Dhar, R

Inwald, DP

Nadel, S

Noren, DP

Peters, MJ

Ray, S

Rogers, L

UCL Discovery

Intensive Care Medicine Risk of over-diagnosis of hypotension in children: a comparative analysis of over 50000blood pressure measurements--Manuscript Draft-- Manuscript Number: ICME-D-17-00551Full Title: Risk of over-diagnosis of hypotension in children: a comparative analysis of over50000 blood pressure measurementsArticle Type: LetterFunding Information:Corresponding Author: Samiran Ray, MBBChir, MAUniversity College London Institute of Child HealthLondon, UNITED KINGDOMCorresponding Author SecondaryInformation:Corresponding Author's Institution: University College London Institute of Child HealthCorresponding Author's SecondaryInstitution:First Author: Samiran Ray, MBBChir, MAFirst Author Secondary Information:Order of Authors: Samiran Ray, MBBChir, MALibby RogersDavid P Noren, PhDRanjana Dhar, MBBSSimon Nadel, MDMark J Peters, MBChB, PhDDavid P Inwald, MBBS, PhDOrder of Authors Secondary Information:Author Comments: Dear Editor,Thank you for your consideration of the manuscript entitled 'Risk of over-diagnosis ofhypotension in children: a comparative analysis of over 50000 blood pressuremeasurements'.We have previously presented these data to ICM in an Original Paper format (ICME-D-16-01926). We believe the size of the sample makes these data robust. we would begrateful for your consideration of the data presented more succinctly as a Letter, with asimple but powerful message regarding standard monitoring systems used inpaediatric intensive care systems worldwide. We have also re-presented the data visually, with more information presented on thehypotensive cohort.Thank youSuggested Reviewers:Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationRisk of over-diagnosis of hypotension in children: a comparative analysis of over 50000 blood pressure measurements  Samiran Ray1,2 MBBChir, Libby Rogers3 MMath, David P Noren4 PhD, Ranjana Dhar2 MBBS, Simon Nadel5 MD, Mark J Peters1,2 PhD, David P Inwald5 PhD    Author affiliations: 1 Respiratory, Critical Care and Anaesthesia Section, UCL GOS Institute of Child Health, London, UK 2 Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Trust, London, UK 3 UCL Clinical Operations Research Unit, University College London, London, UK 4 Philips Research North America, Cambridge, MA 02141, USA 5 Paediatric Intensive Care Unit, St Mary’s Hospital, Imperial College London NHS Trust, London, UK  Corresponding author: Samiran Ray Respiratory, Critical Care & Anaesthesia Section, UCL GOS Institute of Child Health, 30 Guildford Street, London, UK WC1N 1EH  Phone: 02074059200 ext 0032 Fax: 02078138206 Reprints not requested Funding information: No direct funding was received for this study. Part of this work was undertaken at UCL GOS Institute of Child Health, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme. Keywords: blood pressure; children; hypotension; monitoring; critical care  Manuscript Click here to download Manuscript manuscript ICM.docx Click here to view linked References 1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Maintaining a ‘normal’ blood pressure (BP) and avoiding hypotension are key goals in critically-ill children [1]. Invasive arterial blood pressure (IABP) and non-invasive oscillometric blood pressure (NIBP) measurements are typically used interchangeably despite reports of bias and lack of precision [2-5].  We compared concurrently recorded IABP and NIBP in 2 paediatric intensive care units (PICUs). Data were collected from 2 sources: (a) the electronic health record (EHR) (Intellivue Critical Care and Anaesthesia, Philips Electronics, Netherlands), typically recorded each hour (April 2009-October 2015 from one PICU; April 2012-December 2015 from the other), and (b) from the Etiometry T3 (Etiometry Inc., MA, USA) system, recorded directly from the patient bedside monitor at 5-second intervals (June 2015-June 2016) in one PICU. While concurrence of measurement is assumed from EHR data, this is guaranteed using high-resolution monitor data.  After exclusion of ‘out-of-range’ values (systolic measurements <30 mmHg and >250 mmHg, diastolic measurements <10 mmHg and >200 mmHg, and corresponding mean values), EHR data were available from 2459 children, with pairs of 49404 mean, 50397 systolic, and 50266 diastolic BP values.  NIBP gave systematically lower readings for mean and diastolic BP than corresponding IABP. Although statistically systolic NIBP were higher than IABP readings, the difference lacked clinical significance. The biases (mean NIBP-IABP) were as follows: mean BP -9.2 mmHg (95%CI -9.3 to -9.1 mmHg, p<1 x 10-11), systolic BP 1.0 mmHg (95%CI 0.8 to 1.1 mmHg, p<1 x 10-11), diastolic BP -8.7 mmHg (95%CI -8.8 to -8.6 mmHg, p<1 x 10-11) (Figure; diastolic data in Electronic Supplementary Material). Precision, i.e. the 95% limits of agreement (interval within which 95% of NIBP-IABP values lie), was poor: -31.8 and 13.4 mmHg for mean BP; -30.9 and 32.8 mmHg for systolic BP and -32.4 and 15.1 mmHg for diastolic BP. High-resolution T3 data from 253 children confirmed these findings (Electronic Supplementary Material). A multi-level linear regression model failed to reveal a simple relationship between patient age, weight or vaso-active medication use and bias.  