Despite advances in supportive therapy, mortality rates in intensive care unit (ICU) patients with acute circulatory failure (shock) range from 30% to 72% (1). Septic shock is a common cause of cardiovascular failure with the highest degree of morbidity and mortality (2-4). Improving survival seems to be related to early recognition and appropriate therapy (5, 6).
The time of onset of shock may be very important in determining outcome. In a cohort of patients who had positive bacterial cultures and septic shock, Lundberg et al. (7) reported lower mortality rates in patients who developed shock in the ICU than those who acquired septic shock on a general ward despite the fact that the former were younger and had lower Acute Physiology and Chronic Health Evaluation II scores than the latter. These authors (7) proposed that the observed differences in mortality may have been due to earlier therapeutic interventions being administered in patients on the ICU. However, Roman-Marchant et al. (8) showed that, although septic shock in ICU patients was more severe when of early onset, as reflected by more severe organ dysfunction, greater lactic acidosis, and higher vasopressor requirement, the outcome was better, as reflected by a shorter duration of the shock episode, shorter ICU stay, and slightly lower mortality rates, than septic shock of late onset. These observations (7, 8) reflect the possible variability in characteristics and outcome of septic shock according to the location and the time of onset of shock; however, both studies are limited by being single-center experiences and by the relatively small numbers of patients included. Characterizing this variability in a large cohort of ICU patients may be important in identifying high-risk patients, allocating medical recourses, and guiding future therapeutic trials.
The aim of our study was, therefore, to investigate possible differences in epidemiology, clinical course, management, and outcome between patients with early- and late-onset shock due to any cause and due to sepsis among ICU patients included in a large European multicenter study.
This study is a subanalysis of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study (9), a prospective, multicenter, observational study that was initiated by a working group of the European Society of Intensive Care Medicine to evaluate the epidemiology of sepsis in European countries. We included all adult patients (>15 years) admitted to the participating centers (see the "Appendix" for a list of participating countries and centers) between May 1 and May 15, 2002. Patients were followed-up until death, hospital discharge, or for 60 days. Those who stayed in the ICU for routine postoperative observation for less than 24 h were excluded. Institutional review board approval was either waived or expedited in participating institutions, and informed consent was not required because this epidemiologic observational study did not require any deviation from routine medical practice.
Data collection and management
Data were collected using preprinted case report forms. Detailed instructions, explaining the aim of the study, instructions for data collection, and definitions for various important items, were available for all participants on a Web-based Internet site before starting data collection and throughout the study period. The steering committee was available to the investigators at all times and processed all queries during data collection.
Data collection on admission included demographic data and comorbid diseases. Clinical and laboratory data for Simplified Acute Physiology Score (SAPS) II score (10) were reported as the worst value within 24 h after admission. Microbiologic and clinical infections were reported daily as well as the antibiotics administered. A daily evaluation of organ function, based on a set of laboratory and clinical parameters according to the sequential organ failure assessment (SOFA) score (1), was performed, with the most abnormal value for each of the six organ systems (i.e., respiratory, renal, cardiovascular, hepatic, coagulation, and neurologic) being collected on admission and every 24 h thereafter. A number of quality control processes were carried out to assure the integrity of the data and the consistency of data entry and are described elsewhere (9).
Circulatory shock was defined as a cardiovascular SOFA score less than 2, that is, the need for vasopressor agents. Sepsis and septic shock were defined by standard criteria (11). Respiratory, renal, central nervous system, coagulation, and hepatic failure were defined as a SOFA score greater than 2 for that system. We stratified organ failure into early-onset (≤2 days after admission) and late-onset (>2 days after admission) failure. In cases where more than one episode of shock occurred, the first was considered in defining the onset. Recurrent shock was defined as the occurrence of one or more episodes of shock after at least 24 h free of vasopressor support between the subsequent episodes. Daily fluid balance was calculated as the cumulative fluid balance divided by the number of days and was calculated for the whole ICU stay and for the period during which shock criteria were fulfilled.
