- Email: [email protected]
The Power of Flash Mob Research
Accepted Manuscript The Power of Flash Mob Research – Conducting a nationwide observational clinical study on Capillary Refill Time in a single day Jelmer Alsma, MD, Jan LCM van Saase, MD, PhD, Prabath WB Nanayakkara, MD, PhD, WEM Ineke Schouten, MD, Anique Baten, MD, Martijn P. Bauer, MD, PhD, Frits Holleman, MD, PhD, Jack JM. Ligtenberg, MD, PhD, Patricia M. Stassen, MD, PhD, Karin A. Kaasjager, MD, PhD, Harm Haak, MD, PhD, Frank H. Bosch, MD, PhD, Stephanie CE. Schuit, MD, PhD PII:
S0012-3692(16)62563-1
DOI:
10.1016/j.chest.2016.11.035
Reference:
CHEST 846
To appear in:
CHEST
Received Date: 14 June 2016 Revised Date:
12 October 2016
Accepted Date: 23 November 2016
Please cite this article as: Alsma J, LCM van Saase J, WB Nanayakkara P, Schouten WI, Baten A, Bauer MP, Holleman F, Ligtenberg JJ, Stassen PM, Kaasjager KA, Haak H, Bosch FH, Schuit SC, on behalf of the Famous Study Group, The Power of Flash Mob Research – Conducting a nationwide observational clinical study on Capillary Refill Time in a single day, CHEST (2017), doi: 10.1016/ j.chest.2016.11.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Wordcount The total number of words of the manuscript, including entire text from title page to figure legends: 4940 The number of words in the original article: 2890 The number of words in the abstract: 238 The number of figures: 1 The number of tables: 4
Capillary Refill Time in a single day. 1
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The Power of Flash Mob Research – Conducting a nationwide observational clinical study on
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Jelmer Alsma MD , Jan LCM van Saase MD, PhD , Prabath WB Nanayakkara MD, PhD , WEM Ineke Schouten MD , Anique 4 5 6 7 Baten MD , Martijn P Bauer MD, PhD , Frits Holleman MD, PhD , Jack JM Ligtenberg MD, PhD , Patricia M Stassen MD, 8,9 10 9,11, 12 13 1 PhD , Karin A Kaasjager MD, PhD , Harm Haak MD, PhD , Frank H Bosch MD, PhD , Stephanie CE Schuit MD, PhD on behalf of the Famous Study Group* Department of Internal Medicine, Erasmus University Medical Center Rotterdam, s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands
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Section Acute Medicine, Department of Internal Medicine, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands
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Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, P.O. Box 95500, 1090 HM Amsterdam, the Netherlands
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Department of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, the Netherlands
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Department of Internal Medicine, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, the Netherlands Section Acute Medicine F4-112, Department of Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands Emergency Department, Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
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Department of Internal Medicine, Division General Medicine, section Acute Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands
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Maastricht University, Department of Health Services Research, and CAPHRI School for Public Health and Primary Care, P.O. Box 616, 6200 MD Maastricht, the Netherlands
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Netherlands
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10. Department of Internal Medicine, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands 11. Department of Internal Medicine, Máxima Medical Centre,Dominee Theodor Fliednerstraat 1, 5631 BM Eindhoven, the
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12. Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands 13. Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, the Netherlands
Corresponding author: Jelmer Alsma MD Department of Internal Medicine, Erasmus University Medical Center, s-Gravendijkwal 230 3015 CE Rotterdam, the Netherlands email: [email protected] Declaration of interests All authors declare no conflict of interests.
*FAMOUS Study Group Collaborators 1
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Joris J Arends MD , Gerba Buunk MD, PhD , Bart JA Veldman MD , Heidi SM Ammerlaan MD , Sanjay UC Sankatsing MD, 5 6 7 8 9 10 PhD , Esther MG Jacobs MD , Thomas van Bemmel MD , Rikje Ruiter MD PhD , Eva MT Bots MD , Ralf A Reuters MD , 11 12 13 14 Ginette Carels MD , Sabine HA Diepeveen MD , Anne Floor N Heitz MD , TT Hien van Leeuwen-Nguyen MD , Pim AJ 15 16 17 18 19 Keurlings MD , Renske Barnhard MD , Rachel HP Schreurs MD , Ewoud ter Avest MD , Hans S Brink MD, PhD ,
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Caroline MJ van Kinschot MD , Niels van der Hoeven MD , Mark A van der Zijden MD , Ilse MG Hageman MD , Timo C 24 25 26 27 28 Roeleveld MD , Carolijn MC Klomp MD , Douwe Dekker MD , Anneke Blom MD , Hilde M Wesselius MD , Marieke M 29 30 31 32 32 van Bemmel MD , Ben de Jong MD , Judith Hillen MD , Ginger-Beau Langbroek , Sandra de Bie MD PhD
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Department of Internal Medicine, Albert Schweitzer Hospital, Albert Schweitzerplaats 25, 3318 AT Dordrecht, the Netherlands Department of Internal Medicine, Amphia Hospital, Langendijk 75, 4819 EV Breda, the Netherlands Department of Internal Medicine, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, the Netherlands Department of Internal Medicine, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, the Netherlands Department of Internal Medicine, Diakonessen Hospital , Bosboomstraat 1, 3582 KE, Utrecht, the Netherlands Department of Internal Medicine, Elkerliek hospital, Wesselmanlaan 25, 5707 HA, Helmond, the Netherlands Department of Internal Medicine, Gelre Hospitals Apeldoorn, Albert Schweitzerlaan 31, 7334 DZ, Apeldoorn, the Netherlands Department of Internal Medicine, Groene Hart Hospital, Bleulandweg 10, 2803 HH Gouda, the Netherlands Department of Internal Medicine, Harbour Hospital & Institute for Tropical Diseases, Haringvliet 2, 3011 TD Rotterdam, the Netherlands Department of Internal Medicine, IJsselland Hospital, Prins Constantijnweg 2, 2906 ZC, Capelle aan den Ijssel, the Netherlands Department of Internal Medicine, Ikazia hospital, Montessoriweg 1, 3083 AN, Rotterdam, the Netherlands Department of Internal Medicine, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, the Netherlands Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, the Netherlands Department of Emergency Medicine, Maashospital Pantein, Dokter Kopstraat 1, 5835 DV, Beugen, the Netherlands Department of Emergency Medicine, Martini Hospital, Van Swietenplein 1, 9728 NT, Groningen, the Netherlands Department of Internal Medicine, Máxima Medical Centre, Dominee Theodor Fliednerstraat 1, 5631 BM, Eindhoven, the Netherlands Department of Emergency Medicine, Medical Center Leeuwarden, Henri Dunantweg 2, 8934 AD, Leeuwarden, the Netherlands Department of Internal Medicine, Medisch Spectrum Twente, Haaksbergerstraat 55, 7513 ER, Enschede, the Netherlands Department of Internal Medicine, Reinier de Graaf Group of Hospitals, Reinier de Graafweg 3-11, 2625AD, Delft, the Netherlands Departement of Internal Medicine, Rode Kruis Ziekenhuis, Vondellaan 13, 1942 LE, Beverwijk, the Netherlands Department of Internal Medicine, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, the Netherlands Department of Internal Medicine, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE, Amsterdam, the Netherlands Department of Internal Medicine, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, the Netherlands Department of Internal Medicine, Elisabeth Tweesteden Hospital, Doctor Deelenlaan 5, 5042 AD, Tilburg, the Netherlands Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands Department of Emergency Medicine, Wilhelmina Hospital, Europaweg-Zuid 1, 9401 RK Assen, the Netherland Department of Internal Medicine, Zaandam Medical Center, Koningin Julianaplein 58, 1502 DV, Zaandam, the Netherlands Department of Internal Medicine, Amstelland Hospital, Laan van de Helende Meesters 8, 1186 AM, Amstelveen, the Netherlands Department of Internal Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, the Netherlands Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD, Arnhem, the Netherlands Department of Internal Medicine, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, the Netherlands
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ACCEPTED MANUSCRIPT Abstract: Background: Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients, and there are various methods to assess CRT. Conventional clinical research often demands large
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numbers of patients, making it costly, labor-intensive and time consuming. We studied the interobserver agreement on CRT in a nationwide study using a novel methodology of research called ‘Flash Mob Research’ (FMR).
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Methods:
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Physicians in the Netherlands were recruited by word-of-mouth, conventional media and social media to participate in a nationwide, single-day, “nine-to-five”, multi-center, cross-sectional, observational study to evaluate CRT. Patients 18 years and older presenting to the emergency department or hospitalized were eligible for inclusion. CRT was measured independently by two
seconds (15s). Results:
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investigators at the sternum and distal phalanx after application of pressure for 5 (5s) and 15
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On October 29th 2014, 458 investigators in 38 Dutch hospitals enrolled 1.734 patients. The mean CRT measured at the distal phalanx were 2.3 seconds (5s, SD1.1) and 2.4 seconds (15s, SD1.3). The mean
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CRT measured at the sternum were 2.6 seconds (5s, SD1.1) and 2.7 seconds (15s, SD1.1). Interobserver agreement was higher for the distal phalanx (κ-value 0.40) than for the sternum (κvalue 0.30).
Conclusions: Interobserver agreement on CRT is at best moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared to sternal CRT. FMR proved a valuable instrument to investigate a relative simple clinical question in an inexpensive, quick and reliable manner. 3
ACCEPTED MANUSCRIPT BACKGROUND Evidence assessing the usefulness and reliability of commonly used bedside diagnostic tests is not always available or easily obtained. Capillary refill time (CRT) is frequently used to judge a patient’s circulatory status: a prolonged CRT is thought to be associated with an inadequate perfusion.1,2
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Despite few outcome data to support the use of CRT in adults outside of the ICU, the use of CRT is widespread.3-5 CRT is a standard part of rapid primary assessment of critically ill patients in various advanced life support guidelines (e.g. ALS).2,6
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Originally, CRT was defined without strict time limits, i.e. as “normal”, “definite slowing”, and “very sluggish”,7 which left room for subjective interpretation, making reproducibility difficult. In the
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1980s, an operational definition of 2 seconds as upper limit of normal CRT was recommended, which was replaced in 1988 with less used upper limits of normal adjusted for age and sex.1,8 Despite these recommendations, the measurement and interpretation of CRT remain inconsistent.9,10 CRT is measured at different sites and with different pressure times. In adult ICU settings application of
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pressure at the fingertip for 15 seconds is considered the standard and in children CRT is mostly measured at the sternum.5,10-12 Interpretation is hindered by ambient and patient factors that are not always easy to control (e.g. ambient temperature, light, and patient peripheral temperature). Even in controlled circumstances the interobserver reliability of CRT measurements has been
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questioned.2,11,17-19 In addition, the different methods to measure CRT have been never compared in
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adults.
