were statistically significant from 5 min to 25 h, inclusive. At 5 min, the geometric least squares mean values for FEV(1) were 3.08 and 3.22 L for the 200 and 400 microg doses, respectively, compared with 2.99 L for placebo. At 24 h after dosing, the baseline-adjusted geometric least square mean FEV(1) was 3.13, 3.11, 3.24 and 3.30 L for indacaterol 50, 100, 200 and 400 microg, respectively, and 2.98 L for placebo. All treatments were well tolerated. Once-daily indacaterol at doses of 200 and 400 microg provided sustained 24-h bronchodilation, with a rapid onset and a good tolerability and safety profile.

Assessment of progression of COPD: report of a workshop held in Leuven, 11-12 March 2004.

Recently performed long term trials have enhanced the insight into the assessment of progression of COPD. The present review focuses on the initial assessment of COPD in general practice and the assessment of disease progression. Several variables may be used to assess this progression, all of which are associated with significant methodological problems. Finding the appropriate mix of outcome measures to capture all aspects of disease progression is a significant challenge.

Tiotropium bromide: a long-acting anticholinergic bronchodilator for the treatment of patients with chronic obstructive pulmonary disease.

Prevention and relief of symptoms by regular use of bronchodilators is central to the management of patients with chronic obstructive pulmonary disease (COPD). The bronchodilators in use are beta2-agonists, anticholinergics and theophylline. Since the 1970s the anticholinergic ipratropium bromide has been widely used for the treatment of patients with regular symptoms, but because it has a relatively short duration of action, it needs to be administered four times a day. Tiotropium bromide is a long-acting anticholinergic suitable for once daily administration. It has been developed as a dry powder inhaler for the treatment of patients with COPD. Large clinical trials with administration of the drug for one year have now been published. Compared with placebo and ipratopium bromide, significant and long-lasting bronchodilatation was observed, which was maintained over the year. The bronchodilator effect of tiotropium bromide was accompanied by improvements in other health outcomes. A significant decrease in dyspnoea, improvement in health-related quality of life, and a reduction in the number of COPD exacerbations and hospitalisations were noted. In this review we summarise the clinical development of this compound.

Lung deposition and protective effect of terbutaline delivered from pressurized metered-dose inhalers and the Turbuhaler in asthmatic individuals.

We investigated the relationship between pulmonary deposition of terbutaline and bronchoprotection against methacholine and histamine with the Turbuhaler (AstraZeneca, Lund, Sweden) and a pressurized metered dose inhaler (pMDI) in 13 asthmatic patients. The study was done with a randomized, double blind, double dummy, and crossover design. On different days, the provocative concentration of histamine causing a 20% decrease in FEV(1) (PC(20) histamine) and PC(20) methacholine were determined before and at 1.5, 3, and 6 h after inhalation of 0.25 or 0.5 mg of terbutaline sulfate. The Turbuhaler delivered significantly more drug than did the pMDI (% of the nominal metered dose and 95% confidence interval): 20.8% (16.4 to 26.6%) and 16.9% (13.2 to 21.7%) versus 4.8% (3.8 to 6.1%) and 7.4% (5.8 to 9.5%), respectively. Average protection against histamine over 6 h was 0.66 (95% CI: 0.45 to 0.87) doubling concentrations (DC) after inhalation of 0.25 mg and 1.08 (95% CI: 0.87 to 1.29) DC after 0.5 mg terbutaline via pMDI, and 1.07 (95% CI: 0.87 to 1.29) DC after 0.25 mg and 1.24 (95% CI: 1.03 to 1.45) DC after 0.50 mg via Turbuhaler. Protection against methacholine was also dose- and device-dependent. The dose needed to obtain the same pulmonary deposition with the pMDI was 3.14 times greater than with the Turbuhaler, and that needed for the same protective effect was 2.1 and 3.2 times greater for histamine and methacholine, respectively. We conclude that pulmonary deposition of terbutaline was predictive of the clinical response.

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler.

In vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, while a corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drug between the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler(R) than for the corresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher, both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors such as the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle of inhalation via Turbuhaler.

Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma.

We assessed the systemic effects of budesonide (BUD) and fluticasone propionate (FP) in 23 patients with asthma, using a double-blind, placebo-controlled, double-dummy, and cross-over design. The following five treatments were given in a randomized order for 1 wk with a washout period in between of 2 wk: (1) placebo; (2) FP, 200 micrograms twice a day, inhaled from a Diskhaler; (3) FP, 1,000 micrograms twice a day, inhaled from a Diskhaler; (4) BUD, 200 micrograms twice a day, inhaled from a Turbuhaler; and (5) BUD, 800 micrograms twice a day, inhaled from a Turbuhaler. The primary variable was the area under the curve of serum cortisol versus time (AUC0-20), derived from serum samples taken every 2 h over a 20-h period following the last evening dose at 10:00 P.M. The lower doses of BUD and FLU did not cause any adrenal suppression. Compared with placebo, however, FP (1, 000 micrograms, twice daily and BUD (800 micrograms, twice daily) decreased the AUC0-20 by 34 and 16%, respectively. Fluticasone (1,000 micrograms, twice daily) was more suppressive than BUD (800 micrograms, twice daily) (p = 0.0006). The FEV1, measured the morning after the last inhalation, was significantly higher after the active treatments, compared with placebo (p < 0.02), but did not differ between all active treatments. We conclude that high doses of BUD and FP (in particular the latter), inhaled via their respective dry powder inhalers for 1 wk, result in a measurable systemic activity in patients with asthma.

Neck and abdominal muscle activity in patients with severe thoracic scoliosis.