Data were analyzed using SPSS 13.0 for Windows (SPSS Inc., Chicago, Ill). A Kolmogorov-Smirnov test was used to verify the normality of distribution of continuous variables. Nonparametric measures of comparison were used for variables evaluated as not normally distributed. Difference testing between groups was performed using the two-tailed t test, Mann-Whitney U test, chi-square test, and Fisher exact test as appropriate. Multivariate forward stepwise logistic regression analysis was performed with ICU outcome as the dependent factor in patients with shock, and independent factors including SAPS II score, age, sex, comorbidities on admission, individual early and late organ failures, procedures, use of catecholamines and albumin, and daily fluid balance. To determine the predictors of development of late shock, we constructed another multivariate model (excluding patients with early-onset shock) with the development of late shock as the dependent variable, including only variables related to admission, fluid balance during the first 2 days, and early organ failures. Both multivariate analyses were preceded by a univariate selection of potential prognostic variables (P < 0.2). Colinearity between variables was ruled out before covariates were introduced in the models. The country effect was introduced in the final multivariate models as a random effect and was not found to be significant. Goodness of fit was tested using a Hosmer and Lemeshow test, and odds ratio (OR) was computed. Continuous variables are presented as mean ± SD or median (25%, 75% interquartile range [IQ]) and categorical variables as percentage (%). All statistics were two-tailed, and P < 0.05 was considered to be significant.
Characteristics of the study population on admission to the ICU
Of 3,147 patients included in the SOAP study, 1,058 (33.6%) had circulatory shock due to any cause during the ICU stay, of whom 462 (43.7%) had septic shock. Late-onset shock contributed to only 9.7% of shock episodes, 11.9% of septic shock episodes (n = 55/462), and 8.2% of nonseptic shock episodes (n = 48/588). Simplified Acute Physiology Score II scores on admission were greater in patients with early-onset shock (Table 1) compared with those with late-onset shock irrespective of a septic or nonseptic etiology. A higher incidence of chronic obstructive pulmonary disease (COPD) was observed in patients with late-onset shock due to any cause (19.4% vs. 10.2%, P < 0.01) and late-onset shock due to sepsis (23.6% vs. 11.8%, P < 0.05), compared with the corresponding early shock groups. Patients with late-onset shock due to sepsis were more likely to have been admitted for medical reasons (67.3% vs. 51.4%, P < 0.05) than patients with early-onset shock due to sepsis.
Patterns of management and outcome in patients with shock due to any cause
More patients with late-onset shock due to any cause received dopamine (44.7% vs. 34.5%, P < 0.05) and albumin (31.1% vs. 20.3%, P < 0.05) than those with early-onset shock. Catecholamine administration was otherwise similar irrespective of the time of onset of shock (Table 2). Most patients (>92%) were treated by mechanical ventilation. There was no difference in the use of pulmonary artery catheter, renal replacement therapies, or red blood cell transfusion. Fluid balance during the ICU stay and during shock was greater in patients with early-onset shock compared with late-onset shock (Table 2). However, the difference in fluidbalance was observed only in the early phase of shock (Fig. 1).
The incidence of respiratory failure was higher in patients with late-onset shock than in those with early-onset shock due to any cause (87.4% vs. 69.7%, P < 0.001). Hepatic failure occurred more often in patients with late-onset shock due to any cause (15.5% vs. 8.7%, P < 0.05) than in patients with early-onset shock (Table 3). The pattern of noncardiovascular organ failure and SOFA scores over time during shock was similar irrespective of the time of onset of the shock (Fig. 2). Intensive care unit and hospital mortality rates were higher (52.4% vs. 36.8% and 55.3% vs. 43.4%, P < 0.05), and ICU and hospital lengths of stay were longer (16 [mean, 8-30] vs. 6 [2-12] and 24 [mean, 11-46] vs. 13 [mean, 4-34] days, P < 0.001) in late-onset than in early-onset shock.