Since CRT is used in daily clinical practice worldwide, but it remains questionable which method should be used to measure CRT (sternum or phalanx) and whether the results are reproducible, we designed this study to compare the most frequently used methods to measure CRT in adult patients with variable hemodynamic status in a setting resembling daily practice to determine which measurement has the highest interobserver agreement and to determine if sternum and distal phalanx can be used interchangeably.
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ACCEPTED MANUSCRIPT Conventional clinical research used for answering clinically-oriented research questions often demands large numbers of patients, making it costly, labor-intensive and time consuming. We saw a possible solution in Flash Mob Research (FMR). This is a novel method to organize research, and allows the investigation of clinically relevant questions on a large scale in an abbreviated time
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course.20 FMR is based on the concept of flash mobs: “a sudden and planned gathering of many people at a particular place that has been arranged earlier on an internet website”.21 Using the numerical strength of multiple hospitals, and the professional and social networks of their medical
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staff, it is possible to obtain sufficient data with FMR in a short time course,20 while upholding the same quality standards.
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OBJECTIVES
The primary objective of this study was to determine the interobserver agreement of CRT measurements as measured at the sternum and at the distal phalanx using pressure times of 5 and
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15 seconds and to relate the measurements with hemodynamic characteristics. Our secondary aim was to establish the feasibility of using FMR as a fast, inexpensive and robust method to investigate clinical questions by using the power of social networks and new and
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conventional media to gather as many relevant data as possible in a short period of time.
METHODS
Study Design
This was a nationwide, single-day, “nine-to-five”, multi-center, cross-sectional observational study. Setting up a Flash Mob Research
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ACCEPTED MANUSCRIPT As in flash mobs, preparations for FMR were made in a small group. The research question and study design were conceived in the Erasmus University Medical Center in Rotterdam, the Netherlands (EMCR). During the duration of the study, the EMCR acted as coordination center.
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A steering committee with members from whole of the Netherlands further elaborated the research question and study protocol. The protocol was approved by the Medical Ethics Committee of the EMCR. Members of the steering committee invited physicians from their professional networks from all eight Dutch university hospitals, and subsequently physicians from affiliated regional
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hospitals to participate, resulting in nationwide participation. In each participating hospital a local investigator, designated “ambassador”, coordinated the study. Ambassadors were either medical
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specialists or residents. Ambassadors obtained local ethical board approval of the protocol, recruited and instructed investigators and were responsible for handling data. In agreement with flash mobs, communication with participating investigators, public and peers was mainly done by email, social
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media and our website.
Setting, patients and variables
On October 29th 2014 between 9.00 AM and 5.00 PM data were simultaneously collected in all
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participating hospitals. Patients aged 18 years and older who were able to give informed consent and who presented to the Emergency Department (ED) or were hospitalized within this period were
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eligible for enrolment. After giving consent, patients were examined independently by two investigators working within a 5 minute interval. Investigators were physicians (medical specialists, residents), nurses and medical students in their clinical rotations. Investigators were instructed on and worked according to standard operating procedures, which described the order of the tests. Investigators measured CRT at two sites twice; the sternum (CRTs) and distal phalanx of the finger (CRTp). First after application of pressure for 5 seconds (CRTs5, CRTp5), and second for 15 seconds (CRTs15, CRTp15). CRTp was measured by applying sufficient pressure at the distal phalanx of the finger with the hand held at heart level to cause blanching of the skin, and CRT was defined as the 6
ACCEPTED MANUSCRIPT time necessary for the skin to regain its color.1 CRTs was measured by applying sufficient pressure to achieve blanching of the skin of the sternum, and again CRT was defined as the time necessary for the skin to regain its color. Investigators were advised to determine CRT by counting and no timing devices were advised, mimicking daily practice. CRT was measured in seconds and results were
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rounded off to the nearest half second. This resolution allowed categorization of the outcome using upper values of normal as suggested in other studies1,5,8, and this method was previously used by Anderson et al.17 Investigators subjectively assessed the peripheral temperature by placing the back
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of the hand on the patients’ hand (cold vs not cold). Investigators gave their subjective conclusion of the patient’s hemodynamic status (adequate vs inadequate) using all available clinical information.
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Investigators also gave their subjective conclusion of the observed CRT (normal vs prolonged), without predefining normality. The subjective conclusion was chosen to resemble daily practice, as clinicians often present measured CRT with a dichotomous outcome. Pulse rate, blood pressure, respiratory rate, temperature and oxygen saturation were measured using local standard
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procedures. All data were entered into local databases, which were subsequently combined at the EMCR. All patients with CRT measured by two investigators were included in the final analysis. Mean arterial pressure (MAP) was calculated and dichotomized (<65 mmHg vs ≥ 65 mmHg). A MAP <65
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mmHg was considered inadequate.22 Pulse rate was categorized in one of the following three: <60 bpm, 60-100 bpm, >100 bpm. CRT was categorized using definitions found in the literature. CRTs5
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and CRTp5 were categorized using the upper limits of normal as defined by Champion8 and age and by Schriger and Baraff.1 For CRTs15 and CRTp15 an upper limit of normal of 4.0 seconds was used.5 Study size
The study size could not be predicted due to the FMR design. In principle, a successful FMR should include a large sample size for reliable conclusions. Statistical Methods Data were summarized in terms of mean, median, 95% confidence intervals (CI) and standard
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ACCEPTED MANUSCRIPT deviation (SD) when appropriate. Categorical data were analyzed using Chi-squared test. Means of two groups were compared using the student’s t-test (normal distribution) or Mann-Whitney-U test (non-normal distribution); means of three groups were compared using Kruskal-Wallis test. Differences between continuous data with non-normal distribution were analyzed using Wilcoxon
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signed-rank sum test. Interobserver agreement was analyzed for discrete values of CRT using the intraclass correlation coefficient (ICC). In addition, interobserver agreement was analyzed for
categorical values of CRT using the kappa statistics (κ). The variation of CRT with age and sex was
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analyzed using linear regression. Missing data were considered missing at random and were
therefore ignored. A difference of 0.5 seconds between CRTs and CRTp was considered clinically
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relevant.10,17 A p-value < 0.05 was considered statistical significant. Statistical analyses were performed using Statistical Package for the Social Sciences 21.0 (SPSS, SPSS Inc., Chicago, IL, USA). RESULTS Participating hospitals
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A total of 38 hospitals, located all over the Netherlands, participated in the study (representing 45% of the total number of 85 Dutch hospital organizations), including all eight university hospitals, 29
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teaching hospitals (56% of non-academic teaching hospitals) and one non-teaching hospital. Mean inclusion was 46 patients per hospital (median 39, range 3-130). Of the participating hospitals almost
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40% provided data with 24 hours and 76% within one week. All data were available within 19 days. Participating Investigators
A total of 458 investigators participated in the study (33 medical specialists, 246 residents, 122 medical students, and 57 nurses). Mean number of enrolments was 7 patients per investigator (Range 1-65). Most enrolments were done by residents (N=1.916; mean=8), followed by medical students (N=1.096, mean=9), medical specialists (N=288; mean=9) and nurses (N=168; mean=3).
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ACCEPTED MANUSCRIPT Patient characteristics A total of 1.734 patients (3.468 examinations) were included in the study with a slight preponderance of males (51.6%, n=893). Patients overall had a mean age of 65 years. The majority (78.1%) were inpatients. Patient characteristics are presented in table 1.
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Capillary Refill Time
The mean peripheral CRT was 2.3 seconds (CRTp5, SD 1.1) and 2.4 seconds (CRTp15, SD 1.3) and mean
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sternal CRT was 2.6 seconds (CRTs5, SD 1.1) and 2.7 seconds (CRTs15, SD 1.1). CRTp5 was shorter in women (2.2 seconds, SD 1.0) than men (2.4 seconds, SD 1.2 p=0.006) and increased with age (0.16
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seconds per 10 years p<0.001, figure 1). On average, CRTp5 was 0.3 seconds shorter than CRTs5 (p<0.001) and CRTp15 was 0.3 seconds shorter than CRTs15 (p<0.001). CRT correlated positively with MAP, subjective peripheral temperature and subjective assessment of the hemodynamic status. There was no correlation with pulse rate (table 2).
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The mean difference between measurements of the first and second investigator was 0.1 seconds (CRTp5 0.1 seconds (CI 0.0-0.1), CRTp15 0.1 (95% CI 0.0-0.1), CRTs5 0.1 (CI 0.0-0.1), and CRTs15 0.1 (CI 0.0-0.1)). Median difference was 0 seconds in all groups. Interobserver agreement, assessed by
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calculating the ICC between the measurements of CRTp of both investigators was 0.52 (CRTp5, CI 0.49-0.56) and 0.54 (CRTp15, CI 0.50-0.57) (p<0.001), and interobserver agreement on measurements
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of CRTs was 0.43 (CRTs5, CI 0.39-0.47) and 0.46 (CRTs15, CI 0.42-0.49) (p<0.001) (table 3a). The agreement between the two investigators on whether the subjective CRT was normal or prolonged was assessed using the kappa statistics. Application of pressure for 5 seconds yielded a κvalue of 0.40 for CRTp (CI 0.36-0.45) and 0.30 for CRTs (CI 0.26-0.35) (both fair agreement)23 when using 2 seconds as the upper value of normal, and a κ-value of 0.20 for CRTp (CI 0.12-0.29) and 0.13 for CRTs (CI 0.04-0.22) (both slight agreement)23 when using upper limits of normal based on age and sex. Using 4 seconds as the upper value of normal after application of 15 seconds of pressure yielded
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ACCEPTED MANUSCRIPT a κ-value of 0.32 for CRTp (CI 0.24-0.41) measurements and 0.23 for CRTs measurements (CI 0.150.31) (both fair agreement).23 Agreement between two investigators on the subjective conclusion of whether the CRT was normal or prolonged yielded a κ-value of 0.44 (CI 0.37-0.51) (moderate agreement) (table 3b).23
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DISCUSSION
Our nationwide, single-day, “nine-to-five”, multi-center, cross-sectional observational study is the first to study the interobserver agreement of four frequently used methods to measure CRT.
