Communicating uncertainty: contrasting the communication experiences of patients with advanced COPD and incurable lung cancer.

BACKGROUND: Due to the uncertain disease trajectory and variable rate of progression in chronic obstructive pulmonary disease (COPD), health care professionals (HCPs) are challenged in explaining what the future may hold for patients compared to those with lung cancer (LC). Support and communication of timely information can significantly improve health outcomes. OBJECTIVE: This study sought to identify factors that impact communication and support and recommend ways to improve patients' understanding of living with life-threatening illness. METHODS: Semi-structured interviews with patients with LC (n = 22) and advanced COPD (n = 18), their informal carers (21 LC and 18 COPD) and HCPs (n = 51). Patients were recruited from primary and secondary care in the East of England, UK, during 2010-12. RESULTS: Directness and clarity characterized communication in LC, whereas uncertainty and limited explanations predominated in COPD. Discussions on how the disease might impact on decisions and preferences to be made in the future were less common in COPD. Information for LC patients was mainly from hospital clinicians and any information for COPD patients mainly from primary care clinicians. CONCLUSIONS: The experience of COPD patients could be improved by professionals soon after diagnosis explaining to them the typical pattern of decline in COPD, highlighting the inherent uncertainties about when exacerbations and death may occur. This conversation should lead to planning for the different challenges that the patient and informal carer recognize as most important to them. This contrasts with the 'breaking bad news' conversation that oncologists are highly trained to deliver.

People living with lung cancer (LC) or chronic obstructive pulmonary disease (COPD) have poor health-related quality of life. However, more people with LC receive holistic palliative care (which involves supportive advance care planning) than those with COPD. We interviewed patients with LC or COPD, their informal carers (family/friends who support them) and health care professionals (HCPs) about their experiences and our findings confirmed this: HCPs said the uncertainty of COPD prognosis made starting advance care planning conversations challenging. The level of uncertainty and unpredictability is very different in LC and COPD: the cancer diagnosis is made at a single point in time with mortality immediately on the agenda, while COPD is a chronic condition that develops over many years. We urge clinicians to share this uncertainty with patients and to try to explain and communicate it sooner than later. These conversations should also continue as a recognized part of ongoing care so that COPD patients can benefit from understanding the uncertainties they are dealing and living with. LC and COPD should be approached differently to meet patients' condition-specific needs in order that the existing disparity in holistic care can be remedied.

Metabolic phenotype of skeletal muscle in early critical illness.

OBJECTIVES: To characterise the sketetal muscle metabolic phenotype during early critical illness. METHODS: Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). MEASUREMENTS AND MAIN RESULTS: From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (-27.4CN (95% CI -123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (-1859CN (IQR -5557-1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (-4.8 mmol/kg dw (IQR -8.0-1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR -0.09-2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5-1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR -0.44-3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4-39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR -7-100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered. CONCLUSIONS: Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. TRIAL REGISTRATION NUMBER: NCT01106300.

Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease.

RATIONALE: Impaired skeletal muscle function contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). This is characterized by reduced mitochondrial adenosine triphosphate generation, and greater reliance on nonmitochondrial energy production. Dichloroacetate (DCA) infusion activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and diminishing anaerobic energy production. OBJECTIVES: This study aimed to determine whether DCA infusion enhanced mitochondrial energy delivery during symptom-limited maximal exercise, thereby reducing exercise-induced lactate and ammonia accumulation and, consequently, improving exercise performance in patients with COPD. METHODS: A randomized, double-blind crossover design was used. Eighteen subjects with COPD performed maximal cycle exercise after an intravenous infusion of DCA (50 mg/kg body mass) or saline (control). Exercise work output was determined, and blood lactate and ammonia concentrations were measured at rest, 1 and 2 minutes of exercise, peak exercise, and 2 minutes postexercise. MEASUREMENTS AND MAIN RESULTS: DCA infusion reduced peak blood lactate concentration by 20% (mean [SE]; difference, 0.48 [0.11] mmol/L, P < 0.001) and peak blood ammonia concentration by 15% (mean [SE]; difference, 14.2 [2.9] mumol/L, P < 0.001] compared with control. After DCA, peak exercise workload improved significantly by a mean (SE) of 8 (1) W (P < 0.001) and peak oxygen consumption by 1.2 (0.5) ml/kg/minute (P = 0.03) compared with control. CONCLUSIONS: We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.

Impact of transcutaneous neuromuscular electrical stimulation or resistance exercise on skeletal muscle mRNA expression in COPD.

Background: Voluntary resistance exercise (RE) training increases muscle mass and strength in patients with chronic obstructive pulmonary disease (COPD). Nonvolitional transcutaneous neuromuscular electrical stimulation (NMES) may be an alternative strategy for reducing ambulatory muscle weakness in patients unable to perform RE training, but little comparative data are available. This study, therefore, investigated changes in muscle mRNA abundance of a number of gene targets in response to a single bout of NMES compared with RE. Methods: Twenty-six patients with stable COPD (15 male; FEV1, 43±18% predicted; age, 64±8 years; fat free mass index, 16.6±1.8 kg/m2) undertook 30 minutes of quadriceps NMES (50 Hz, current at the limit of tolerance) or 5×30 maximal voluntary isokinetic knee extensions. Vastus lateralis muscle biopsies were obtained at rest immediately before and 24 hours after intervention. Expression of 384 targeted mRNA transcripts was assessed by real time TaqMan PCR. Significant change in expression from baseline was determined using the ΔΔCT method with a false discovery rate (FDR) of <5%. Results: NMES and RE altered mRNA abundance of 18 and 68 genes, respectively (FDR <5%), of which 14 genes were common to both interventions and of the same magnitude of fold change. Biological functions of upregulated genes included inflammation, hypertrophy, muscle protein turnover, and muscle growth, whilst downregulated genes included mitochondrial and cell signaling functions. Conclusions: Compared with NMES, RE had a broader impact on mRNA abundance and, therefore, appears to be the superior intervention for maximizing transcriptional responses in the quadriceps of patients with COPD. However, if voluntary RE is not feasible in a clinical setting, NMES by modifying expression of genes known to impact upon muscle mass and strength may have a positive influence on muscle function.