Early- versus late-onset shock according to the type of shock
Simplified Acute Physiology Score II scores on admission were greater in patients with early-onset compared with late-onsetshock irrespective of the type of shock (Table 1). Patients with late-onset shock due to sepsis were more likely to be admitted to the ICU because of medical reasons and had a higher incidence of associated comorbidities (COPD and diabetes mellitus) on admission. The incidence of respiratory failure was also higher in patients with late-onset than those with early-onset shock due to sepsis (98.2% vs. 81.8%, P < 0.01). However, in patients with shock of nonseptic origin, comorbidities, type of admission, and the incidence of organ failure during the ICU stay were similar irrespective of the time of onset of shock in the ICU. During the period where shock criteria were fulfilled, fluid balance was more positive in patients with early-onset than in those with late-onset shock irrespective of the type of shock (Table 2).
Intensive care unit and hospital mortality rates were higher (Table 3) in patients with late-onset shock than in those with early-onset shock due to sepsis (63.6% vs. 45.2% and 68.5%vs. 47.8%, respectively, P < 0.05) but were not significantly different in those with shock of nonseptic origin (39.6% vs. 30.5% and 41.7% vs. 36.8%, respectively, P > 0.1).
In a multivariate, forward stepwise, logistic regression analysis, late-onset shock was an independent risk factor for ICU mortality in patients with shock (OR, 2.61; 95% confidence interval (CI), 1.59-4.27; P < 0.001). Other independent risk factors for ICU mortality included higher fluid balance; central nervous system (CNS), coagulation, and renal failures; medical admission; SAPS II score; albumin and dopamine administration; and older age (Table 4). Late-onset shock was also an independent risk factor for ICU mortality in patients with septic shock (OR, 6.36; 95% CI, 2.79-13.61, P< 0.001).
Factors predicting the development of late shock
By univariate ANOVA, factors associated with a higher risk of developing late-onset shock in patients without early shock (n = 2,192) were SAPS II score on admission (OR, 1.03; 95% CI, 1.02-1.05; P < 0.001), COPD (OR, 2.02; 95% CI, 1.21-3.35; P < 0.001), early respiratory failure (OR, 2.77; 95% CI, 1.85-4.13; P < 0.001), infection on admission (OR, 3.22; 95% CI, 2.15-4.84; P < 0.001), early coagulation failure (OR, 3.07; 95% CI, 1.62-5.82, P = 0.001), and mechanical ventilation on admission (OR, 1.78; 95% CI, 1.19-2.67; P=0.005). None of these remained significant in a multivariable analysis.
Of 1,058 patients with shock due to any cause, 119 (11.2%) had a recurrent episode of shock, mostly a single episode (81.5%). The first recurrent episode occurred after a median of 3 (median, 1-7) days. Recurrent shock occurred more often in shock due to sepsis (n = 92) than in shock of nonseptic etiology (n = 27), and after early- (n = 105), rather than late-onset, shock (n = 14). Intensive care unit and hospital mortality rates were similar in patients with recurrent shock compared with nonrecurrent shock due to any cause (42.0% vs. 37.8% and 49.6% vs. 43.9%), septic shock (43.5% vs. 48.4% and 50.2% vs. 55%), and nonseptic shock (37.0% vs. 30.9% and 48.1% vs. 36.7%). However, patients with late-onset or recurrent shock pooled together had significantly higher ICU and hospital mortality rates (47.1% vs. 36.1% and 52.9% vs. 42.6%; P < 0.01) than patients with a single episode of early shock.
The main finding of our study is that patients with late-onset shock had higher mortality rates than patients with early-onset shock despite having similar patterns of noncardiovascular organ failure over time. These observations were also present in patients with septic shock. In other forms of shock, these differences were also observed but did not reach statistical significance. In a multivariate analysis, late-onset shock was an independent risk factor for ICU mortality in patients with shock and those with septic shock. As expected, patients with early shock had higher severity scores on ICU admission than those who developed shock later, and this observation highlights the inadequacy of admission severity scores in stratifying patients without taking into account postadmission events.