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These measurements were performed in a setting specifically designed to resemble daily practice at the ED and the ward, with two observers using identical methods under similar conditions. CRT
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measurement had slight to moderate agreement at best using a dichotomous outcome (normal vs prolonged), and moderate correlation using a continuous outcome (seconds). To be of use in clinical practice the interpretation of the results of CRT measurements should be easily reproducible. To date, there are only three studies in adults that report on interobserver
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agreement of CRT measurement at the distal phalanx after 5 seconds of pressure.17-19 These studies show moderate agreement at best. In only one study CRT was measured without a timing device.17 The other studies either showed a video with CRT18 or used healthy volunteers in controlled
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circumstances, and CRT was determined with a chronometer or a video,19 which does not reflect the
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worldwide use and interpretation of CRT in daily practice.9 To our knowledge, our study was the first to study the optimal site and duration of pressure
for CRT measurement in adults. As expected, our study shows a correlation between the CRT measured at the distal phalanx and sternum. CRT measured at the distal phalanx is shorter than measured at the sternum, as is found in children,10 and we conclude that phalanx and sternum cannot be used interchangeably. The interobserver agreement on CRT was higher for the distal phalanx then sternum. A prolonged application of pressure (15 seconds), as used solely in the ICU, only resulted in a slightly higher interobserver correlation. Application of pressure for 5 seconds at 10
ACCEPTED MANUSCRIPT the distal phalanx is easier to use, and most studies on CRT in the ED and the ward use 5 seconds application of pressure.5,12 Therefore, based on our findings we recommend uniform use of CRT, and propose that CRT should only be measured at the distal phalanx with 5 seconds of pressure. But why measure CRT? CRT was introduced by Beecher in World War II to identify shock in
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battlefield survivors,24 and nowadays, it is still used to assess the peripheral circulation and in early detection of shock.2,6 Although our study showed correlation between CRT and a MAP under 65 mmHg, we showed no correlation between CRT and an abnormal pulse rate, which is an early
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indicator of shock. In the detection of shock in its early stages, the additional value of CRT seems limited, which is supported by previous research.15,25 However, some studies show the predictive
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value of CRT on long-term and short-term mortality. In a retrospective study on oncology patients a prolonged CRT (≥2 seconds) was predictive for both CCU admission and 30 day mortality.3 A prospective study in ED patients found that a prolonged CRT as a continuous variable was associated with an increased risk of mortality at 1 and 7 days.4
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With our study we also showed the power of FMR study design and its potential as a methodological tool for clinical research. When compared with conventional studies, FMR has
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multiple similarities. In preparation of the study, FMR requires the same steps in designing and setting up (e.g. protocol development, ethical board approval, instruction of collaborators).
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However, FMR showed many additional advantages. It facilitated inclusion of large numbers of patients from multiple centers – and the resulting data – within a short period of time. The inspiring and new research method combined with an appealing research question led to high participation of hospitals. FMR also encouraged all the members of the medical team to participate in research. Most investigators in our study and almost half of the ambassadors were residents, who are often mainly focused on patient care and otherwise not regular participants of research. FMR engaged them in the process of research and exposed them to its various aspects. All these advantages come with limited time investment and low costs.
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ACCEPTED MANUSCRIPT Our study has limitations. Given the cross-sectional nature of this study no follow up data was collected. Therefore no associations with outcomes of disease, including mortality were examined. Data collection was done in standardized procedures after standardized instructions, however given the large number of centers and investigators it is inevitable that small differences
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exist in the collection of data. Many of the collected variables are subjective and therefore subject to interpretation and can be influenced by the clinical experience of the investigator. The application of pressure could differ between investigators, which could also affect CRT. In children, light pressure
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resulted in shorter CRT2, but in adults this effect has not been studied. We propagated counting, instead of using timing devices, to a resolution of a half second, which could have led to lower
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agreement. Since the mean difference between all measurements was 0.1 second, the influence on our results was little, while it enabled us to compare various upper limits of normal. We think that our study represents how CRT is used as a bedside test in daily practice worldwide, with all its shortcomings that hinder its users. Also, with 45% of the Dutch hospital organizations involved, our
Conclusions
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results are generalizable.
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Based on the results of our study, especially the low interobserver agreement on a test that is difficult to standardize, combined with the currently available evidence, we conclude that the
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value of CRT in clinical practice is limited, and its routine use should be reconsidered. When CRT is used, it should be measured at the distal phalanx after applying pressure for 5 seconds. The practice of using the sternum as site for CRT measurement should be discarded. In addition, the FMR methodology proved to be an inexpensive, quick and reliable method
to investigate “simple” clinical questions. We used FMR to recruit 1.734 participants in a single day, and the majority of the data were ready for analysis within 24 hours. We therefore believe this study exemplifies the power of FMR.
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ACCEPTED MANUSCRIPT Guarantor Jelmer Alsma takes responsibility for the content of the manuscript, including data and analysis Author Contributions
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JA and SS conceived and designed the study. JA, PN, IS, AB, MB, FH, JL, PS, KK, HH, and FB were locally responsible for the coordination of the study and recruited investigators in the region. JA nationally coordinated the study. JA, JS and SS wrote the first draft of the manuscript. JA, JS, PN, IS,
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AB, MB, FH, JL, PS, KK, HH, FB, and SS contributed to the writing of the manuscript. JA, JS, PN, IS, AB,
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MB, FH, JL, PS, KK, HH, FB, and SS agree with manuscript results and conclusions. * The collaborators of the FAMOUS study group: 1
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10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
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Department of Internal Medicine, Albert Schweitzer Hospital, Albert Schweitzerplaats 25, 3318 AT Dordrecht, the Netherlands Department of Internal Medicine, Amphia Hospital, Langendijk 75, 4819 EV Breda, the Netherlands Department of Internal Medicine, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, the Netherlands Department of Internal Medicine, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, the Netherlands Department of Internal Medicine, Diakonessen Hospital , Bosboomstraat 1, 3582 KE, Utrecht, the Netherlands Department of Internal Medicine, Elkerliek hospital, Wesselmanlaan 25, 5707 HA, Helmond, the Netherlands Department of Internal Medicine, Gelre Hospitals Apeldoorn, Albert Schweitzerlaan 31, 7334 DZ, Apeldoorn, the Netherlands Department of Internal Medicine, Groene Hart Hospital, Bleulandweg 10, 2803 HH Gouda, the Netherlands Department of Internal Medicine, Harbour Hospital & Institute for Tropical Diseases, Haringvliet 2, 3011 TD Rotterdam, the Netherlands Department of Internal Medicine, IJsselland Hospital, Prins Constantijnweg 2, 2906 ZC, Capelle aan den Ijssel, the Netherlands Department of Internal Medicine, Ikazia hospital, Montessoriweg 1, 3083 AN, Rotterdam, the Netherlands Department of Internal Medicine, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, the Netherlands Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, the Netherlands Department of Emergency Medicine, Maashospital Pantein, Dokter Kopstraat 1, 5835 DV, Beugen, the Netherlands Department of Emergency Medicine, Martini Hospital, Van Swietenplein 1, 9728 NT, Groningen, the Netherlands Department of Internal Medicine, Máxima Medical Centre, Dominee Theodor Fliednerstraat 1, 5631 BM, Eindhoven, the Netherlands Department of Emergency Medicine, Medical Center Leeuwarden, Henri Dunantweg 2, 8934 AD, Leeuwarden, the Netherlands Department of Internal Medicine, Medisch Spectrum Twente, Haaksbergerstraat 55, 7513 ER, Enschede, the Netherlands Department of Internal Medicine, Reinier de Graaf Group of Hospitals, Reinier de Graafweg 3-11, 2625AD, Delft, the Netherlands Departement of Internal Medicine, Rode Kruis Ziekenhuis, Vondellaan 13, 1942 LE, Beverwijk, the Netherlands Department of Internal Medicine, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, the Netherlands Department of Internal Medicine, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE, Amsterdam, the Netherlands Department of Internal Medicine, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, the Netherlands
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1. 2. 3. 4. 5. 6. 7. 8. 9.
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Joris J Arends MD , Gerba Buunk MD, PhD , Bart JA Veldman MD , Heidi SM Ammerlaan MD , Sanjay UC Sankatsing MD, 5 6 7 8 9 10 PhD , Esther MG Jacobs MD , Thomas van Bemmel MD , Rikje Ruiter MD PhD , Eva MT Bots MD , Ralf A Reuters MD , 11 12 13 14 Ginette Carels MD , Sabine HA Diepeveen MD , Anne Floor N Heitz MD , TT Hien van Leeuwen-Nguyen MD , Pim AJ 15 16 17 18 19 Keurlings MD , Renske Barnhard MD , Rachel HP Schreurs MD , Ewoud ter Avest MD , Hans S Brink MD, PhD , 20 21 22 23 Caroline MJ van Kinschot MD , Niels van der Hoeven MD , Mark A van der Zijden MD , Ilse MG Hageman MD , Timo C 24 25 26 27 28 Roeleveld MD , Carolijn MC Klomp MD , Douwe Dekker MD , Anneke Blom MD , Hilde M Wesselius MD , Marieke M 29 30 31 32 32 van Bemmel MD , Ben de Jong MD , Judith Hillen MD , Ginger-Beau Langbroek , Sandra de Bie MD PhD
13
ACCEPTED MANUSCRIPT 25. 26. 27. 28. 29. 30. 31. 32.
Department of Internal Medicine, Elisabeth Tweesteden Hospital, Doctor Deelenlaan 5, 5042 AD, Tilburg, the Netherlands Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands Department of Emergency Medicine, Wilhelmina Hospital, Europaweg-Zuid 1, 9401 RK Assen, the Netherland Department of Internal Medicine, Zaandam Medical Center, Koningin Julianaplein 58, 1502 DV, Zaandam, the Netherlands Department of Internal Medicine, Amstelland Hospital, Laan van de Helende Meesters 8, 1186 AM, Amstelveen, the Netherlands Department of Internal Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, the Netherlands Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD, Arnhem, the Netherlands Department of Internal Medicine, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, the Netherlands
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JJA, GB, BV, HA, SUS, EJ, TB, RR, EB, RR, GC, SD, AH, HL, PK, RB, RS, EA, HB, CK, NH, MZ, IH, TC, CMK, DD, AB, HW, MMB, BJ, JH were ambassadors and were responsible for local coordination of the study, local approval of the protocol, recruitment and instruction of investigators, collecting and
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processing data. SB and GBL were involved in design and testing of the study protocol. All
collaborators critically read the manuscript. All collaborators agree with manuscript results and
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conclusions.
Funding
None Acknowledgments
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Declaration of interests
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None
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We thank all participating patients, investigators and hospitals for their contribution. References 1. 2. 3. 4.
