Correspondence

to ensuring nursing’s contribution by: (1) leading and supporting the development of interprofessional health-worker education and practice; (2) advocating for a shift in health care that balances illness-focused care with population health; (3) identifying and championing of strategies to address health workforce misdistribution and migration; (4) strengthening of primary health care by offering the breadth and depth of knowledge and skills needed to attend to people’s complex health and social needs; (5) bringing a strong voice in all policy and development planning and governance; (6) attending to broader system issues related to regulation and legislation; (7) building and synthesising the best evidence related to human resources for health and health systems; and (8) considering the effect of pervasive contextual issues such as social determinants of health and gender inequality and inequity. We declare no competing interests.

*Judith Shamian, Gail Tomblin Murphy, Annette Elliott Rose, Lianne Jeffs [email protected] International Council of Nurses, 1201 Geneva, Switzerland (JS); University of Toronto, Toronto, Canada (JS); Faculty of Health Professions (GTM), and WHO/Pan American Health Organization collaborating Centre on Health Workforce Planning and Research (AER), School of Nursing, and Faculty of Medicine, Department of Community Health and Epidemiology (GTM), Dalhousie University, Halifax, Canada; and Keenan Research Centre, Li Ka Shing Knowledge Institute of St Micheal’s Hospital, Toronto, Ontario, Canada (LJ)

Mechanical chest compression in the PARAMEDIC trial In the PARAMEDIC trial, Gavin Perkins and colleagues (March 14, p 947)1 did not identify any improvement in 30 day survival with the LUCAS-2 mechanical chest compression device compared with manual compressions for out-of-hospital cardiac arrest. 26

Although their results are in accordance with previous studies,2,3 the use of mechanical chest compression devices might be particularly beneficial for patients transported to hospital during resuscitation.4 In their study, Perkins and colleagues included 1721 patients (38·5%) being transported to hospital during resuscitation. This subgroup might therefore deserve a more detailed description of their in-hospital management and an enquiry into whether survival improved with the use of the LUCAS-2 device. Additionally, we have also some concerns about the delivery of defibrillation with simultaneous continuous mechanical chest compressions, without synchronisation with the LUCAS-2.1 During the chest compressions, the chest wall and the heart are subject to morphological changes, which could affect the success of defibrillation. In animal studies, the optimum timing for defibrillation during continuing chest compression occurs during the upstroke phase of chest compression, which is also the case with manual chest compression resuscitation. 5 Uncoordinated defibrillation with the cycle of mechanical chest compression– relaxation in the test group but coordinated in the control group might therefore have introduced a bias against the LUCAS-2 group. Addressing our concerns could help to identify the patients best able to benefit from mechanical chest compression and improve the delivery of shock during mechanical chest compression. These two key factors need to be answered before mechanical chest compression is dismissed. We declare no competing interests.

*Pierre-Nicolas Carron, Rémy Pantet, Mathieu Pasquier, Olivier Hugli [email protected] Emergency Department, Lausanne University Hospital, 1011 Lausanne, Switzerland 1

Perkins GD, Lall R, Quinn T, et al. Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial. Lancet 2015; 385: 947–55.

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Rubertsson S, Lindgren E, Smekal D, et al. Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial. JAMA 2014; 311: 53–61. Smekal D, Johansson J, Huzevka T, et al. A pilot study of mechanical chest compressions with the LUCAS™ device in cardiopulmonary resuscitation. Resuscitation 2011; 82: 702–06. Ong ME, Mackey KE, Zhang ZC, et al. Mechanical CPR devices compared to manual CPR during out-of-hospital cardiac arrest and ambulance transport: a systematic review. Scand J Trauma Resusc Emerg Med 2012; 20: 39. Carron PN, Yersin B. Cardiopulmonary resuscitation with mechanical chest compressions and simultaneous defibrillation. JAMA 2014; 311: 2234.

Authors’ reply Pierre-Nicolas Carron and colleagues1 enquire about the effect of mechanical chest compression in patients transported to hospital with continuing chest compressions during the PARAMEDIC trial. This effect was not reported in the original trial because the subgrouping variable (transport to hospital with ongoing chest compression) arises after randomisation and might be affected by the study treatments. Bias is expected in this comparison. In the LUCAS-2 group, 640 (38·7%) of 1652 patients were transported to hospital with continuing cardiopulmonary resuscitation (CPR) compared with 1081 (38·3%) of 2819 patients in the manual CPR group. Among those transported with CPR in progress, only a small number survived to 30 days (11 [1·7%] of 640 patients compared with 11 [1·0%] of 1081 patients in the manual CPR group). The treating clinician established treatment pathways after return of spontaneous circulation.2 The intentionto-treat survival outcomes reported in the Article included the effects of postresuscitation care treatments.1 In our study, the proportion of patients in an initially shockable rhythm were similar in the LUCAS-2 group 364 (22%) of 1652 patients versus the manual group 597 (21%) of 2819 patients. Shocks were delivered to the patient during mechanical www.thelancet.com Vol 386 July 4, 2015