The higher mortality in patients with late-onset shock is probably multifactorial. Baseline characteristics, namely, the presence of COPD and admission due to medical reasons, may in part explain the observed mortality difference. Importantly, patients who develop shock later in the course of an ICU stay are those with a complicated evolution. Previous observations have suggested that the administration of strong vasopressor therapy in some patients with persistent multiple organ failure may become futile (12). The degree of organ dysfunction/failure is an important determinant of outcome in critically ill patients (1, 9, 13), and the higher incidence of noncirculatory failure is a potential reason for the higher mortality rates in patients with late-onset compared with those with early-onset shock. Therapeutic factors may also have played an important role in influencing outcome. In our study, patients with late-onset shock received more dopamine and albumin; these factors may be associated with an increased risk of mortality in ICU patients (14, 15). Although the recent saline versus albumin fluid evaluation study suggested no differences in mortality rates with the use of albumin compared with isotonic sodium chloride solution in the resuscitation of ICU patients (16), another subgroup analysis of the SOAP database suggested that albumin administration was independently associated with increased mortality (15). Similarly, although dopamine may have beneficial hemodynamic effects, it can produce tachyarrhythmias and may also suppress pituitary function, particularly prolactin secretion (17). Again, a subgroup analysis of the SOAP database showed that dopamine administration was independently associated with increased mortality rates (14). Interestingly, fluid balance was more positive, especially in the early phase of shock, in patients with early-onset compared with those with late-onset shock. Positive fluid balance has been reported in earlier SOAP publications to be an independent risk factor for mortality (9, 14), although in the present study, patients with late-onset shock (and lower fluid balance) had higher mortality rates than those with early-onset shock. One explanation for this apparent contradiction may be that patients with late-onset shock were already volume loaded in the days preceding the development of shock in the ICU. In addition, the increased risk of death associated with the late onset of shock may have outweighed the increased risk of death associated with a higher fluid balance; hence, these results are not necessarily contradictory. Indeed, the fact that patients with late-onset shock received less fluid but still had higher mortality rates supports the suggestion that late-onset shock itself, irrespective of fluid therapy, is associated with a higher risk of death. In multivariate analysis, correcting for all these confounding variables, late-onset shock did remain an independent risk factor for ICU mortality in patients with shock due to any cause and in those with septic shock, supporting the assumption that late-onset shock is associated with worse outcome independent of therapeutic interventions.
We observed similar evolutions of organ dysfunction/failure during shock irrespective of the time of onset. However, shock recurred in 11.2% of patients, more commonly after septic or early-onset shock than after nonseptic or late-onset shock. Factors associated with a higher risk of developing late-onset shock were a greater SAPS II score on admission, presence of COPD, early respiratory failure, sepsis on admission, early coagulation failure, and mechanical ventilation on admission. None of these factors remained significant in a multivariate analysis, reflecting the complex interactions between those variables. Hence, it is difficult to predict who will develop shock during the ICU stay. Our report is the largest to date characterizing the epidemiology of shock according to the time of onset in the ICU; however, our analysis has some limitations. The inclusion period was relatively short (2 weeks), and participation was voluntary, so the results may not be extrapolated to all ICU patients. In addition, multivariable analyses cannot take all possible confounding factors into account, and, as a subgroup analysis, it may be limited by the data collected for the parent study. Finally, in cases of nonseptic shock, we were not able to separate the etiologies (anaphylactic, cardiogenic, or hypovolemic) and potential differences in their outcomes.
In conclusion, this observational study reveals that late-onset shock is independently associated with a higher risk of ICU death than early shock. The incidence of noncardiovascular organ failure was higher in patients with late-onset shock than those with early-onset shock, but the evolution of organ dysfunction/failure was similar between the two groups. Factors associated with the development of shock in the ICU included the presence of sepsis and COPD on admission, early respiratory failure, and mechanical ventilation. These data are important in the risk stratification and interpretation of data from clinical studies in ICU patients.