Schriger DL, Baraff L. Defining normal capillary refill: variation with age, sex, and temperature. Ann Emerg Med. 1988;17(9):932-935. Pickard A, Karlen W, Ansermino JM. Capillary refill time: is it still a useful clinical sign? Anesth Analg. 2011;113(1):120-123. Cooksley T, Kitlowski E, Haji-Michael P. Effectiveness of Modified Early Warning Score in predicting outcomes in oncology patients. QJM. 2012;105(11):1083-1088. Mrgan M, Rytter D, Brabrand M. Capillary refill time is a predictor of short-term mortality for adult patients admitted to a medical department: an observational cohort study. Emerg Med J. 2014;31(12):954-958.
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13. 14. 15. 16. 17. 18. 19.
20. 21. 22.
23. 24. 25.
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11.
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10.
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9.
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8.
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6. 7.
Lima A, Jansen TC, van Bommel J, Ince C, Bakker J. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med. 2009;37(3):934938. Lockey. Advanced Life Support ERC 2010 Edition. Beecher HK, Simeone FA, et al. The internal state of the severely wounded man on entry to the most forward hospital. Surgery. 1947;22(4):672-711. Champion HR, Sacco WJ, Carnazzo AJ, Copes W, Fouty WJ. Trauma score. Crit Care Med. 1981;9(9):672-676. Lobos AT, Menon K. A multidisciplinary survey on capillary refill time: Inconsistent performance and interpretation of a common clinical test. Pediatr Crit Care Med. 2008;9(4):386-391. Crook J, Taylor RM. The agreement of fingertip and sternum capillary refill time in children. Arch Dis Child. 2013;98(4):265-268. King D, Morton R, Bevan C. How to use capillary refill time. Arch Dis Child Educ Pract Ed. 2014;99(3):111-116. van Genderen ME, Lima A, Akkerhuis M, Bakker J, van Bommel J. Persistent peripheral and microcirculatory perfusion alterations after out-of-hospital cardiac arrest are associated with poor survival. Crit Care Med. 2012;40(8):2287-2294. Anderson B, Kelly AM, Kerr D, Clooney M, Jolley D. Impact of patient and environmental factors on capillary refill time in adults. Am J Emerg Med. 2008;26(1):62-65. McGee S, Abernethy WB, 3rd, Simel DL. The rational clinical examination. Is this patient hypovolemic? JAMA. 1999;281(11):1022-1029. Schriger DL, Baraff LJ. Capillary Refill - Is It a Useful Predictor of Hypovolemic States. Annals of Emergency Medicine. 1991;20(6):601-605. Lewin J, Maconochie I. Capillary refill time in adults. Emerg Med J. 2008;25(6):325-326. Anderson B, Kelly A, Kerr D, Jolley D. Capillary refill time in adults has poor inter-observer agreement. Hong Kong Journal of Emergency Medicine. 2008;15:71-74. Brabrand M, Hosbond S, Folkestad L. Capillary refill time: a study of interobserver reliability among nurses and nurse assistants. Eur J Emerg Med. 2011;18(1):46-49. Espinoza ED, Welsh S, Dubin A. Lack of agreement between different observers and methods in the measurement of capillary refill time in healthy volunteers: an observational study. Rev Bras Ter Intensiva. 2014;26(3):269-276. Semler MW, Stover DG, Copland AP, et al. Flash mob research: a single-day, multicenter, resident-directed study of respiratory rate. Chest. 2013;143(6):1740-1744. Longman Dictionary of Contemporary English. http://www.ldoceonline.com/dictionary/flashmob. Last visited on August 16th 2016 Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228. Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37(5):360-363. Beecher HK. The specialty of anesthesia and its application in the Harvard UniversityMassachusetts General Hospital Department. Ann Surg. 1947;126(4):486-499. McGee S, Abernethy WB, Simel DL. Is this patient hypovolemic? Jama-J Am Med Assoc. 1999;281(11):1022-1029.
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ACCEPTED MANUSCRIPT Male N= 894 Female N= 840
Total N=1734
(48.4%)
65 (16)
65 (18)
65 (17)
Systolic blood pressure in mmHg * (n=1728)
131 (21)
133 (23)
132 (22)
Diastolic blood pressure in mmHg† (n=1728)
75 (12)
72(13)
173 (13)
Mean arterial pressure* (n=1728)
93 (14)
Pulse frequency per minute‡ (n=1731)
79 (16)
Age in years* (n=1734)
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(51.6%)
92 (14)
93 (14)
81 (16)
80 (16)
96 (3)
96 (3)
96 (3)
Respiratory rate per minute* (n=1598)
17 (4)
16 (4)
17 (4)
36.8 (0.7)
36.9 (0.7)
36.9 (0.7)
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Temperature in degrees centigrade† (n=1723)
Table 1: Characteristics of patients. Mean (SD)
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*: not significant, †: p < 0.001, ‡ p=0.008
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Oxygen saturation in percentage* (n=1628)
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CRTp15 2.4
95% CI 2.4-2.5
Cold Warm p-value*
3.2 2.1 p<0.001
3.0-3.4 2.1-2.2
3.3 2.3 p<0.001
3.1-3.6 2.2-2.3
95% CI 2.5-2.6
CRTs15 2.7
95% CI 2.7-2.8
2.5-2.6 2.8-3.1
3.0 2.6 p<0.001
2.9-3.2 2.6-2.7
Inadequate Adequate p-value*
3.2 2.2 p<0.001
2.8-3.5 2.2-2.3
3.6 2.4 p<0.001
3.1- 4.2 2.3-2.4
3.2 2.6 p<0.001
2.9-3.5 2.5-2.6
3.5 2.7 p<0.001
3.2-3.8 2.6-2.7
<65 >=65 p-value*
3.0 2.3 p=0.001
2.6-3.5 2.2-2.3
3.3 2.4 p<0.001
2.7-3.9 2.3-2.5
3.4 2.6 p=0.01
2.7-4.1 2.5-2.6
3.6 2.7 p=0.002
3.0-4.2 2.6-2.7
<60 60-100 >100 p-value**
2.3 2.3 2.2 p= 0.407
2.1-2.5 2.2-2.3 2.0-2.4
2.6 2.4 2.4 p=0.397
2.3-2.9 2.3-2.5 2.2-2.6
2.6 2.6 2.6 p=0.800
2.5-2.9 2.5-2.6 2.4-2.7
2.8 2.7 2.7 p=0.862
2.5-3.0 2.6-2.8 2.5-2.9
Prolonged Normal p-value *
3.5 2.1 p<0.001
3.9 2.2 p<0.001
3.6-4.1 2.2-2.3
3.6 2.5 p<0.001
3.4-3.7 2.4-2.5
3.8 2.6 p<0.001
3.6-4.0 2.5-2.6
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Subjective hemodynamic status
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Subjective conclusion of the CRT
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Mean arterial pressure in mmHg
Pulse rate per minute
3.3-3.7 2.1-2.1
CRTs5 2.6
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95% CI 2.2-2.3
2.9 2.5 p<0.001
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CRTp5 2.3
Total Subjective peripheral temperature
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Temperature in degrees centigrade 2.4-2.9 2.2-2.3 1.9-2.5
2.8 2.4 2.5
0.003
0.002
2.6-3.1 2.3-2.5 2.1-2.8
2.6 2.6 2.5
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p-value**
2.6 2.3 2.2
0.907
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<36 36-38 >38
2.4-2.8 2.5-2.6 2.3-2.8
2.8 2.7 2.7
2.5-3.0 2.6-2.8 2.4-3.0
0.870
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Table 2: Mean capillary refill times. Abbreviations: CRT: capillary refill time. CRTp5: peripheral capillary refill time, application of pressure 5 s. CRTp15: peripheral capillary refill time, application of pressure 15 seconds CRTs5: sternal capillary refill time, application of pressure 5 s. CRTs15: sternal capillary refill time, application of pressure 15 seconds. 95% CI 95% confidence interval of the mean (lower bound and upper bound) * Determined by Mann-Whitney-U test ** Difference between groups as determined by Kruskal-Wallis test
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Intraclass correlation coefficient 0.52 0.54 0.43 0.46
Interpretation Moderate correlation Moderate correlation Low correlation Low correlation
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CRTp5 CRTp15 CRTs5 CRTs15
95% Confidence interval (lower and upper bound) 0.49-0.56 0.50-0.57 0.39-0.47 0.42-0.49
Table 3a: Agreement between two investigators assessed using intraclass correlation coefficient. All results p<0.001
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Abbreviations: CRT: capillary refill time, p: peripheral, s: sternal, 5: 5 seconds, 15: 15 seconds.
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CRTp5, upper range of normal 2 seconds CRTs5, upper range of normal 2 seconds
0.40
95% Confidence interval (lower and upper bound) 0.36 – 0.45
0.30
0.26-0.35
fair agreement
CRTp5, upper range of normal based on age and gender CRTs5, upper range of normal based on age and gender
0.20
0.12 – 0.29
slight agreement
0.13
0.04 – 0.22
CRTp15, upper range of normal of 4 seconds CRTs15, upper range of normal of 4 seconds
0.32
0.24 – 0.41
0.23
0.15 – 0.31
0.44
0.37 – 0.51
Interpretation fair agreement
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Subjective conclusion on CRT
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kappa statistics
slight agreement
fair agreement
fair agreement
moderate agreement
Table 3b: Agreement between two investigators assessed using kappa statistics.
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Abbreviations: CRT: capillary refill time, p: peripheral, s: sternal, 5: 5 seconds, 15: 15 seconds. All results p <0.001
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Figure 1: Mean Capillary Refill Time in seconds for different age categories in years Abbreviations:
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CRT: Capillary Refill Time. P5: Peripheral measurement after application of pressure for 5 seconds. S5: Sternal measurement after application of pressure for 5 seconds. P15: Peripheral measurement after application of pressure for seconds. S15: Sternal measurement after application of pressure for 15 seconds.
