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Postanaesthesia pulmonary complications after use of muscle relaxants in Europe

Study protocol of the POPULAR study

Fagerlund, Malin Jonsson; Fink, Heidrun; Baumüller, Eva; Ulm, Kurt; Hollmann, Markus W.; Meistelman, Claude; Hunter, Jennifer; Leva, Brigitte; Damster, Sandrine; Eriksson, Lars I.; Blobner, Manfred

European Journal of Anaesthesiology (EJA): May 2016 - Volume 33 - Issue 5 - p 381–382
doi: 10.1097/EJA.0000000000000363

From the Department of Anesthesiology, Surgical Services and Intensive Care, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden (MJF, LIE); Department of Anesthesiology, Technische Universität München, Munich, Germany (HF, EB, MB); Department of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany (KU); Department of Anesthesiology, Academic Medical Centre, Amsterdam University, Amsterdam, The Netherlands (MH); Department of Anesthesiology, University of Nancy, Nancy, France (CM); Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Liverpool University, Liverpool, UK (JMH); and Research department, European Society of Anaesthesiology, Brussels, Belgium (BL, SD)

Correspondence to Malin Jonsson Fagerlund, MD, PhD, DESA, Senior Consultant/Associate Professor, Department of Anaesthesiology and Intensive Care Medicine, Karolinska University Hospital and Karolinska Institutet, SE-171 76, Stockholm, Sweden Tel: +46 8 51772107; fax: +46 8 307795; e-mail:

* Malin Jonsson Fagerlund and Heidrun Fink equally contributed to the manuscript and share the position of the first authors.

† Manfred Blobner and Lars I. Eriksson share the position of the last authors.

Published online 7 November 2015


There is growing evidence that the use of neuromuscular blocking agents (NMBAs) in routine surgery may be associated with significant adverse respiratory outcomes postoperatively.1,2 Recent outcome studies suggest that perioperative management of neuromuscular block, including use of neuromuscular transmission monitoring and/or administration of reversal agents, may affect early postoperative outcomes and length of stay in the postanaesthesia care unit.2–4 Incomplete return of neuromuscular function is associated with an increased risk of impaired respiratory and airway control,5 risk of aspiration and postoperative hypoxic events4 and pulmonary complications.1,2 Hence, there are reasons to believe that key elements in routine perioperative management of neuromuscular function may significantly impact on long-term outcomes after anaesthesia. In general, postoperative pulmonary complications are associated with significant morbidity and increased mortality.

Consequently, there is a need for increased efforts to explore the influence of key components of perioperative management of neuromuscular block on postoperative pulmonary complications (e.g. timing and dosing of NMBAs and reversal agents, use of intraoperative neuromuscular monitoring). At present, there are insufficient data on in-hospital pulmonary outcomes after anaesthesia involving NMBAs, primarily because of a lack of prospective studies with a sufficient sample size and appropriate study design focusing only on perioperative management of neuromuscular function and NMBAs.

An observational study, sponsored by the European Society of Anaesthesiology (ESA), was launched with the primary hypothesis that inappropriate use of NMBAs or reversal agents or neuromuscular transmission monitoring increased the incidence of postoperative pulmonary complications. The secondary hypothesis was that inappropriate use of NMBAs increased in-hospital mortality. We present the study protocol and statistical analyses of this European multicentre study.

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Research questions and study design

There were three main research questions. First, does inappropriate use of NMBAs or their reversal agents or neuromuscular monitoring increase the incidence of postoperative pulmonary complications? Second, does the use of NMBAs increase in-hospital mortality? And third, does the use of NMBAs increase the duration of hospital stay? The study was designed as an international multicentre observational study of a random-sample cohort of patients undergoing any in-hospital surgical procedures under general anaesthesia during a continuous 14-day period of recruitment from July 2014 to the end of April 2015. The study protocol was registered ( identifier NCT01865513).

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Inclusion and noninclusion criteria

Patients undergoing any emergency or elective in-hospital surgical procedure under general anaesthesia during a defined continued 14-day period were recruited. Exclusion criteria were patients less than 18 years of age; patients scheduled for local or regional anaesthesia only; an anaesthetic procedure scheduled outside an operating room; ambulatory patients, that is discharge planned within 12 h after anaesthesia; patients with a preoperatively intubated trachea; patients from an ICU; patients scheduled for an additional surgical/anaesthetic procedure within the next 7 days; patients who had a surgical/anaesthetic procedure within the past 7 days; and patients born outside the predetermined ‘month(s)’ allocated for the specific study centre. For centres with more than 50 eligible patients per week, it was possible to reduce the number of patients to be included by a randomised selection process organised by the ESA Research Office. Each study centre included patients born on predefined month(s). At least all patients born in 1 month (allocated by the study organization) have to be included. This random selection of patients was done before induction of anaesthesia for each individual patient scheduled for surgery.