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Participants by country (listed alphabetically)
Austria: University Hospital of Vienna (G. Delle Karth); LKH Steyr (V. Draxler); LKH-Deutschlandsberg (G. Filzwieser); Otto Wagner Spital of Vienna (W. Heindl); Krems of Donau (G. Kellner, T. Bauer); Barmherzige Bruede of Linz (K. Lenz); KH Floridsdorf of Vienna (E. Rossmann); University Hospital of Innsbruck (C. Wiedermann); Belgium: CHU of Charleroi (P. Biston); Hôpitaux Iris Sud of Brussels (D. Chochrad); Clinique Europe Site St Michel of Brussels (V. Collin); C.H.U. of Liège (P. Damas); University Hospital Ghent (J. Decruyenaere, E. Hoste); CHU Brugmann of Brussels (J. Devriendt); Centre Hospitalier Jolimont-Lobbes of Haine St Paul (B. Espeel); CHR Citadelle of Liege (V. Fraipont); UCL Mont-Godinne of Yvoir (E. Installe); ACZA Campus Stuivenberg (M. Malbrain); OLV Ziekenhuis Aalst (G. Nollet); RHMS Ath-Baudour-Tournai (J.C. Preiser); AZ St Augustinus of Wilrijk (J. Raemaekers); CHU Saint-Pierre of Brussels (A. Roman); Cliniques du Sud-Luxembourg of Arlon (M. Simon); Academic Hospital Vrije Universiteit Brussels (H. Spapen); AZ Sint-Blasius of Dendermonde (W. Swinnen); Clinique Notre-Dame of Tournai (F. Vallot); Erasme University Hospital of Brussels (J.L. Vincent); Czech Republic: University Hospital of Plzen (I. Chytra); U SV.Anny of Brno (L. Dadak); Klaudians of Mlada Boleslav (I. Herold); General Faculty Hospital of Prague (F. Polak); City Hospital of Ostrava (M. Sterba); Denmark: Gentofte Hospital, University of Copenhagen (M. Bestle); Rigshospitalet of Copenhagen (K. Espersen); Amager Hospital of Copenhagen (H. Guldager); Rigshospitalet, University of Copenhagen (K-L. Welling); Finland: Aland Central Hospital of Mariehamn (D. Nyman); Kuopio University Hospital (E. Ruokonen); Seinajoki Central Hospital (K. Saarinen); France: Raymond Poincare of Garches (D. Annane); Institut Gustave Roussy of Villejuif (P. Catogni); Jacques Monod of Le Havre (G. Colas); CH Victor Jousselin of Dreux (F. Coulomb); Hôpital St Joseph & St Luc of Lyon (R. Dorne); Saint Joseph of Paris (M. Garrouste); Hôpital Pasteur of Nice (C. Isetta); CHU Brabois of Vandoeuvre Les Nancy (J. Larché); Saint Louis of Paris (J-R. LeGall); CHU de Grenoble (H. Lessire); CHU Pontchaillou of Rennes (Y. Malledant); Hôpital des Hauts Clos of Troyes (P. Mateu); CHU of Amiens (M. Ossart); Hôpital Lariboisière of Paris (D. Payen); CHD Félix Gyuon of Saint Denis La Reunion (P. Schlossmacher); Hôpital Bichat of Paris (J-F. Timsit); Hôpital Saint Andre of Bordeaux (S. Winnock); Hôpital Victor Dupouy of Argentueil (J-P. Sollet); CH Auch (L. Mallet); CHU Nancy-Brabois of Vandoeuvre (P. Maurer); CH William Morey of Chalon (J-M. Sab); Victor Dupouy of Argenteuil (J-P. Sollet); Germany: University Hospital Heidelberg (G. Aykut); Friedrich Schiller University Jena (F. Brunkhorst); University Clinic Hamburg-Eppendorf (A. Nierhaus); University Hospital Mainz (M. Lauterbach); University Hospital Carl Gustav Carus of Dresden (M. Ragaller); Hans Sushemihl Krankenhaus of