ACCEPTED MANUSCRIPT Abbreviation list kappa statistics
5s
5 seconds of pressure
15s
15 seconds of pressure
ALS
Advanced Life Support
ANOVA
Analysis of variance
BPM
Beats per minute
CI
95% confidence intervals
CRT
Capillary refill time
CRTs
Capillary refill time measured at the sternum
CRTp
Capillary refill time measured at the distal phalanx of the finger
ED
Emergency Department
EMCR
Erasmus University Medical Center, Rotterdam, The Netherlands
FMR
Flash Mob Research
ICC
Intraclass Correlation Coefficient
ICU
Intensive Care Unit
MAP
Mean Arterial Pressure
N
Number
SD
Standard Deviation
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κ
S0012-3692(16)62563-1
DOI:
10.1016/j.chest.2016.11.035
Reference:
CHEST 846
To appear in:
CHEST
Received Date: 14 June 2016 Revised Date:
12 October 2016
Accepted Date: 23 November 2016
Please cite this article as: Alsma J, LCM van Saase J, WB Nanayakkara P, Schouten WI, Baten A, Bauer MP, Holleman F, Ligtenberg JJ, Stassen PM, Kaasjager KA, Haak H, Bosch FH, Schuit SC, on behalf of the Famous Study Group, The Power of Flash Mob Research – Conducting a nationwide observational clinical study on Capillary Refill Time in a single day, CHEST (2017), doi: 10.1016/ j.chest.2016.11.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Wordcount The total number of words of the manuscript, including entire text from title page to figure legends: 4940 The number of words in the original article: 2890 The number of words in the abstract: 238 The number of figures: 1 The number of tables: 4
Capillary Refill Time in a single day. 1
1
2
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The Power of Flash Mob Research – Conducting a nationwide observational clinical study on
3
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Jelmer Alsma MD , Jan LCM van Saase MD, PhD , Prabath WB Nanayakkara MD, PhD , WEM Ineke Schouten MD , Anique 4 5 6 7 Baten MD , Martijn P Bauer MD, PhD , Frits Holleman MD, PhD , Jack JM Ligtenberg MD, PhD , Patricia M Stassen MD, 8,9 10 9,11, 12 13 1 PhD , Karin A Kaasjager MD, PhD , Harm Haak MD, PhD , Frank H Bosch MD, PhD , Stephanie CE Schuit MD, PhD on behalf of the Famous Study Group* Department of Internal Medicine, Erasmus University Medical Center Rotterdam, s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands
2.
Section Acute Medicine, Department of Internal Medicine, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands
3. 4.
Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, P.O. Box 95500, 1090 HM Amsterdam, the Netherlands
5. 6.
Department of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, the Netherlands
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1.
Department of Internal Medicine, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, the Netherlands Section Acute Medicine F4-112, Department of Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands Emergency Department, Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
8.
Department of Internal Medicine, Division General Medicine, section Acute Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands
9.
Maastricht University, Department of Health Services Research, and CAPHRI School for Public Health and Primary Care, P.O. Box 616, 6200 MD Maastricht, the Netherlands
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7.
Netherlands
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10. Department of Internal Medicine, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands 11. Department of Internal Medicine, Máxima Medical Centre,Dominee Theodor Fliednerstraat 1, 5631 BM Eindhoven, the
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12. Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands 13. Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, the Netherlands
Corresponding author: Jelmer Alsma MD Department of Internal Medicine, Erasmus University Medical Center, s-Gravendijkwal 230 3015 CE Rotterdam, the Netherlands email: [email protected] Declaration of interests All authors declare no conflict of interests.
*FAMOUS Study Group Collaborators 1
2
3
4
Joris J Arends MD , Gerba Buunk MD, PhD , Bart JA Veldman MD , Heidi SM Ammerlaan MD , Sanjay UC Sankatsing MD, 5 6 7 8 9 10 PhD , Esther MG Jacobs MD , Thomas van Bemmel MD , Rikje Ruiter MD PhD , Eva MT Bots MD , Ralf A Reuters MD , 11 12 13 14 Ginette Carels MD , Sabine HA Diepeveen MD , Anne Floor N Heitz MD , TT Hien van Leeuwen-Nguyen MD , Pim AJ 15 16 17 18 19 Keurlings MD , Renske Barnhard MD , Rachel HP Schreurs MD , Ewoud ter Avest MD , Hans S Brink MD, PhD ,
1
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21
22
23
Caroline MJ van Kinschot MD , Niels van der Hoeven MD , Mark A van der Zijden MD , Ilse MG Hageman MD , Timo C 24 25 26 27 28 Roeleveld MD , Carolijn MC Klomp MD , Douwe Dekker MD , Anneke Blom MD , Hilde M Wesselius MD , Marieke M 29 30 31 32 32 van Bemmel MD , Ben de Jong MD , Judith Hillen MD , Ginger-Beau Langbroek , Sandra de Bie MD PhD
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21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
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18. 19. 20.
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10. 11. 12. 13. 14. 15. 16. 17.
Department of Internal Medicine, Albert Schweitzer Hospital, Albert Schweitzerplaats 25, 3318 AT Dordrecht, the Netherlands Department of Internal Medicine, Amphia Hospital, Langendijk 75, 4819 EV Breda, the Netherlands Department of Internal Medicine, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, the Netherlands Department of Internal Medicine, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, the Netherlands Department of Internal Medicine, Diakonessen Hospital , Bosboomstraat 1, 3582 KE, Utrecht, the Netherlands Department of Internal Medicine, Elkerliek hospital, Wesselmanlaan 25, 5707 HA, Helmond, the Netherlands Department of Internal Medicine, Gelre Hospitals Apeldoorn, Albert Schweitzerlaan 31, 7334 DZ, Apeldoorn, the Netherlands Department of Internal Medicine, Groene Hart Hospital, Bleulandweg 10, 2803 HH Gouda, the Netherlands Department of Internal Medicine, Harbour Hospital & Institute for Tropical Diseases, Haringvliet 2, 3011 TD Rotterdam, the Netherlands Department of Internal Medicine, IJsselland Hospital, Prins Constantijnweg 2, 2906 ZC, Capelle aan den Ijssel, the Netherlands Department of Internal Medicine, Ikazia hospital, Montessoriweg 1, 3083 AN, Rotterdam, the Netherlands Department of Internal Medicine, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, the Netherlands Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, the Netherlands Department of Emergency Medicine, Maashospital Pantein, Dokter Kopstraat 1, 5835 DV, Beugen, the Netherlands Department of Emergency Medicine, Martini Hospital, Van Swietenplein 1, 9728 NT, Groningen, the Netherlands Department of Internal Medicine, Máxima Medical Centre, Dominee Theodor Fliednerstraat 1, 5631 BM, Eindhoven, the Netherlands Department of Emergency Medicine, Medical Center Leeuwarden, Henri Dunantweg 2, 8934 AD, Leeuwarden, the Netherlands Department of Internal Medicine, Medisch Spectrum Twente, Haaksbergerstraat 55, 7513 ER, Enschede, the Netherlands Department of Internal Medicine, Reinier de Graaf Group of Hospitals, Reinier de Graafweg 3-11, 2625AD, Delft, the Netherlands Departement of Internal Medicine, Rode Kruis Ziekenhuis, Vondellaan 13, 1942 LE, Beverwijk, the Netherlands Department of Internal Medicine, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, the Netherlands Department of Internal Medicine, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE, Amsterdam, the Netherlands Department of Internal Medicine, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, the Netherlands Department of Internal Medicine, Elisabeth Tweesteden Hospital, Doctor Deelenlaan 5, 5042 AD, Tilburg, the Netherlands Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands Department of Emergency Medicine, Wilhelmina Hospital, Europaweg-Zuid 1, 9401 RK Assen, the Netherland Department of Internal Medicine, Zaandam Medical Center, Koningin Julianaplein 58, 1502 DV, Zaandam, the Netherlands Department of Internal Medicine, Amstelland Hospital, Laan van de Helende Meesters 8, 1186 AM, Amstelveen, the Netherlands Department of Internal Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, the Netherlands Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD, Arnhem, the Netherlands Department of Internal Medicine, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, the Netherlands
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1. 2. 3. 4. 5. 6. 7. 8. 9.
2
ACCEPTED MANUSCRIPT Abstract: Background: Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients, and there are various methods to assess CRT. Conventional clinical research often demands large
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numbers of patients, making it costly, labor-intensive and time consuming. We studied the interobserver agreement on CRT in a nationwide study using a novel methodology of research called ‘Flash Mob Research’ (FMR).
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Methods:
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Physicians in the Netherlands were recruited by word-of-mouth, conventional media and social media to participate in a nationwide, single-day, “nine-to-five”, multi-center, cross-sectional, observational study to evaluate CRT. Patients 18 years and older presenting to the emergency department or hospitalized were eligible for inclusion. CRT was measured independently by two
seconds (15s). Results:
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investigators at the sternum and distal phalanx after application of pressure for 5 (5s) and 15
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On October 29th 2014, 458 investigators in 38 Dutch hospitals enrolled 1.734 patients. The mean CRT measured at the distal phalanx were 2.3 seconds (5s, SD1.1) and 2.4 seconds (15s, SD1.3). The mean
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CRT measured at the sternum were 2.6 seconds (5s, SD1.1) and 2.7 seconds (15s, SD1.1). Interobserver agreement was higher for the distal phalanx (κ-value 0.40) than for the sternum (κvalue 0.30).
Conclusions: Interobserver agreement on CRT is at best moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared to sternal CRT. FMR proved a valuable instrument to investigate a relative simple clinical question in an inexpensive, quick and reliable manner. 3
ACCEPTED MANUSCRIPT BACKGROUND Evidence assessing the usefulness and reliability of commonly used bedside diagnostic tests is not always available or easily obtained. Capillary refill time (CRT) is frequently used to judge a patient’s circulatory status: a prolonged CRT is thought to be associated with an inadequate perfusion.1,2
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Despite few outcome data to support the use of CRT in adults outside of the ICU, the use of CRT is widespread.3-5 CRT is a standard part of rapid primary assessment of critically ill patients in various advanced life support guidelines (e.g. ALS).2,6
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Originally, CRT was defined without strict time limits, i.e. as “normal”, “definite slowing”, and “very sluggish”,7 which left room for subjective interpretation, making reproducibility difficult. In the
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1980s, an operational definition of 2 seconds as upper limit of normal CRT was recommended, which was replaced in 1988 with less used upper limits of normal adjusted for age and sex.1,8 Despite these recommendations, the measurement and interpretation of CRT remain inconsistent.9,10 CRT is measured at different sites and with different pressure times. In adult ICU settings application of
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pressure at the fingertip for 15 seconds is considered the standard and in children CRT is mostly measured at the sternum.5,10-12 Interpretation is hindered by ambient and patient factors that are not always easy to control (e.g. ambient temperature, light, and patient peripheral temperature). Even in controlled circumstances the interobserver reliability of CRT measurements has been
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2,13-16
questioned.2,11,17-19 In addition, the different methods to measure CRT have been never compared in
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adults.
Since CRT is used in daily clinical practice worldwide, but it remains questionable which method should be used to measure CRT (sternum or phalanx) and whether the results are reproducible, we designed this study to compare the most frequently used methods to measure CRT in adult patients with variable hemodynamic status in a setting resembling daily practice to determine which measurement has the highest interobserver agreement and to determine if sternum and distal phalanx can be used interchangeably.