Correspondence

All authors acknowledge support from the National Institute for Health Research’s Health Technology Assessment Programme (NIHR HTA; Grant Reference Number HTA—07/37/69). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

*Gavin D Perkins, Tom Quinn, Charles D Deakin, Ranjit Lall, Simon Gates [email protected] Warwick Clinical Trials Unit, University of Warwick, Coventry, UK, CV4 7AL (GDP, RL, SG); Heart of England NHS Foundation Trust, Birmingham, UK (GDP); Surrey Peri-operative Anaesthesia Critical care collaborative Research Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK (TQ); South Central Ambulance Service NHS Foundation Trust, Otterbourne, UK (CDD); and University Hospital Southampton, Southampton, UK (CDD)

www.thelancet.com Vol 386 July 4, 2015

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Perkins GD, Lall R, Quinn T, et al. Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial. Lancet 2015; 385: 947–55. Perkins GD, Woollard M, Cooke MW, et al. Prehospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial protocol. Scand J Trauma Resusc Emerg Med 2010; 18: 58. Wik L, Olsen JA, Persse D, et al. Manual vs integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation 2014; 85: 741–48. Steinberg MT, Olsen J-A, Brunborg C, et al. Abstract 85: defibrillation during mechanical chest compressions should be avoided during the downstroke phase of the chest compression cycle. Circulation 2014; 130 (suppl 2): A85.

Trials of obeticholic acid for non-alcoholic steatohepatitis We read with interest the results of the FLINT trial (March 14, p 956)1 that investigate the effect of obeticholic acid on liver histology in non-alcoholic steatohepatitis . A remarkable yet overlooked result in the appendix of this trial was the difference in histological response between participants with diabetes and those without: for participants with diabetes, liver histology improved in 53% of patients who received obeticholic acid versus 19% for placebo (odds ratio [OR] for improvement with obeticholic acid 4·6, 95% CI 2·0–10·6, p=0·0003), while for patients without diabetes, liver histology improved in 37% patients with obeticholic acid versus 23% with placebo (OR 2·0, 95% CI 0·8–4·7, p=0·12). The effect of glucose intolerance on histological response to obeticholic acid was also shown across the progressive stages of pancreatic β cell dysfunction, as estimated by HOMA β cell index.1 Other than the FLINT trial, only one randomised trial, which enrolled participants with diabetes, has assessed obeticholic acid for nonalcoholic fatty liver disease.2 Therefore evidence for the effectiveness of

farnesoid X receptor agonists is absent for individuals without diabetes, who represent a substantial proportion of the population with non-alcoholic steatohepatitis. Additionally, consistent with other randomised trials of non-alcoholic steatohepatitis, the percentage of responders was less than 50% in the FLINT trial, leaving a substantial proportion of patients without an effective treatment.3 Non-alcoholic steatohepatitis is a heterogeneous disorder and diverse mechanisms of liver injury that promote disease progression might exist in different patient populations. Altered bile acid metabolism—the rationale for use of semisynthetic bile acids—has been more convincingly shown in individuals with diabetes than in those without,4 which might explain the absence of response to obeticholic acid in individuals without diabetes in the FLINT trial. Consequently, further assessment of farnesoid X receptor agonists for nondiabetic non-alcoholic steatohepatitis is essential, and an approach tailored to individual metabolic profiles might be needed to tackle the non-alcoholic steatohepatitis epidemic.

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compressions, whereas compressions were paused briefly to allow defibrillation attempts in the manual group. Our predefined subgroup analysis showed that 30 day survival was lower in the group assigned to mechanical CPR (69 [18%] of 376 patients) compared with manual CPR (148 [24%] of 615 patients). Shocks were not synchronised with the LUCAS-2 device so the shock was likely to be equally distributed throughout the compression cycle. Carron and colleagues cite evidence from porcine studies which suggests a high shock success rate if shocks are delivered during the upstroke of mechanical CPR. We are unaware of any randomised human studies in which this hypothesis has been tested. In the CIRC trial3 (which assessed the AutoPulse device—a different method of chest compression), the chance that ventricular fibrillation was terminated 5 s after a shock was 5% lower when shocks were delivered during the downstroke of mechanical chest compressions. At 60 s after shock delivery, the rate of return of organised rhythm was similar irrespective of the timing of shock delivery in relation to the compression phase.4 We deem the synchronisation of shock with compression cycle in our study would have been unlikely to have led to better outcomes in the mechanical CPR group.

We declare no competing interests.

*Giovanni Musso, Maurizio Cassader, Roberto Gambino [email protected] Gradenigo Hospital, Torino 10132, Italy (GM); and Department of Medical Sciences, University of Turin, Italy (MC, RG) 1

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Neuschwander-Tetri BA, Sanyal AJ, Lavine JE, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956–65. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574–82. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55: 885–904. Ma H, Patti ME. Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28: 573–83.

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Mechanical chest compression in the PARAMEDIC trial - Authors' reply.

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