Emden (R. Gatz); Vivantes-Klinikum Neukoelln of Berlin (H. Gerlach); University Hospital RWTH Aachen (D. Henzler); Kreisklinik Langen-Seligenstadt (H-B Hopf); GKH Bonn (H.Hueneburg); Zentralklinik Bad Berka (W. Karzai); Neuwerk of Moenchengladbach (A. Keller); Philipps University of Marburg (U. Kuhlmann); University Hospital Regensburg (J. Langgartner); ZKH Links der Weser of Bremen (C. Manhold); University Hospital of Dresden (M. Ragaller); University of Wuerzburg (B. Reith); Hannover Medical School (T. Schuerholz); Universitätsklinikum Charité Campus Mitte of Berlin (C. Spies); Bethanien Hospital of Moers (R. Stögbauer); KhgmbH Schongau (J. Unterburger); Greece: Thriassio Hospital of Athens (P-M. Clouva-Molyvdas); Sismanoglion General Hospital of Athens (G. Giokas); KAT General Hospital of Athens (E. Ioannidou); G. Papanikolaou General Hospital of Thessaloniki (A. Lahana); Agios Demetrios of Thessaloniki (A. Liolios); Onassis Cardiac Surgery Center of Athens (K. Marathias); University Hospital of Ioannina (G. Nakos); Tzanio Hospital of Athens (A. Tasiou); Athens Gen. Hosp. Gennimatas (H. Tsangaris); Hungary: Peterfy Hospital of Budapest (P. Tamasi); Ireland: Mater Hospital of Dublin (B. Marsh); Beaumont Hospital of Dublin (M. Power); Israel: Hadassah Hebrew University Medical Center (C. Sprung); Italy: Azienda Ospedaliera Senese o Siena (B. Biagioli); S. Martino of Genova (F. Bobbio Pallavicini); Azienda Ospedaliera S. Gerardo dei Tintori of Monza (A. Pesenti); Osp Regionale of Saronno (C. Capra); Ospedale Maggiore-University A. Avogadro of Novara (F. Della Corte); Osp. Molinette of Torino (P. P. Donadio); A.O. Umberto I Ancona, Rianimazione Clinica (A. Donati); Azienda Ospedaliera Universitaria Policlinico of Palermo (A. Giarratano); San Giovanni Di Dio of Florence (T. Giorgio); H San Raffaele IRCCS of Milano (D. Giudici); Ospedale Di Busto Arsizio (S. Greco); Civile Di Massa (A. Guadagnucci); San Paolo of Milano (G. Lapichino); S. Giovanni Bosco Torino (S. Livigni); Osp. San Giovanni of Sesto (G. Moise); S Camillo of Roma (G. Nardi); Vittorio Emanuele of Catania (E. Panascia); Hospital of Piacenza (M. Pizzamiglio); Universita di Torino-Ospedale S. Giovanni Battista (V. M. Ranieri); Policlinico Le Scotte of Siena (R. Rosi); Ospedale Maggiore Policlinico IRCCS of Milano (A. Sicignano); A. Uboldo of Cernusco Sul Naviglio (M. Solca); P.O. Civile Carrara of Massa (G. Vignali); San Giovanni of Roma (I. Volpe Rinonapoli); Netherlands: Boven IJ Ziekenhuis of Amsterdam (M. Barnas); UMC St Radboud of Nijmegen (E.E. De Bel); Academic Medical Center of Amsterdam (A-C. De Pont); VUMC of Amsterdam (J. Groeneveld); Groningen University Hospital (M Nijsten); Waterlandziekenhuis of Purmerend (L. Sie); OLVG of Amsterdam (D.F. Zandstra); Norway: Sentralsjukehuset i Rogaland of Stavanger (S. Harboe); Sykehuset Østfold of Fredrikstad (S. Lindén); Aker University Hospital of Oslo (R. Z. Lovstad); Ulleval University Hospitalof Oslo (H. Moen); Akershus University Hospital of Nordbyhagen (N. Smith-Erichsen); Poland: Paediatric University