Patients with severe chronic obstructive pulmonary disease (COPD) do not use the sternocleidomastoid muscles when breathing at rest, but have a greater than normal neural drive to the rib-cage inspiratory muscles, the abdominal muscles, and the diaphragm. Yet the increased activation of the abdominal muscles and diaphragm in such patients has only limited mechanical effects, and this has led to the suggestion that the overall increase in neural drive is simply an automatic response of the respiratory system to a greater than resting stimulation. To test this hypothesis, we examined the pattern of respiratory-muscle activation in eight patients with severe thoracic scoliosis (Cobb angle between 100 degrees and 136 degrees). We recorded electromyograms of the sternocleidomastoid, scalene, rectus abdominis, external oblique, and transversus abdominis muscles; esophageal (Pes) and gastric (Pga) pressures; and the anteroposterior (AP) diameter of the abdomen during resting breathing in the seated posture. All patients had invariable phasic inspiratory activity in the scalenes; and five patients had invariable phasic expiratory activity in the transversus; intermittent expiratory activity in the transversus was also recorded in three patients. In contrast, only one patient had invariable phasic inspiratory activity in the sternocleidomastoid, and only one patient had invariable phasic expiratory activity in the external oblique. The decrease in abdominal AP diameter during expiration was commonly associated with a rise in Pga. These observations therefore indicate that the pattern of respiratory-muscle activation in patients with severe thoracic scoliosis is essentially similar to that seen in patients with severe COPD. This supports the concept that the order of recruitment of the respiratory muscles during breathing is an automatic response of the central controller.

Onset and duration of action of single doses of formoterol inhaled via Turbuhaler.

The aim of the study was to investigate the time of onset and the duration of the bronchodilating effect of different doses of formoterol administered via Turbuhaler in patients with moderate asthma. Thirty-one patients (five women) with a mean forced expiratory volume in 1 s (FEV1) of 1.97 +/- 0.54 1 and a mean reversibility of 31 +/- 14% of baseline were included in this double-blind, randomized, placebo-controlled and cross-over study. The patients inhaled single doses of placebo, i.e. 6, 12, 24, or 48 micrograms formoterol fumarate, on 5 separate days. Serial measurements of specific airways conductance (SGAW) and FEV1 were performed at regular time intervals for 12 h. The majority of the patients had at least a 50% increase in SGAW within 1-4 min after administration of all active treatments. The maximum increase in FEV1 over placebo was dose-dependent: 12% (6 micrograms), 18% (12 micrograms), 19% (24 micrograms), and 26% (48 micrograms) (P < 0.001). Twelve hours after administration of 6, 12, 24, and 48 micrograms formoterol, the mean increase in FEV1 was still 7%, 15%, 18%, and 27%, respectively, above the value following placebo. Headache was the most frequently reported adverse event in all treatments including placebo. After inhalation of 48 micrograms, three patients experienced mild tremor lasting for less than 1 h; likewise, one patient experienced the same event for 3 h after placebo. Formoterol administered via Turbuhaler10 gave a rapid and dose-related bronchodilating effect lasting for 12 h and was well tolerated.

Broxaterol increases force output of fatigued canine diaphragm more than salbutamol.

We previously demonstrated that broxaterol enhanced recovery of fatigued canine diaphragm. The aim of this study was to compare the inotropic effects of salbutamol and broxaterol on fatigued canine diaphragm. Low-frequency fatigue was induced in 14 mongrel dogs by electrophrenic stimulation, which was continued until transdiaphragmatic pressure (Pdi) at 20 Hz was reduced by 50% or for 1 h. After stabilization of fatigue, the animals received a bolus (18.5 microg/kg) of either broxaterol or salbutamol, followed by a continuous infusion (0.43 microg/kg/min). A second bolus of 74.0 microg/kg, followed by a continuous infusion of 1.72 microg/kg/min, was given after 90 min. Both drugs significantly increased twitch Pdi. Twitch Pdi measured 90 min after the first and second doses of broxaterol increased by 28 +/- 23% and 42 +/- 34%, respectively, whereas the salbutamol-induced increase was clearly smaller (9 +/- 10% and 17 +/- 15%, respectively). Broxaterol increased Pdi at 20 Hz by 25 +/- 28% with the first dose and by 29 +/- 21% with the second dose. In contrast, salbutamol did not alter Pdi at 20 Hz. Neither drug affected Pdi at 100 Hz. We conclude that broxaterol promoted recovery of low-frequency fatigue of the canine diaphragm in vivo in a dose-dependent manner, whereas salbutamol only minimally improved force production by the fatigued diaphragm.

The inhalation device influences lung deposition and bronchodilating effect of terbutaline.

The development of new inhalation devices for asthma drugs raises the issue of the relationship between pulmonary deposition and therapeutic effect of inhaled drugs in patients with obstructive lung diseases. We thus conducted a randomized, double-blind and double-dummy, four-period crossover study in 13 patients with moderate asthma (mean age 36 yr; FEV1 59% of predicted), who inhaled 0.25 and 0.5 mg terbutaline sulphate on separate occasions either via a pressurized metered dose inhaler (pMDI) or Turbuhaler (TBH). Pulmonary deposition was 8.1 +/- 2.7% and 8.3 +/- 2.3%, respectively, of the nominal dose for pMDI and 19.0 +/- 7.3%, and 22.0 +/- 8.1% for TBH. The FEV1 increase after 0.25 mg terbutaline sulphate via TBH was significantly greater than after 0.25 mg via pMDI. No significant differences in FEV1 increase were observed between 0.25 mg via TBH, 0.5 mg via pMDI, or 0.5 mg via TBH. Other lung function variables showed similar dose- and device-related changes. We concluded that: (1) the dose of terbutaline sulphate deposited in the lungs is dependent on which inhalation system is used; (2) TBH delivers about twice the amount of drug to the lungs as the pMDI; and (3) the observed difference in deposition is reflected in the bronchodilating effect.