Enhanced delivery of nebulised salbutamol during non-invasive ventilation.

Non-invasive ventilation (NIV) is used to treat acute respiratory failure. Nebulised drugs can be delivered concurrently with NIV or during breaks from ventilatory support. We hypothesised that the amount of nebulised salbutamol inhaled when delivered via bi-level ventilation would be no different to the amount available directly from the same nebuliser. A standard bi-level ventilation circuit was attached to a lung model simulating adult respiration. Drug delivery was compared when salbutamol (5 mg) was nebulised at different positions in the circuit and separately, with no ventilator. The amount of salbutamol contained in various particle size fractions was also determined. Nebuliser position within the NIV circuit was critically important for drug delivery. Optimal delivery of salbutamol occurred with the expiration port between the facemask and nebuliser (647+/-67 micro g). This was significantly better than nebulisation without the ventilator (424+/-61 micro g; P < 0.01). Delivery when the nebuliser was positioned between the facemask and expiration port was 544+/-85 micro g. The amount of salbutamol contained in particles < 5 micro m was significantly increased when the nebuliser was used in conjunction with bi-level ventilation (576+/-60 micro g vs 300+/-43 micro g, P < 0.001). We conclude that nebulised bronchodilator therapy, using a Cirrus jet nebuliser, during bi-level ventilation increases respirable particles likely to be inhaled when the nebuliser is optimally positioned within the circuit.

Exercise induced skeletal muscle metabolic stress is reduced after pulmonary rehabilitation in COPD.

In COPD, skeletal muscle ATP resynthesis may be insufficient to meet demand during exercise due to excessive anaerobic and reduced oxidative (mitochondrial) energy production, leading to metabolic stress. We investigated the effect of outpatient pulmonary rehabilitation (PR) on the metabolic response (measured by exercise-induced accumulation of plasma ammonia) and determined whether this response predicted functional improvement following PR. 25 subjects with stable COPD [mean (SD) age 67 (8)years and FEV(1) 47 (18)% predicted] performed maximal cycling ergometry before and after PR. Plasma ammonia was measured at rest, during exercise and 2 min post-exercise. Following PR, there were significant increases in peak cycle WR and ISWT performance (Mean (SEM) changes 13.1 (2.0) W and 93 (15) m respectively, p < 0.001). Mean (SEM) rise in plasma ammonia was reduced at peak (Pre vs Post-PR: 29.0 (4.5) vs 20.2 (2.5) µmol/l, p < 0.05) and isotime (Pre vs Post-PR: 29.0 (4.5) vs 10.6 (1.7) µmol/l, p < 0.001) exercise. Improvements in exercise performance after PR were similar among subgroups who did versus those who did not show a rise in ammonia at baseline. The results suggest that muscle cellular energy production was better matched to the demands of exercise following PR. We conclude that a pragmatic outpatient PR programme involving high intensity walking exercise results in significant adaptation of the skeletal muscle metabolic response with a reduction in exercise-related metabolic stress. However, the outcome of PR could not be predicted from baseline metabolic response.

Dichloroacetate modulates the oxidative stress and inflammatory response to exercise in COPD.

BACKGROUND: Impaired skeletal muscle function contributes to exercise intolerance in patients with COPD. Exercise-induced oxidative stress may initiate or accelerate impaired muscle function. Dichloroacetate (DCA) activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and thereby diminishing anaerobic energy production. This study aimed to determine whether DCA infusion also may reduce exercise-induced systemic oxidative stress and inflammatory response in patients with COPD. METHODS: A randomized, double-blind crossover design was used in which 13 patients with COPD performed maximal cycle exercise after an IV infusion of DCA (50 mg/kg body mass) or saline solution (placebo). Venous blood was sampled before exercise, and immediately, 30 min, and 2 h after exercise. Urine samples were obtained before and 2 h after exercise. RESULTS: Peak workload improved significantly after DCA infusion compared to placebo (10%; p < 0.01). Urinary uric acid levels after exercise were significantly lower in the DCA condition than in the placebo condition, whereas no significant difference was observed for urinary malondialdehyde levels. Oxidized glutathione (GSSG) levels were significantly increased 2 h after exercise in the placebo condition (p < 0.02) but not after DCA infusion. No changes in reduced glutathione (GSH), GSSG/GSH ratio, and superoxide dismutase activity were observed. Plasma interleukin (IL)-6 levels significantly increased 2 h after exercise only in the DCA condition (p < 0.01). CONCLUSIONS: This study shows that improved performance after a pharmacologic intervention known to activate PDC was accompanied by an enhanced IL-6 response and a limited reduction in exercise-induced systemic oxidative stress.