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Participating centres and ethical considerations

All European hospitals/centres were welcome to participate as a study centre. Each centre had to recruit patients during a continuous 14-day period chosen as appropriate for the specific centre. A responsible investigator was assigned for each centre. In this nonrandomised prospective observational trial with no experimental intervention, patients were studied under routine care. Apart from information from medical records, no other data or samples were taken. Consequently, there were no ethical concerns. Institutional ethical approval was required for each participating centre to conduct this observational trial.

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Data collection

All patients undergoing surgery during the predefined 2-week period of recruitment in each centre were eligible. Each local research team prospectively entered data into predefined paper case report forms (CRFs) starting on the day of surgery and up to the discharge from the hospital or at a maximum 28 days postoperatively. Data was coded and anonymised when entering a web-based electronic CRF (Open Clinica, Waltham, Massachusetts, USA). All investigators logged in with a personal code and therefore all data changes were tracked in the system. The Research Office of the ESA managed the access to the electronic CRF system.

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The collected data were part of routine care of the patients and the investigators did not change a participating centre's routine practice. Five data complexes were collected: First, preoperative data including physical characteristics, medical history and preoperative respiratory status; second, intraoperative data about surgical details, anaesthetic details with focus on use and monitoring of muscle relaxants and reversal agents from induction of anaesthesia until discharge from the operating room; third, respiratory complications in the postoperative care unit or recovery room at admission and discharge; fourth, postoperative complications with focus on pulmonary complications at postoperative days 1, 2 or 3 during a personal visit at the ward; fifth, postoperative complications at hospital discharge or maximum at postoperative day 28, by reviewing the patient's medical charts. Patients were followed at postoperative days 1, 2 or 3 and at discharge from hospital or at a maximum at postoperative day 28 for postoperative pulmonary complications, length of hospital stay and mortality.

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The primary study outcome was the rate of in-hospital postoperative pulmonary complications (POPCs) up to 28 days post surgery, defined as at least one fatal or nonfatal postoperative pulmonary or respiratory event (respiratory failure, suspected pulmonary infection, suspected pulmonary infiltrates, atelectasis, aspiration pneumonitis, bronchospasm or pulmonary oedema). Secondary outcomes were duration of hospital stay and postoperative mortality up to 28 days.

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Sample size calculation

POPULAR (POstanaesthesia PULmonary complications After the use of muscle Relaxants in Europe: an international prospective cohort study) is an observational study investigating the effect of the most frequent techniques of management of the neuromuscular function in relation to POPC. To receive clinically relevant results, at least 10 observed events of POPC for each factor were needed.6 Sample size was therefore estimated as 10 times the number of factors and co-factors divided by the incidence of POPC. Based on preliminary data from PERISCOPE study,7 as well as unpublished data from a German survey, a 2 to 4% incidence of patients with POPC was expected. For a conservative approach, the lower level of the expectation (incidence of POPC, 2%) was chosen. Accordingly, based on 10 factors and 32 co-factors, a sample size of 21 000 patients was calculated. Based on an estimated range of on average 10 to 200 patients per centre, we targeted a participation of 400 centres.

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In this study, the impact of multiple factors related to the incidence of POPC after general anaesthesia with focus on variables describing the management of neuromuscular function are analysed. These variables are defined as ‘factors’. Other variables known or suspected to have an impact on POPC are defined as ‘co-factors’ (definitions, see Three methodological approaches were chosen. First, a confirmatory analysis to prove the impact of the 10 factors characterising the management of neuromuscular function. These are grouped into three factor complexes: NMBAs (use of any NMBA, use of combinations of NMBAs, weighted total dose of NMBAs, timing of last incremental dose of NMBAs); neuromuscular monitoring (use of any neuromuscular monitoring, technique of neuromuscular monitoring, train-of-four ratio at extubation) and reversal agents (use of any reversal agent, use of sugammadex or cholinesterase inhibitor, dosing-regime of reversal agents). Second, a comparative analysis of the most frequent and relevant techniques to manage neuromuscular function. And third, an exploratory analysis of all factors and co-factors of POPC. A detailed statistical plan can be found on

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The research team consisted of a steering committee, and nationally and locally responsible investigators on behalf of the ESA. General and local training sessions were held to instruct the investigators on how to fill in the structured questionnaire and how to identify the POPC outcomes recorded in the charts. Locally responsible investigators supervised data collection and ensured all local regulatory approvals.

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Acknowledgements related to this article

Assistance with the Letter: none.

Financial support and sponsorship: the POPULAR study was funded by a grant of the ESA (sponsor) through the ESA Clinical Trial Network.

Conflicts of interest: CM has received honoraria for scientific lectures from MSD, Baxter and Abbvie. MH has received research support and honoraria for lectures from MSD. JMH and MB are paid expert advisors to MSD. LIE has received lecture fees from Merck Inc and is paid expert advisor to Abbvie.

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1. Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand 1997; 41:1095–1103.
2. Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting nondepolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ 2012; 345:e6329.
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5. Sundman E, Witt H, Olsson R, et al. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology 2000; 92:977–984.
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7. Mazo V, Sabate S, Canet J, et al. Prospective external validation of a predictive score for postoperative pulmonary complications. Anesthesiology 2014; 121:219–231.
© 2016 European Society of Anaesthesiology