Hospital of Lodz (A.Piotrowski); Central Clinic Hospital SLAM of Katowice (E.Karpel); Portugal: Garcia de Orta of Almada (E.Almeida); Hospital de St. António dos Capuchos of Lisboa (R. Moreno); Hospital de Santa Maria of Lisboa (A. Pais-De-Lacerda); Hospital S.Joao of Porto (J. A. Paiva); Fernado Fonseca of Masama (I. Serra); São Teotonio Viseu (A. Pimentel); Romania: Inst of Cardiovascular Diseases of Bucharest (D. Filipescu); Serbia and Montenegro: Military Medical Academy of Belgrade (K. Jovanovic); Slovakia: SUSCH of Bratislava (P. Malik); Slovenia: General Hospital of Novo Mesto (K. Lucka); General Hospital of Celje (G. Voga); Spain: Hospital Universitario Rio Hortega of Valladolid (C. Aldecoa Alvarez-Santullano); Sabadell Hospital (A.Artigas); Hospital Clinic of Barcelona (E. Zavala, A. Escorsell, J. Nicolas); Virgen del Camino of Pamplona (J. J. Izura Cea); Virgen de la Salud of Toledo (L. Marina); 12 de Octubre of Madrid (J. Montejo); Gregorio Maranon of Madrid (E. Palencia); General Universitario de Elche (F. Santos); Puerta del Mar of Cadiz (R. Sierra-Camerino); Fundación Jiménez Díaz of Madrid (F. Sipmann); Hospital Clinic of Barcelona (E. Zavala); Sweden: Central Hospital of Kristianstad (K. Brodersen); Stockholm Soder Hospital (J. Haggqvist); Sunderby Hospital of Luleå (D. Hermansson); Huddinge University Hospital of Stockholm (H. Hjelmqvist); Switzerland: Kantonsspital Luzern (K. Heer); Hirslanden Klinik Beau-Site of Bern (G. Loderer); University Hospital of Zurich (M. Maggiorini); Hôpital de la ville of La Chaux-de-Fonds (H. Zender); United Kingdom: Western General Hospital of Edinburgh (P. Andrews); Peterborough Hospitals NHS Trust of Peterborough (B. Appadu); University Hospital Lewisham, London (C. Barrera Groba); Bristol Royal Infirmary (J. Bewley); Queen Elizabeth Hospital Kings Lynn (K. Burchett); Milton Keynes General (P. Chambers); Homerton University Hospital of London (J. Coakley); Charing Cross Hospital of London (D. Doberenz); North Staffordshire Hospital of Stoke On Trent (N. Eastwood); Antrim Area Hospital (A. Ferguson); Royal Berkshire Hospital of Reading (J. Fielden); The James Cook University Hospital of Middlesbrough (J. Gedney); Addenbrookes of Cambridge (K. Gunning); Rotherham DGH (D. Harling); St. Helier of Carshalton (S. Jankowski); Southport & Formby (D. Jayson); Freeman of Newcastle Upon Tyne (A. Kilner); University Hospital of North Tees at Stockton on Tees (V. Krishna-Kumar); St. Thomas Hospital of London (K. Lei); Royal Infirmary of Edinburgh (S. Mackenzie); Derriford of Plymouth (P. Macnaughton); Royal Liverpool University Hospital (G. Marx); Stirling Royal Infirmary (C. McCulloch); University Hospital of Wales, Cardiff (P. Morgan); St George's Hospital of London (A. Rhodes); Gloucestershire Royal Hospital (C. Roberts); St Peters of Chertsey (M. Russell); James Paget Hospital of Great Yarmouth (D. Tupper-Carey, M. Wright); Kettering General Hospital (L. Twohey); Burnley DGH (J. Watts); Northampton General Hospital (R. Webster); Dumfries Royal Infirmary (D. Williams).