2013 Research Highlights

However, the lack of novel drugs is the real problem for COPD and the millions of patients with this disease. Apart from roflumilast no new COPD drugs have been launched in more than 25 years, despite an obvious unmet need. The arrival of fixed combinations of longacting bronchodilators, although undoubtedly an improvement with regard to convenience and perhaps also medication adherence, is not really much of a change. Fear of safety is unlikely to be the main reason for this stagnation in drug development. Rather, our insight into COPD and the pathways responsible for the different components of this heterogeneous syndrome is still too vague for researchers in academia and the pharmaceutical industry to develop specific compounds for use in COPD or any of its phenotypes. There is a divide between how we manage COPD and how we should approach future research. Management is becoming more inclusive, taking not only the degree of airflow limitation into account but also encompassing both COPD and its comorbidities— as mentioned in the latest GOLD suggestions for patient assessment.4 This inclusivity can almost be thought an expansion of our syndromic view of COPD. However, to better understand the pathways and mechanisms leading to development and progression of COPD—and through that identifying novel targets—we probably need to focus on the airway and lung parenchyma changes only. Without closer scrutiny of disease mechanisms it seems unlikely that we will develop new drugs other than the iterative improvements of known substances currently being launched.

*Jørgen Vestbo, Peter Lange Department of Respiratory Medicine and Institute of Clinical Research, Odense University Hospital and University of Southern Denmark, Odense Denmark (JV); Manchester Academic Health Science Centre, University Hospital South Manchester NHS Foundation Trust, Southmoor Road, M23 9LT Manchester, UK (JV); Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen , Denmark (PL); and Section of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark (PL) [email protected] JV has received honoraria for consulting and presenting for AstraZeneca, Bioxydyn, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Takeda. PL has received honoraria for consulting and presenting for Almirall, Astra Zeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Mundipharma, Pfizer, and Takeda. 1

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Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J 2009; 34: 641–47. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ 2011; 342: d3215. Jenkins CR, Beasley R. Tiotropium Respimat increases the risk of mortality. Thorax 2013; 68: 5–7. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187: 347–65. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359: 1543–54. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med 2013; 369: 1491–501. Jenkins CR. More than just reassurance on tiotropium safety. N Engl J Med 2013; 369: 1555–56. Verhamme KMC, Afonso A, Romio S, Stricker BC, Brusselle GGO, Sturkenboom MCJM. Use of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients with COPD. Eur Respir J 2013; 42: 606–15. Janson C, Larsson K, Lisspers KH, et al. Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting β2 agonist: observational matched cohort study (PATHOS). BMJ 2013; 346: f3306. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1: 210–23.

Early feeding during critical illness Early feeding of critically ill patients is a common intensive-care practice and is supported by international clinical recommendations.1 One of the major goals of feeding in general is to attenuate wasting of skeletal muscle and enhance long-term functional outcome. However, there are few data informing the type, quantity, and timing of feeding; skeletal muscle wasting is often evident in critically ill patients despite feeding and many experience long-term physical disability.2–4 This lack of evidence has driven the present focus on feeding, in particular the importance of targeted feeding www.thelancet.com/respiratory Vol 2 January 2014

to match nutritional needs during the early period of critical illness.5–7 Data from recent multicentre trials7,8 have not supported the goal of meeting nutritional targets within the first week of critical illness. Indeed, in the European EPaNIC trial,7 patients receiving late parenteral nutrition (from day 8 of admission) had fewer infections and shorter length of intensive care unit (ICU) stay compared with patients receiving early parenteral nutrition (within 48 hours of admission). Furthermore, the North American EDEN trial,8 comparing trophic and full enteral feeding in patients

Published Online December 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70262-5

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2013 Research Highlights

with acute lung injury, showed that there was no difference in short-term or long-term clinical outcome between the groups.3,4,8 These data therefore question present feeding practice in critical care. The explanation for these disappointing results from clinical studies is provided, at least in part, by emerging translational data in this area. In particular, two recent studies have investigated the mechanism of acute skeletal muscle wasting during critical illness and have reported on the relation between skeletal muscle wasting and feeding.9,10 In a nested sub-study of the EPaNIC trial,9 Greet Hermans and colleagues investigated the effect of macronutrient deficiency on muscle-mass regulation with a specific focus on the pathways controlling muscle-protein breakdown, including the ubiquitin proteasome and autophagy– lysosomal pathways.9 There were no differences in myofibre size and density, assessed by vastus lateralis muscle biopsies, in patients receiving late compared with early parenteral feeding; however, both groups showed skeletal muscle wasting compared with the healthy age-matched controls. This muscle wasting was accompanied by upregulation of E3 ligases, as part of the ubiquitin proteasome muscle breakdown pathway. This upregulation suggests that skeletal muscle wasting occurred early in critical illness irrespective of the feeding regimen. As expected, autophagosome activity was greater in patients in both feeding groups than in controls, but surprisingly the presence of autophagy markers was higher in the late parenteral nutrition group compared 16