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 The main utility of BP monitoring in intensive care is to detect and respond to hypotension. If IABP is considered as gold standard and hypotension defined as age-defined systolic BP <5th centile, NIBP has poor positive predictive value (58.2%, 95%CI 57.3-59.1%) but good negative predictive value (86.1%, 95%CI 85.8-86.5%) in detecting hypotension. While a ‘normal’ NIBP value is useful in ruling out hypotension, treating hypotension based on an NIBP value can lead to over-treatment over 40% of the time. The rule-in value of NIBP can be increased by repeating NIBP measurements. Using Bayes theory (pre-test odd x likelihood ratio = post-test odds), 3 successive measurements of systolic NIBP <5th centile increases the likelihood of the corresponding IABP being <5th centile to 96.3% (pre-test odds of 0.31 x likelihood ratio of 4.423 = post-test odds of 21, or post-test probability of 96.3%). These data demonstrate that use of low NIBP measurements in isolation to guide treatment for hypotension in children could lead to over-treatment. Prospective studies of vital sign targets in critically-ill children are urgently needed.   Ethical approval and consent to participate: Ethical approval was not sought as we used routinely collected clinical data retrospectively. Consent to participate was not sought as this is a retrospective observational study and no patient identifiable data are presented.  Consent to publish: Consent was not sought as no patient identifiable data are reported. Availability of data and materials: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Competing interest: The authors declare that they have no conflict of interest. Author’s contributions: SR, MJP, SN and DPI conceived and designed the study; SR, LR, RD and DPN collected and verified the data; SR and LR analysed the data. SR and DPI drafted the manuscript, all authors contributed to and approved the final version of the manuscript. Acknowledgements: Not applicable  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Authors’ information: DPI is the chief investigator and MJP and SN are co-investigators on the UK NIHR funded Fluids in Shock (FiSh) external pilot trial (IRAS 195544)    1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 References: 1. Brierley J, Carcillo JA, Choong K et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009;37:666–688 2. Joffe R, Duff J, Garcia Guerra G, et al. The accuracy of blood pressure measured by arterial line and non-invasive cuff in critically ill children. Crit Care. 2016 Jun 8;20(1):177. 3. Holt TR, Withington DE, Mitchell E. Which pressure to believe? A comparison of direct arterial with indirect blood pressure measurement techniques in the pediatric intensive care unit. Pediatr Crit Care Med. 2011 Nov;12(6):e391-4.  4. Clark JA, Lieh-Lai MW, Sarnaik A, et al. Discrepancies between direct and indirect blood pressure measurements using various recommendations for arm cuff selection. Pediatrics. 2002 Nov;110(5):920-3. 5. Meyer S, Sander J, Gräber S, et al. Agreement of invasive versus non-invasive blood pressure in preterm neonates is not dependent on birth weight or gestational age. J Paediatr Child Health. 2010 May;46(5):249-54.   Figure: Bland-Altman plot of systolic (left) and mean (right) blood pressures using electronic health record data. For systolic blood pressure, non-invasive measurements have a low systematic bias (red line) (1.0 mmHg, 95%CI 0.8 to 1.1 mmHg, p<1 x 10-11), but show poor precision, with 95% limits of agreement (blue lines) being -30.9 and 32.8 mmHg. The green dots show non-invasive measurements that were <5th centile for age (assuming 50th centile height as these data were not available). There is a skew towards negative values in this sub-population, demonstrating that non-invasive measurements tend to under-read blood pressure in the hypotensive range. For mean blood pressure, the bias is clinically significant (-9.2 mmHg, 95%CI -9.3 to -9.1 mmHg, p<1 x 10-11), with equally poor precision (95% limits of agreement -31.8 and 13.4 mmHg). The green dots  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 represent non-invasive measurements <5th centile for age (and 50th centile of height): as with systolic measurements there is a skew towards negative values.  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Figure Click here to download Figure Figure.tif   Figure ESM1Click here to access/downloadSupplementary MaterialFigure ICM ESM1.tif  Supplementary MaterialClick here to access/downloadSupplementary MaterialFigure ICM ESM2.tif

Risk of over-diagnosis of hypotension in children: a comparative analysis of over 50,000 blood pressure measurements

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