4
ACCEPTED MANUSCRIPT Conventional clinical research used for answering clinically-oriented research questions often demands large numbers of patients, making it costly, labor-intensive and time consuming. We saw a possible solution in Flash Mob Research (FMR). This is a novel method to organize research, and allows the investigation of clinically relevant questions on a large scale in an abbreviated time
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course.20 FMR is based on the concept of flash mobs: “a sudden and planned gathering of many people at a particular place that has been arranged earlier on an internet website”.21 Using the numerical strength of multiple hospitals, and the professional and social networks of their medical
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staff, it is possible to obtain sufficient data with FMR in a short time course,20 while upholding the same quality standards.
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OBJECTIVES
The primary objective of this study was to determine the interobserver agreement of CRT measurements as measured at the sternum and at the distal phalanx using pressure times of 5 and
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15 seconds and to relate the measurements with hemodynamic characteristics. Our secondary aim was to establish the feasibility of using FMR as a fast, inexpensive and robust method to investigate clinical questions by using the power of social networks and new and
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conventional media to gather as many relevant data as possible in a short period of time.
METHODS
Study Design
This was a nationwide, single-day, “nine-to-five”, multi-center, cross-sectional observational study. Setting up a Flash Mob Research
5
ACCEPTED MANUSCRIPT As in flash mobs, preparations for FMR were made in a small group. The research question and study design were conceived in the Erasmus University Medical Center in Rotterdam, the Netherlands (EMCR). During the duration of the study, the EMCR acted as coordination center.
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A steering committee with members from whole of the Netherlands further elaborated the research question and study protocol. The protocol was approved by the Medical Ethics Committee of the EMCR. Members of the steering committee invited physicians from their professional networks from all eight Dutch university hospitals, and subsequently physicians from affiliated regional
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hospitals to participate, resulting in nationwide participation. In each participating hospital a local investigator, designated “ambassador”, coordinated the study. Ambassadors were either medical
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specialists or residents. Ambassadors obtained local ethical board approval of the protocol, recruited and instructed investigators and were responsible for handling data. In agreement with flash mobs, communication with participating investigators, public and peers was mainly done by email, social
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media and our website.
Setting, patients and variables
On October 29th 2014 between 9.00 AM and 5.00 PM data were simultaneously collected in all
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participating hospitals. Patients aged 18 years and older who were able to give informed consent and who presented to the Emergency Department (ED) or were hospitalized within this period were
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eligible for enrolment. After giving consent, patients were examined independently by two investigators working within a 5 minute interval. Investigators were physicians (medical specialists, residents), nurses and medical students in their clinical rotations. Investigators were instructed on and worked according to standard operating procedures, which described the order of the tests. Investigators measured CRT at two sites twice; the sternum (CRTs) and distal phalanx of the finger (CRTp). First after application of pressure for 5 seconds (CRTs5, CRTp5), and second for 15 seconds (CRTs15, CRTp15). CRTp was measured by applying sufficient pressure at the distal phalanx of the finger with the hand held at heart level to cause blanching of the skin, and CRT was defined as the 6
ACCEPTED MANUSCRIPT time necessary for the skin to regain its color.1 CRTs was measured by applying sufficient pressure to achieve blanching of the skin of the sternum, and again CRT was defined as the time necessary for the skin to regain its color. Investigators were advised to determine CRT by counting and no timing devices were advised, mimicking daily practice. CRT was measured in seconds and results were
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rounded off to the nearest half second. This resolution allowed categorization of the outcome using upper values of normal as suggested in other studies1,5,8, and this method was previously used by Anderson et al.17 Investigators subjectively assessed the peripheral temperature by placing the back
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of the hand on the patients’ hand (cold vs not cold). Investigators gave their subjective conclusion of the patient’s hemodynamic status (adequate vs inadequate) using all available clinical information.
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Investigators also gave their subjective conclusion of the observed CRT (normal vs prolonged), without predefining normality. The subjective conclusion was chosen to resemble daily practice, as clinicians often present measured CRT with a dichotomous outcome. Pulse rate, blood pressure, respiratory rate, temperature and oxygen saturation were measured using local standard
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procedures. All data were entered into local databases, which were subsequently combined at the EMCR. All patients with CRT measured by two investigators were included in the final analysis. Mean arterial pressure (MAP) was calculated and dichotomized (<65 mmHg vs ≥ 65 mmHg). A MAP <65
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mmHg was considered inadequate.22 Pulse rate was categorized in one of the following three: <60 bpm, 60-100 bpm, >100 bpm. CRT was categorized using definitions found in the literature. CRTs5
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and CRTp5 were categorized using the upper limits of normal as defined by Champion8 and age and by Schriger and Baraff.1 For CRTs15 and CRTp15 an upper limit of normal of 4.0 seconds was used.5 Study size
The study size could not be predicted due to the FMR design. In principle, a successful FMR should include a large sample size for reliable conclusions. Statistical Methods Data were summarized in terms of mean, median, 95% confidence intervals (CI) and standard
7
ACCEPTED MANUSCRIPT deviation (SD) when appropriate. Categorical data were analyzed using Chi-squared test. Means of two groups were compared using the student’s t-test (normal distribution) or Mann-Whitney-U test (non-normal distribution); means of three groups were compared using Kruskal-Wallis test. Differences between continuous data with non-normal distribution were analyzed using Wilcoxon
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signed-rank sum test. Interobserver agreement was analyzed for discrete values of CRT using the intraclass correlation coefficient (ICC). In addition, interobserver agreement was analyzed for
categorical values of CRT using the kappa statistics (κ). The variation of CRT with age and sex was
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analyzed using linear regression. Missing data were considered missing at random and were
therefore ignored. A difference of 0.5 seconds between CRTs and CRTp was considered clinically
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relevant.10,17 A p-value < 0.05 was considered statistical significant. Statistical analyses were performed using Statistical Package for the Social Sciences 21.0 (SPSS, SPSS Inc., Chicago, IL, USA). RESULTS Participating hospitals
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A total of 38 hospitals, located all over the Netherlands, participated in the study (representing 45% of the total number of 85 Dutch hospital organizations), including all eight university hospitals, 29
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teaching hospitals (56% of non-academic teaching hospitals) and one non-teaching hospital. Mean inclusion was 46 patients per hospital (median 39, range 3-130). Of the participating hospitals almost
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40% provided data with 24 hours and 76% within one week. All data were available within 19 days. Participating Investigators
A total of 458 investigators participated in the study (33 medical specialists, 246 residents, 122 medical students, and 57 nurses). Mean number of enrolments was 7 patients per investigator (Range 1-65). Most enrolments were done by residents (N=1.916; mean=8), followed by medical students (N=1.096, mean=9), medical specialists (N=288; mean=9) and nurses (N=168; mean=3).
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ACCEPTED MANUSCRIPT Patient characteristics A total of 1.734 patients (3.468 examinations) were included in the study with a slight preponderance of males (51.6%, n=893). Patients overall had a mean age of 65 years. The majority (78.1%) were inpatients. Patient characteristics are presented in table 1.
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Capillary Refill Time
The mean peripheral CRT was 2.3 seconds (CRTp5, SD 1.1) and 2.4 seconds (CRTp15, SD 1.3) and mean
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sternal CRT was 2.6 seconds (CRTs5, SD 1.1) and 2.7 seconds (CRTs15, SD 1.1). CRTp5 was shorter in women (2.2 seconds, SD 1.0) than men (2.4 seconds, SD 1.2 p=0.006) and increased with age (0.16
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seconds per 10 years p<0.001, figure 1). On average, CRTp5 was 0.3 seconds shorter than CRTs5 (p<0.001) and CRTp15 was 0.3 seconds shorter than CRTs15 (p<0.001). CRT correlated positively with MAP, subjective peripheral temperature and subjective assessment of the hemodynamic status. There was no correlation with pulse rate (table 2).
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The mean difference between measurements of the first and second investigator was 0.1 seconds (CRTp5 0.1 seconds (CI 0.0-0.1), CRTp15 0.1 (95% CI 0.0-0.1), CRTs5 0.1 (CI 0.0-0.1), and CRTs15 0.1 (CI 0.0-0.1)). Median difference was 0 seconds in all groups. Interobserver agreement, assessed by
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calculating the ICC between the measurements of CRTp of both investigators was 0.52 (CRTp5, CI 0.49-0.56) and 0.54 (CRTp15, CI 0.50-0.57) (p<0.001), and interobserver agreement on measurements
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of CRTs was 0.43 (CRTs5, CI 0.39-0.47) and 0.46 (CRTs15, CI 0.42-0.49) (p<0.001) (table 3a). The agreement between the two investigators on whether the subjective CRT was normal or prolonged was assessed using the kappa statistics. Application of pressure for 5 seconds yielded a κvalue of 0.40 for CRTp (CI 0.36-0.45) and 0.30 for CRTs (CI 0.26-0.35) (both fair agreement)23 when using 2 seconds as the upper value of normal, and a κ-value of 0.20 for CRTp (CI 0.12-0.29) and 0.13 for CRTs (CI 0.04-0.22) (both slight agreement)23 when using upper limits of normal based on age and sex. Using 4 seconds as the upper value of normal after application of 15 seconds of pressure yielded
9
ACCEPTED MANUSCRIPT a κ-value of 0.32 for CRTp (CI 0.24-0.41) measurements and 0.23 for CRTs measurements (CI 0.150.31) (both fair agreement).23 Agreement between two investigators on the subjective conclusion of whether the CRT was normal or prolonged yielded a κ-value of 0.44 (CI 0.37-0.51) (moderate agreement) (table 3b).23
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DISCUSSION
Our nationwide, single-day, “nine-to-five”, multi-center, cross-sectional observational study is the first to study the interobserver agreement of four frequently used methods to measure CRT.