with the early parenteral group. This suggests enhanced acute muscle wasting in the late nutrition group, which is at odds with the inverse relation between autophagy markers and ICU acquired weakness. Although this is an interesting finding that needs further investigation, the message from the EPaNIC substudy9 is that skeletal muscle wasting occurs irrespective of the timing of targeted feeding to match macronutrient deficiency. These data, which challenge the effect of feeding on acute skeletal muscle wasting during critical illness, have been further developed in the MUSCLE-UK study.10 The MUSCLE-UK study10 was a comprehensive characterisation of the trajectory of acute skeletal muscle wasting during the first week of critical illness, with a focus on defining the pathogenic roles of altered protein synthesis and breakdown. Data from this study showed that muscle wasting occurred early and rapidly during the first week of critical illness, and was more severe in those patients with multiorgan failure compared with single organ failure. Importantly, the level of muscle-protein synthesis was the same as starved controls on admission to the ICU, but synthesis recovered to the level of fed controls by the end of the first week. However, muscle-protein breakdown was raised on admission and remained raised with an ongoing overall net catabolic balance after 7 days. These pathophysiological findings occurred despite standard enteral nutrition, and higher protein delivery was paradoxically associated with greater muscle wasting.10 These data support and extend the previous findings of Hermans and colleagues9 and suggest that the type and timing of nutrition delivered might, at best, have little or no effect and, at worst, could be detrimental to muscle-protein homoeostasis and lead to acute muscle loss. This controversial statement, which opposes previous clinical data suggesting the beneficial shortterm and long-term effects of high protein delivery,11 is supported by physiological studies that have shown an early rise and subsequent fall in muscle-protein synthesis, with a peak around 2 h after initiation of continuous parenteral12 or enteral13 aminoacid feeding. These translational data reporting the mechanism of muscle-protein homoeostasis in skeletal muscle potentially provide a direction for future nutritional trials. Furthermore, not only have the recent nutrition trials failed to show clinical benefit,7,8 but also a recent rehabilitation trial,14 which advocated the continuum www.thelancet.com/respiratory Vol 2 January 2014

2013 Research Highlights

of rehabilitation from ICU admission to the home setting, showed no benefit of clinical outcome. These negative results, in terms of functional outcome, are perhaps to be expected in view of what is known about skeletal muscle physiology. Physical activity before nutritional intake enhances skeletal muscle anabolism by enhancing baseline and postprandial muscleprotein synthesis.15 These data promote the rationale for combined nutrition and specific muscle exercise therapy that respect the complex interactions between nutrition and stimuli of muscle-protein synthesis, allowing the development of intervention strategies to modify skeletal muscle wasting during critical illness. The low level of muscle-protein synthesis despite enteral feeding reported in the MUSCLE-UK study,10 and data from the EDEN trial8 in which trophic feeding showed no benefit over enteral feeding in patients with acute lung injury,8 support the approach of withholding feeding, at least for the first 24 h after ICU admission. The benefits of continuous and bolus protein loading need to be carefully considered in terms of muscle-protein synthesis,10 and failure to incorporate translational skeletal muscle science into the design of future nutritional and exercise therapy clinical trials might be counterproductive. Data are needed on skeletal muscle mitochondrial activity and substrate use during early critical illness to further facilitate the clinical approach to feeding and rehabilitation in these patients with complex needs. Danielle E Bear, Zudin A Puthucheary, *Nicholas Hart Department of Dietetics (DEB), Department of Critical Care (DEB), and Lane Fox Respiratory Unit (NH), Guy’s & St Thomas’ NHS Foundation Trust, London, UK; Institute of Health and Human Performance, University College London, London, UK (ZAP); Division of Respiratory and Critical Care Medicine, University

Medicine Cluster, National University Health System, Singapore (ZAP); Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (ZAP); and NIHR Biomedical Research Centre, Guy’s & St Thomas’ NHS Foundation Trust and King’s College London, London, UK (NH) [email protected] We declare that we have no conflicts of interest. 1

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Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit Care Med 2009; 37: 1757–61. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003; 348: 683–93. Needham DM, Dinglas VD, Bienvenu OJ, et al. One year outcomes in patients with acute lung injury randomised to initial trophic or full enteral feeding: prospective follow-up of EDEN randomised trial. BMJ 2013; 346: f1532. Needham DM, Dinglas VD, Morris PE, et al. Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding: EDEN trial follow-up. Am J Respir Crit Care Med 2013; 188: 567–76. Singer P, Anbar R, Cohen J, et al. The tight calorie control study (TICACOS): a prospective, randomised, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med 2011; 37: 601–09. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled trial. Lancet 2013; 381: 385–93. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365: 506–17. Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012; 307: 795–803. Hermans G, Casaer MP, Clerckx B, et al. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med 2013; 1: 621–29. Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle wasting in critical illness. JAMA 2013; 310: 1591–600. Hoffer LJ, Bistrian BR. Appropriate protein provision in critical illness: a systematic and narrative review. Am J Clin Nutr 2012; 96: 591–600. Atherton PJ, Etheridge T, Watt PW, et al. Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. Am J Clin Nutr 2010; 92: 1080–88. Bohé J, Low JF, Wolfe RR, Rennie MJ. Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids. J Physiol 2001; 532: 575–79. Denehy L, Skinner EH, Edbrooke L, et al. Exercise rehabilitation for patients with critical illness: a randomized controlled trial with 12 months of follow-up. Crit Care 2013; 17: R156. Wall BT, van Loon LJ. Nutritional strategies to attenuate muscle disuse atrophy. Nutr Rev 2013; 71: 195–208.

Idiopathic pulmonary fibrosis: on the move Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disorder of unknown cause that is fatal within 3·0–3·5 years irrespective of treatment.1 In 2013, an update of the multidisciplinary classification of idiopathic interstitial pneumonias, including IPF, was published.2 Previous IPF diagnostic criteria were replaced with a more accurate diagnostic algorithm to exclude other known causes of interstitial lung www.thelancet.com/respiratory Vol 2 January 2014

diseases and match combinations of radiological and pathological findings compatible with the pattern of usual interstitial pneumonia. Because the natural course of IPF is highly unpredictable, treatment is ineffective and almost 20% of idiopathic interstitial pneumonias still remain unclassifiable due to major discordance between current diagnostic methods; experts have emphasised the need for reliable diagnostic and

Published Online December 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70240-6

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Early feeding during critical illness.

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