# Fluid challenge in critically ill patients receiving haemodynamic monitoring: a systematic review and comparison of two decades

Antonio Messina, Lorenzo Calabrò, Luca Pugliese, Aulona Lulja, Alexandra Sopuch, Daniela Rosalba, Emanuela Morenghi, Glenn Hernandez, Xavier Monnet, Maurizio Cecconi

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Antonio Messina, Lorenzo Calabrò, Luca Pugliese, Aulona Lulja, Alexandra Sopuch, et al. Fluid challenge in critically ill patients receiving haemodynamic monitoring: a systematic review and comparison of two decades. Critical Care, 2022, 26 (1), pp.186. 10.1186/s13054-022-04056-3. hal-04521666

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# Fluid challenge in critically ill patients receiving haemodynamic monitoring: a systematic review and comparison of two decades

Antonio Messina<fnref n="1" />,²*, Lorenzo Calabrò<fnref n="1" />, Luca Pugliese<fnref n="1" />, Aulona Lulja<fnref n="1" />, Alexandra Sopuch<fnref n="1" />, Daniela Rosalba³, Emanuela Morenghi<fnref n="1" />,², Glenn Hernandez⁴, Xavier Monnet⁵,⁶,⁷ and Maurizio Cecconi<fnref n="1" />,²

**Abstract**

**Introduction:** Fluid challenges are widely adopted in critically ill patients to reverse haemodynamic instability. We reviewed the literature to appraise fluid challenge characteristics in intensive care unit (ICU) patients receiving haemodynamic monitoring and considered two decades: 2000–2010 and 2011–2021.

**Methods:** We assessed research studies and collected data regarding study setting, patient population, fluid challenge characteristics, and monitoring. MEDLINE, Embase, and Cochrane search engines were used. A fluid challenge was defined as an infusion of a definite quantity of fluid (expressed as a volume in mL or ml/kg) in a fixed time (expressed in minutes), whose outcome was defined as a change in predefined haemodynamic variables above a predetermined threshold.

**Results:** We included 124 studies, 32 (25.8%) published in 2000–2010 and 92 (74.2%) in 2011–2021, overall enrolling 6,086 patients, who presented sepsis/septic shock in 50.6% of cases. The fluid challenge usually consisted of 500 mL (76.6%) of crystalloids (56.6%) infused with a rate of 25 mL/min. Fluid responsiveness was usually defined by a cardiac output/index (CO/CI) increase ≥ 15% (70.9%). The infusion time was quicker (15 min vs 30 min), and crystalloids were more frequent in the 2011–2021 compared to the 2000–2010 period.

**Conclusions:** In the literature, fluid challenges are usually performed by infusing 500 mL of crystalloids bolus in less than 20 min. A positive fluid challenge response, reported in 52% of ICU patients, is generally defined by a CO/CI increase ≥ 15%. Compared to the 2000–2010 decade, in 2011–2021 the infusion time of the fluid challenge was shorter, and crystalloids were more frequently used.

**Keywords:** Fluids, Fluid challenge, Fluid bolus, Fluid responsiveness, Critically ill patients

**Introduction**

Fluid administration in the intensive care unit (ICU) is one of the most common and disputed interventions triggered at the bedside by several clinical variables [1, 2].

Fluid therapy aims to increase stroke volume (SV) and cardiac output (CO) to optimise systemic blood flow and tissue perfusion. As with any therapeutic intervention, the final clinical effect elicited may vary because of

<footnote>*Correspondence: antonio.messina@humanitas.it</footnote>

<footnote n="1">¹ Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center—IRCCS, Via Alessandro Manzoni, 56, 20089 Rozzano, Milano, Italy</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
a complex interplay between the patient's intrinsic conditions and the therapy itself.

Fluid responsiveness can occur only if both ventricles work on the ascending, steep part of the Frank–Starling curve, i.e. in cases where CO is preload dependent [3, 4]. Preload dependency is assessed using a diagnostic test performed by infusing a fixed aliquot of fluid, the fluid challenge [5–7]. From a clinical perspective, this approach also allows titration of fluid administration (when the patient becomes no longer responsive to the fluid challenge) and reduces the risk of fluid overload, which worsens the outcome of ICU patients [8, 9].

Several variables defining the characteristics of the fluid challenge have been further investigated in studies adopting continuous haemodynamic monitoring, showing that the amount of fluids given, the rate of administration, and the threshold adopted to define fluid responsiveness impact the outcome of a fluid challenge [10–12]. Moreover, despite conflicting results on shock reversal efficacy between crystalloids and colloids, crystalloids are now recommended as the first-line fluid type in patients with septic shock, being inexpensive and widely available. Also, the administration of colloids compared to crystalloids has not demonstrated any clear benefit in the literature [13, 14].

However, neither the nature, mode of administration, and method to assess the effectiveness of the fluid challenge are standardised in current clinical practice, and the definition of fluid challenge responsiveness is also variable among studies [15–18].

Whether or not these findings have modified the modalities of fluid challenge and the definition of fluid responsiveness in published studies is uncertain. To address this issue, we systematically reviewed existing literature from the year 2000. We appraised the characteristics of fluid challenges in critically ill patients (i.e., amount and kind of fluid administration, time of infusion, hemodynamic variables, and thresholds for fluid responsiveness) enrolled in research studies receiving continuous haemodynamic monitoring and assessed the relationship between the reported fluid responsiveness and predefined independent variables. Secondarily, we compared data from studies published in 2011–2021 versus those published in 2000–2010.

## Material and methods

We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis-Protocols (PRISMA-P) guidelines (Additional file 1: Table S1). The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in November 2021 (CRD42021284761).