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These measurements were performed in a setting specifically designed to resemble daily practice at the ED and the ward, with two observers using identical methods under similar conditions. CRT
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measurement had slight to moderate agreement at best using a dichotomous outcome (normal vs prolonged), and moderate correlation using a continuous outcome (seconds). To be of use in clinical practice the interpretation of the results of CRT measurements should be easily reproducible. To date, there are only three studies in adults that report on interobserver
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agreement of CRT measurement at the distal phalanx after 5 seconds of pressure.17-19 These studies show moderate agreement at best. In only one study CRT was measured without a timing device.17 The other studies either showed a video with CRT18 or used healthy volunteers in controlled
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circumstances, and CRT was determined with a chronometer or a video,19 which does not reflect the
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worldwide use and interpretation of CRT in daily practice.9 To our knowledge, our study was the first to study the optimal site and duration of pressure
for CRT measurement in adults. As expected, our study shows a correlation between the CRT measured at the distal phalanx and sternum. CRT measured at the distal phalanx is shorter than measured at the sternum, as is found in children,10 and we conclude that phalanx and sternum cannot be used interchangeably. The interobserver agreement on CRT was higher for the distal phalanx then sternum. A prolonged application of pressure (15 seconds), as used solely in the ICU, only resulted in a slightly higher interobserver correlation. Application of pressure for 5 seconds at 10
ACCEPTED MANUSCRIPT the distal phalanx is easier to use, and most studies on CRT in the ED and the ward use 5 seconds application of pressure.5,12 Therefore, based on our findings we recommend uniform use of CRT, and propose that CRT should only be measured at the distal phalanx with 5 seconds of pressure. But why measure CRT? CRT was introduced by Beecher in World War II to identify shock in
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battlefield survivors,24 and nowadays, it is still used to assess the peripheral circulation and in early detection of shock.2,6 Although our study showed correlation between CRT and a MAP under 65 mmHg, we showed no correlation between CRT and an abnormal pulse rate, which is an early
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indicator of shock. In the detection of shock in its early stages, the additional value of CRT seems limited, which is supported by previous research.15,25 However, some studies show the predictive
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value of CRT on long-term and short-term mortality. In a retrospective study on oncology patients a prolonged CRT (≥2 seconds) was predictive for both CCU admission and 30 day mortality.3 A prospective study in ED patients found that a prolonged CRT as a continuous variable was associated with an increased risk of mortality at 1 and 7 days.4
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With our study we also showed the power of FMR study design and its potential as a methodological tool for clinical research. When compared with conventional studies, FMR has
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multiple similarities. In preparation of the study, FMR requires the same steps in designing and setting up (e.g. protocol development, ethical board approval, instruction of collaborators).
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However, FMR showed many additional advantages. It facilitated inclusion of large numbers of patients from multiple centers – and the resulting data – within a short period of time. The inspiring and new research method combined with an appealing research question led to high participation of hospitals. FMR also encouraged all the members of the medical team to participate in research. Most investigators in our study and almost half of the ambassadors were residents, who are often mainly focused on patient care and otherwise not regular participants of research. FMR engaged them in the process of research and exposed them to its various aspects. All these advantages come with limited time investment and low costs.
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ACCEPTED MANUSCRIPT Our study has limitations. Given the cross-sectional nature of this study no follow up data was collected. Therefore no associations with outcomes of disease, including mortality were examined. Data collection was done in standardized procedures after standardized instructions, however given the large number of centers and investigators it is inevitable that small differences
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exist in the collection of data. Many of the collected variables are subjective and therefore subject to interpretation and can be influenced by the clinical experience of the investigator. The application of pressure could differ between investigators, which could also affect CRT. In children, light pressure
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resulted in shorter CRT2, but in adults this effect has not been studied. We propagated counting, instead of using timing devices, to a resolution of a half second, which could have led to lower
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agreement. Since the mean difference between all measurements was 0.1 second, the influence on our results was little, while it enabled us to compare various upper limits of normal. We think that our study represents how CRT is used as a bedside test in daily practice worldwide, with all its shortcomings that hinder its users. Also, with 45% of the Dutch hospital organizations involved, our
Conclusions
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results are generalizable.
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Based on the results of our study, especially the low interobserver agreement on a test that is difficult to standardize, combined with the currently available evidence, we conclude that the
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value of CRT in clinical practice is limited, and its routine use should be reconsidered. When CRT is used, it should be measured at the distal phalanx after applying pressure for 5 seconds. The practice of using the sternum as site for CRT measurement should be discarded. In addition, the FMR methodology proved to be an inexpensive, quick and reliable method
to investigate “simple” clinical questions. We used FMR to recruit 1.734 participants in a single day, and the majority of the data were ready for analysis within 24 hours. We therefore believe this study exemplifies the power of FMR.
12
ACCEPTED MANUSCRIPT Guarantor Jelmer Alsma takes responsibility for the content of the manuscript, including data and analysis Author Contributions
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JA and SS conceived and designed the study. JA, PN, IS, AB, MB, FH, JL, PS, KK, HH, and FB were locally responsible for the coordination of the study and recruited investigators in the region. JA nationally coordinated the study. JA, JS and SS wrote the first draft of the manuscript. JA, JS, PN, IS,
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AB, MB, FH, JL, PS, KK, HH, FB, and SS contributed to the writing of the manuscript. JA, JS, PN, IS, AB,
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MB, FH, JL, PS, KK, HH, FB, and SS agree with manuscript results and conclusions. * The collaborators of the FAMOUS study group: 1
2
3
4
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
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Department of Internal Medicine, Albert Schweitzer Hospital, Albert Schweitzerplaats 25, 3318 AT Dordrecht, the Netherlands Department of Internal Medicine, Amphia Hospital, Langendijk 75, 4819 EV Breda, the Netherlands Department of Internal Medicine, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, the Netherlands Department of Internal Medicine, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, the Netherlands Department of Internal Medicine, Diakonessen Hospital , Bosboomstraat 1, 3582 KE, Utrecht, the Netherlands Department of Internal Medicine, Elkerliek hospital, Wesselmanlaan 25, 5707 HA, Helmond, the Netherlands Department of Internal Medicine, Gelre Hospitals Apeldoorn, Albert Schweitzerlaan 31, 7334 DZ, Apeldoorn, the Netherlands Department of Internal Medicine, Groene Hart Hospital, Bleulandweg 10, 2803 HH Gouda, the Netherlands Department of Internal Medicine, Harbour Hospital & Institute for Tropical Diseases, Haringvliet 2, 3011 TD Rotterdam, the Netherlands Department of Internal Medicine, IJsselland Hospital, Prins Constantijnweg 2, 2906 ZC, Capelle aan den Ijssel, the Netherlands Department of Internal Medicine, Ikazia hospital, Montessoriweg 1, 3083 AN, Rotterdam, the Netherlands Department of Internal Medicine, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, the Netherlands Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, the Netherlands Department of Emergency Medicine, Maashospital Pantein, Dokter Kopstraat 1, 5835 DV, Beugen, the Netherlands Department of Emergency Medicine, Martini Hospital, Van Swietenplein 1, 9728 NT, Groningen, the Netherlands Department of Internal Medicine, Máxima Medical Centre, Dominee Theodor Fliednerstraat 1, 5631 BM, Eindhoven, the Netherlands Department of Emergency Medicine, Medical Center Leeuwarden, Henri Dunantweg 2, 8934 AD, Leeuwarden, the Netherlands Department of Internal Medicine, Medisch Spectrum Twente, Haaksbergerstraat 55, 7513 ER, Enschede, the Netherlands Department of Internal Medicine, Reinier de Graaf Group of Hospitals, Reinier de Graafweg 3-11, 2625AD, Delft, the Netherlands Departement of Internal Medicine, Rode Kruis Ziekenhuis, Vondellaan 13, 1942 LE, Beverwijk, the Netherlands Department of Internal Medicine, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, the Netherlands Department of Internal Medicine, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE, Amsterdam, the Netherlands Department of Internal Medicine, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, the Netherlands
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1. 2. 3. 4. 5. 6. 7. 8. 9.
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Joris J Arends MD , Gerba Buunk MD, PhD , Bart JA Veldman MD , Heidi SM Ammerlaan MD , Sanjay UC Sankatsing MD, 5 6 7 8 9 10 PhD , Esther MG Jacobs MD , Thomas van Bemmel MD , Rikje Ruiter MD PhD , Eva MT Bots MD , Ralf A Reuters MD , 11 12 13 14 Ginette Carels MD , Sabine HA Diepeveen MD , Anne Floor N Heitz MD , TT Hien van Leeuwen-Nguyen MD , Pim AJ 15 16 17 18 19 Keurlings MD , Renske Barnhard MD , Rachel HP Schreurs MD , Ewoud ter Avest MD , Hans S Brink MD, PhD , 20 21 22 23 Caroline MJ van Kinschot MD , Niels van der Hoeven MD , Mark A van der Zijden MD , Ilse MG Hageman MD , Timo C 24 25 26 27 28 Roeleveld MD , Carolijn MC Klomp MD , Douwe Dekker MD , Anneke Blom MD , Hilde M Wesselius MD , Marieke M 29 30 31 32 32 van Bemmel MD , Ben de Jong MD , Judith Hillen MD , Ginger-Beau Langbroek , Sandra de Bie MD PhD
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ACCEPTED MANUSCRIPT 25. 26. 27. 28. 29. 30. 31. 32.
Department of Internal Medicine, Elisabeth Tweesteden Hospital, Doctor Deelenlaan 5, 5042 AD, Tilburg, the Netherlands Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands Department of Emergency Medicine, Wilhelmina Hospital, Europaweg-Zuid 1, 9401 RK Assen, the Netherland Department of Internal Medicine, Zaandam Medical Center, Koningin Julianaplein 58, 1502 DV, Zaandam, the Netherlands Department of Internal Medicine, Amstelland Hospital, Laan van de Helende Meesters 8, 1186 AM, Amstelveen, the Netherlands Department of Internal Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP, Ede, the Netherlands Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD, Arnhem, the Netherlands Department of Internal Medicine, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, the Netherlands
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JJA, GB, BV, HA, SUS, EJ, TB, RR, EB, RR, GC, SD, AH, HL, PK, RB, RS, EA, HB, CK, NH, MZ, IH, TC, CMK, DD, AB, HW, MMB, BJ, JH were ambassadors and were responsible for local coordination of the study, local approval of the protocol, recruitment and instruction of investigators, collecting and
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processing data. SB and GBL were involved in design and testing of the study protocol. All
collaborators critically read the manuscript. All collaborators agree with manuscript results and
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conclusions.
Funding
None Acknowledgments
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Declaration of interests
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None
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We thank all participating patients, investigators and hospitals for their contribution. References 1. 2. 3. 4.
Schriger DL, Baraff L. Defining normal capillary refill: variation with age, sex, and temperature. Ann Emerg Med. 1988;17(9):932-935. Pickard A, Karlen W, Ansermino JM. Capillary refill time: is it still a useful clinical sign? Anesth Analg. 2011;113(1):120-123. Cooksley T, Kitlowski E, Haji-Michael P. Effectiveness of Modified Early Warning Score in predicting outcomes in oncology patients. QJM. 2012;105(11):1083-1088. Mrgan M, Rytter D, Brabrand M. Capillary refill time is a predictor of short-term mortality for adult patients admitted to a medical department: an observational cohort study. Emerg Med J. 2014;31(12):954-958.
