The Dose Response Multicentre Investigation on Fluid Assessment (DoReMIFA) in critically ill patients

Garzotto et al. Critical Care (2016) 20:196 DOI 10.1186/s13054-016-1355-9 RESEARCH Open Access The Dose Response Multicentre Investigation on Fluid Assessment (DoReMIFA) in critically ill patients F. Garzotto1,2*, M. Ostermann3, D. Martín-Langerwerf4, M. Sánchez-Sánchez5, J. Teng6, R. Robert7, A. Marinho8, M. E. Herrera-Gutierrez9, H. J. Mao10, D. Benavente11, E. Kipnis12, A. Lorenzin2, D. Marcelli13, C. Tetta13, C. Ronco1,2 and for the DoReMIFA study group Abstract Background: The previously published “Dose Response Multicentre International Collaborative Initiative (DoReMi)” study concluded that the high mortality of critically ill patients with acute kidney injury (AKI) was unlikely to be related to an inadequate dose of renal replacement therapy (RRT) and other factors were contributing. This follow-up study aimed to investigate the impact of daily fluid balance and fluid accumulation on mortality of critically ill patients without AKI (N-AKI), with AKI (AKI) and with AKI on RRT (AKI-RRT) receiving an adequate dose of RRT. Methods: We prospectively enrolled all consecutive patients admitted to 21 intensive care units (ICUs) from nine countries and collected baseline characteristics, comorbidities, severity of illness, presence of sepsis, daily physiologic parameters and fluid intake-output, AKI stage, need for RRT and survival status. Daily fluid balance was computed and fluid overload (FO) was defined as percentage of admission body weight (BW). Maximum fluid overload (MFO) was the peak value of FO. Results: We analysed 1734 patients. A total of 991 (57 %) had N-AKI, 560 (32 %) had AKI but did not have RRT and 183 (11 %) had AKI-RRT. ICU mortality was 22.3 % in AKI patients and 5.6 % in those without AKI (p < 0.0001). Progressive fluid accumulation was seen in all three groups. Maximum fluid accumulation occurred on day 2 in N-AKI patients (2.8 % of BW), on day 3 in AKI patients not receiving RRT (4.3 % of BW) and on day 5 in AKI-RRT patients (7.9 % of BW). The main findings were: (1) the odds ratio (OR) for hospital mortality increased by 1.075 (95 % confidence interval 1. 055–1.095) with every 1 % increase of MFO. When adjusting for severity of illness and AKI status, the OR changed to 1. 044. This phenomenon was a continuum and independent of thresholds as previously reported. (2) Multivariate analysis confirmed that the speed of fluid accumulation was independently associated with ICU mortality. (3) Fluid accumulation increased significantly in the 3-day period prior to the diagnosis of AKI and peaked 3 days later. Conclusions: In critically ill patients, the severity and speed of fluid accumulation are independent risk factors for ICU mortality. Fluid balance abnormality precedes and follows the diagnosis of AKI. Keywords: Fluid overload, RRT, AKI, Critical illness, ICU * Correspondence: 1 Department of Nephrology Dialysis and Transplantation, San Bortolo Hospital, 37 Via Rodolfi, 36100 Vicenza, Italy 2 International Renal Research Institute of Vicenza (IRRIV), San Bortolo Hospital, 37 Via Rodolfi, 36100 Vicenza, Italy Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Garzotto et al. Critical Care (2016) 20:196 Background Renal replacement therapy (RRT) constitutes a key component of modern critical care, together with mechanical ventilation, fluid resuscitation and vasopressor support. The main reasons for initiation are acute kidney injury (AKI) and fluid overload (FO). There is growing evidence that FO is harmful and associated with a longer hospital stay and increased morbidity and mortality [1–3]. FO may be present at admission or develop during ICU stay due to a combination of oliguria and liberal fluid administration leading to a positive fluid balance [4, 5]. FO accounts for an increased risk of death in patients with AKI [6, 7]. Furthermore, fluid accumulation itself may be independently associated with an increased risk of developing AKI and mortality. In a secondary analysis of the SOAP study, Payen et al. showed that the average daily fluid balance in the first 7 days was significantly more positive in patients with AKI [1]. Bouchard et al. demonstrated that crude mortality was higher in AKI patients when fluid overload was present [8]. Subsequent studies confirmed that both, severity of FO and the number of days spent with FO, were risk factors for poor outcome. We previously published a prospective cohort observational study, the “Dose Response Multicentre International Collaborative Initiative (DoReMi)” [9], which evaluated the practice of continuous renal replacement therapy (CRRT) in patients in the intensive care unit (ICU). The study confirmed that in spite of a discrepancy (−25 %) between effective (27 ml/kg/h) and prescribed (34 ml/kg/h) dose, the median delivered dose was considered adequate based on two recent large trials (RCTs) [10, 11]. The DoReMi study therefore concluded that the high mortality observed in AKI patients was not related to inadequate treatment dose but to other possible factors instead. The “Dose Response Multicentre Investigation on Fluid Assessment (DoReMIFA)” study is an evolution of the previous DoReMi study. It aimed to prospectively evaluate the practice of fluid management in the ICU, including patients with AKI (AKI) and without AKI (N-AKI), and patients with AKI treated with RRT (AKI-RRT) in different ICUs (in Europe, the Far East and Latin America). The main objective of this study was to investigate whether fluid balance throughout ICU stay and during RRT affects mortality of ICU patients. Data collection and analysis was facilitated by the use of electronic medical records and web-based case report forms (CRFs). Methods The study protocol was made available for review to ICU physicians from different countries. Once the ICU was enrolled in the research group, data were collected for all admitted patients for 3 consecutive months, in the period between April 2012 and September 2014 Page 2 of 14 using an electronic case report form. Exclusion criteria were (a) age <18 years or >85 years; (b) chronic dialysis; (c) short-term postoperative admission; (d) life expectancy less than 48 h; (e) need for extracorporeal membrane oxygenation (ECMO) within the first 48 h of ICU stay. All types of ICUs were eligible on voluntary basis within the indicated period. Local ethics committees ap (...truncated)