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13. 14. 15. 16. 17. 18. 19.
20. 21. 22.
23. 24. 25.
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10.
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9.
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8.
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6. 7.
Lima A, Jansen TC, van Bommel J, Ince C, Bakker J. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med. 2009;37(3):934938. Lockey. Advanced Life Support ERC 2010 Edition. Beecher HK, Simeone FA, et al. The internal state of the severely wounded man on entry to the most forward hospital. Surgery. 1947;22(4):672-711. Champion HR, Sacco WJ, Carnazzo AJ, Copes W, Fouty WJ. Trauma score. Crit Care Med. 1981;9(9):672-676. Lobos AT, Menon K. A multidisciplinary survey on capillary refill time: Inconsistent performance and interpretation of a common clinical test. Pediatr Crit Care Med. 2008;9(4):386-391. Crook J, Taylor RM. The agreement of fingertip and sternum capillary refill time in children. Arch Dis Child. 2013;98(4):265-268. King D, Morton R, Bevan C. How to use capillary refill time. Arch Dis Child Educ Pract Ed. 2014;99(3):111-116. van Genderen ME, Lima A, Akkerhuis M, Bakker J, van Bommel J. Persistent peripheral and microcirculatory perfusion alterations after out-of-hospital cardiac arrest are associated with poor survival. Crit Care Med. 2012;40(8):2287-2294. Anderson B, Kelly AM, Kerr D, Clooney M, Jolley D. Impact of patient and environmental factors on capillary refill time in adults. Am J Emerg Med. 2008;26(1):62-65. McGee S, Abernethy WB, 3rd, Simel DL. The rational clinical examination. Is this patient hypovolemic? JAMA. 1999;281(11):1022-1029. Schriger DL, Baraff LJ. Capillary Refill - Is It a Useful Predictor of Hypovolemic States. Annals of Emergency Medicine. 1991;20(6):601-605. Lewin J, Maconochie I. Capillary refill time in adults. Emerg Med J. 2008;25(6):325-326. Anderson B, Kelly A, Kerr D, Jolley D. Capillary refill time in adults has poor inter-observer agreement. Hong Kong Journal of Emergency Medicine. 2008;15:71-74. Brabrand M, Hosbond S, Folkestad L. Capillary refill time: a study of interobserver reliability among nurses and nurse assistants. Eur J Emerg Med. 2011;18(1):46-49. Espinoza ED, Welsh S, Dubin A. Lack of agreement between different observers and methods in the measurement of capillary refill time in healthy volunteers: an observational study. Rev Bras Ter Intensiva. 2014;26(3):269-276. Semler MW, Stover DG, Copland AP, et al. Flash mob research: a single-day, multicenter, resident-directed study of respiratory rate. Chest. 2013;143(6):1740-1744. Longman Dictionary of Contemporary English. http://www.ldoceonline.com/dictionary/flashmob. Last visited on August 16th 2016 Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228. Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37(5):360-363. Beecher HK. The specialty of anesthesia and its application in the Harvard UniversityMassachusetts General Hospital Department. Ann Surg. 1947;126(4):486-499. McGee S, Abernethy WB, Simel DL. Is this patient hypovolemic? Jama-J Am Med Assoc. 1999;281(11):1022-1029.
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5.
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ACCEPTED MANUSCRIPT Male N= 894 Female N= 840
Total N=1734
(48.4%)
65 (16)
65 (18)
65 (17)
Systolic blood pressure in mmHg * (n=1728)
131 (21)
133 (23)
132 (22)
Diastolic blood pressure in mmHg† (n=1728)
75 (12)
72(13)
173 (13)
Mean arterial pressure* (n=1728)
93 (14)
Pulse frequency per minute‡ (n=1731)
79 (16)
Age in years* (n=1734)
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(51.6%)
92 (14)
93 (14)
81 (16)
80 (16)
96 (3)
96 (3)
96 (3)
Respiratory rate per minute* (n=1598)
17 (4)
16 (4)
17 (4)
36.8 (0.7)
36.9 (0.7)
36.9 (0.7)
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Temperature in degrees centigrade† (n=1723)
Table 1: Characteristics of patients. Mean (SD)
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*: not significant, †: p < 0.001, ‡ p=0.008
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Oxygen saturation in percentage* (n=1628)
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CRTp15 2.4
95% CI 2.4-2.5
Cold Warm p-value*
3.2 2.1 p<0.001
3.0-3.4 2.1-2.2
3.3 2.3 p<0.001
3.1-3.6 2.2-2.3
95% CI 2.5-2.6
CRTs15 2.7
95% CI 2.7-2.8
2.5-2.6 2.8-3.1
3.0 2.6 p<0.001
2.9-3.2 2.6-2.7
Inadequate Adequate p-value*
3.2 2.2 p<0.001
2.8-3.5 2.2-2.3
3.6 2.4 p<0.001
3.1- 4.2 2.3-2.4
3.2 2.6 p<0.001
2.9-3.5 2.5-2.6
3.5 2.7 p<0.001
3.2-3.8 2.6-2.7
<65 >=65 p-value*
3.0 2.3 p=0.001
2.6-3.5 2.2-2.3
3.3 2.4 p<0.001
2.7-3.9 2.3-2.5
3.4 2.6 p=0.01
2.7-4.1 2.5-2.6
3.6 2.7 p=0.002
3.0-4.2 2.6-2.7
<60 60-100 >100 p-value**
2.3 2.3 2.2 p= 0.407
2.1-2.5 2.2-2.3 2.0-2.4
2.6 2.4 2.4 p=0.397
2.3-2.9 2.3-2.5 2.2-2.6
2.6 2.6 2.6 p=0.800
2.5-2.9 2.5-2.6 2.4-2.7
2.8 2.7 2.7 p=0.862
2.5-3.0 2.6-2.8 2.5-2.9
Prolonged Normal p-value *
3.5 2.1 p<0.001
3.9 2.2 p<0.001
3.6-4.1 2.2-2.3
3.6 2.5 p<0.001
3.4-3.7 2.4-2.5
3.8 2.6 p<0.001
3.6-4.0 2.5-2.6
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Subjective hemodynamic status
EP
AC C
Subjective conclusion of the CRT
TE D
Mean arterial pressure in mmHg
Pulse rate per minute
3.3-3.7 2.1-2.1
CRTs5 2.6
RI PT
95% CI 2.2-2.3
2.9 2.5 p<0.001
SC
CRTp5 2.3
Total Subjective peripheral temperature
ACCEPTED MANUSCRIPT
Temperature in degrees centigrade 2.4-2.9 2.2-2.3 1.9-2.5
2.8 2.4 2.5
0.003
0.002
2.6-3.1 2.3-2.5 2.1-2.8
2.6 2.6 2.5
RI PT
p-value**
2.6 2.3 2.2
0.907
SC
<36 36-38 >38
2.4-2.8 2.5-2.6 2.3-2.8
2.8 2.7 2.7
2.5-3.0 2.6-2.8 2.4-3.0
0.870
AC C
EP
TE D
M AN U
Table 2: Mean capillary refill times. Abbreviations: CRT: capillary refill time. CRTp5: peripheral capillary refill time, application of pressure 5 s. CRTp15: peripheral capillary refill time, application of pressure 15 seconds CRTs5: sternal capillary refill time, application of pressure 5 s. CRTs15: sternal capillary refill time, application of pressure 15 seconds. 95% CI 95% confidence interval of the mean (lower bound and upper bound) * Determined by Mann-Whitney-U test ** Difference between groups as determined by Kruskal-Wallis test
ACCEPTED MANUSCRIPT
Intraclass correlation coefficient 0.52 0.54 0.43 0.46
Interpretation Moderate correlation Moderate correlation Low correlation Low correlation
RI PT
CRTp5 CRTp15 CRTs5 CRTs15
95% Confidence interval (lower and upper bound) 0.49-0.56 0.50-0.57 0.39-0.47 0.42-0.49
Table 3a: Agreement between two investigators assessed using intraclass correlation coefficient. All results p<0.001
AC C
EP
TE D
M AN U
SC
Abbreviations: CRT: capillary refill time, p: peripheral, s: sternal, 5: 5 seconds, 15: 15 seconds.
ACCEPTED MANUSCRIPT
CRTp5, upper range of normal 2 seconds CRTs5, upper range of normal 2 seconds
0.40
95% Confidence interval (lower and upper bound) 0.36 – 0.45
0.30
0.26-0.35
fair agreement
CRTp5, upper range of normal based on age and gender CRTs5, upper range of normal based on age and gender
0.20
0.12 – 0.29
slight agreement
0.13
0.04 – 0.22
CRTp15, upper range of normal of 4 seconds CRTs15, upper range of normal of 4 seconds
0.32
0.24 – 0.41
0.23
0.15 – 0.31
0.44
0.37 – 0.51
Interpretation fair agreement
RI PT
M AN U
Subjective conclusion on CRT
SC
kappa statistics
slight agreement
fair agreement
fair agreement
moderate agreement
Table 3b: Agreement between two investigators assessed using kappa statistics.
AC C
EP
TE D
Abbreviations: CRT: capillary refill time, p: peripheral, s: sternal, 5: 5 seconds, 15: 15 seconds. All results p <0.001
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
Figure 1: Mean Capillary Refill Time in seconds for different age categories in years Abbreviations:
AC C
EP
CRT: Capillary Refill Time. P5: Peripheral measurement after application of pressure for 5 seconds. S5: Sternal measurement after application of pressure for 5 seconds. P15: Peripheral measurement after application of pressure for seconds. S15: Sternal measurement after application of pressure for 15 seconds.
ACCEPTED MANUSCRIPT Abbreviation list kappa statistics
5s
5 seconds of pressure
15s
15 seconds of pressure
ALS
Advanced Life Support
ANOVA
Analysis of variance
BPM
Beats per minute
CI
95% confidence intervals
CRT
Capillary refill time
CRTs
Capillary refill time measured at the sternum
CRTp
Capillary refill time measured at the distal phalanx of the finger
ED
Emergency Department
EMCR
Erasmus University Medical Center, Rotterdam, The Netherlands
FMR
Flash Mob Research
ICC
Intraclass Correlation Coefficient
ICU
Intensive Care Unit
MAP
Mean Arterial Pressure
N
Number
SD
Standard Deviation
M AN U
TE D
EP
AC C
SC
RI PT
κ