## Search strategy

A systematic literature search was performed, including the following databases: PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials register. The following keywords and their related MeSh terms were used: "fluid challenge", "fluid responsiveness", "stroke volume variation", "pulse pressure variation", "dynamic indices OR indexes", "passive leg raising", OR "passive leg raising test", "functional haemodynamic test OR tests". Included papers were also examined to identify other studies of interest missed during the primary search.

## Study selection and inclusion criteria

Articles enrolling at least 20 adult critically ill patients, written in English and published from 1st January 2000 to 31st December 2021 in indexed scientific journals, were considered. Editorials, commentaries, letters to the editor, opinion articles, reviews, and meeting abstracts were excluded. Studies enrolling paediatric or obstetric populations were excluded. References of selected papers, review articles, commentaries, and editorials on this topic were also reviewed to identify other studies of interest missed during the primary search. When multiple publications of the same research group/centre described potentially overlapping cohorts, the most recent publications were selected.

A fluid challenge was defined as an infusion of a definite quantity of fluid (expressed as a volume in mL or ml/ kg) in a fixed time (expressed in minutes), whose outcome was defined as a change in one of the following haemodynamic variables above a predetermined threshold: CO, cardiac index (CI), SV, SV index (SVI), or surrogate of SV, i.e., velocity–time integral (VTI) in the left ventricular outflow tract and aortic blood flow (ABF), as assessed by transthoracic, transoesophageal echocardiography or oesophageal Doppler. We included studies adopting both a specific (i.e., Ringer lactate, saline, etc.) and a broad definition (i.e., crystalloids, colloids, etc.) of the fluid used for the fluid challenge. Studies adopting changes in systemic arterial pressure to define fluid responsiveness were excluded. Finally, we considered the predefined clinical reasons and triggers to start fluid challenge infusion.

## Data extraction

Three couples of examiners independently evaluated titles and abstracts. The articles were then subdivided into three subgroups: "included" and "excluded" (if the two examiners agreed with the selection) or "uncertain" (in case of disagreement). In the case of "uncertain" classification, discrepancies were resolved by further examination performed by one of the three expert authors
(A.M., X.M., or M.C.). We used a standardised electronic
spreadsheet (Microsoft Excel, V 14.4.1; Microsoft, Red-
mond, WA) to extract data from all included studies,
recording: the study setting (type of study, geographical
area and time, where and when the study was carried
out, and sample size), patient characteristics (gender, age,
reason for admission, underlying diseases, ICU scores
of severity, mode of ventilation, and inotropic/vasopres-
sor support), criteria for haemodynamic instability, fluid
challenge characteristics, pre- and post-fluid challenge
haemodynamic variables. When necessary, the corre-
sponding authors of the included studies were contacted
to obtain missing data related to trial demographics,
methods, and outcomes (Additional file 1: Table S2).

Statistical analysis

Statistical analysis was conducted on the summary sta-
tistics described in the selected articles (e.g., means,
medians, proportions) and, therefore, the statistical unit
of observation for all the selected variables was the sin-
gle study and not the patient. Due to the discrepancy
between the overall patients enrolled in the trials over
the two considered decaders, the comparisons were not
weighted for study size.

Fluid challenge was the exposure variable, and clinical
and haemodynamic characteristics were considered out-
come variables. Descriptive statistics of individual studies
used different statistical indicators for central tendency
and variability, such as means and standard deviations
(i.e., age, tidal volume, fluid responders, severity scores),
whereas absolute and relative frequencies were adopted
for qualitative variables. To show one indicator for the
quantitative variables, we collected means with stand-
ard deviations (SD) or medians and inter-quartile ranges
(IQR).

Student's t test or Mann-Whitney test in case of para-
metric or nonparametric distributions, respectively, were
used to assess the difference in mean values between
responders and non-responders.

Statistical analyses were conducted using GraphPad
PRISM® 8 (GraphPad Software Inc., San Diego, CA,
USA) and STATA®15 (StataCorp, College Station, TX,
USA). For all comparisons, we considered *p* values < 0.05
significant.

Results

The electronic search identified 3,963 potentially relevant
studies. Figure 1 and Additional file 1: Table S3 provide
a detailed description of the selection process flow. After
evaluating 160 full-text manuscripts, the inclusion crite-
ria were met by 124 studies, 32 (25.8%) published in the
period 2000–2010 and 92 (74.2%) in the period 2011–
2021. Ten studies (8.1%) required revision by senior

examiners because of disagreement regarding inclusion
criteria between the initial examiners. We did not find
any further relevant publications by reviewing the bibli-
ography of the selected studies.

The general characteristics of the patients are reported
in Table 1. We included 6,086 patients, with a median
(IQR) of 38 (30–59) patients enrolled in each study. Six
studies (4.8%) [20–25] were retrospective, while the oth-
ers were prospective. The median (IQR) period of enrol-
ment [reported in 66 (52.8%) studies] was 12 (6–18)
months. At baseline, 2,985 (49.0%) patients received
norepinephrine, 179 (2.9%) dopamine, 416 (6.8%) dobu-
tamine, and 177 (2.8%) epinephrine.

The reliability of a functional haemodynamic test
in predicting fluid responsiveness was assessed in 46
(37.1%) studies. Comparing the two considered decades,
no difference was found in the rate of FC administra-
tion [17 min (17–33) vs. 33 min (17–50); *p* = 0.39], in
the percentage of fluid responders [52% (43–67) vs. 53%
(45–60); *p* = 0.91], in the percentage of studies adopting
crystalloids over colloids [63.6% vs. 67.9%; *p* = 1.00], or
in the threshold of increase in CO or surrogates adopted
to define fluid responsiveness (10% over 15%) [18.2% vs.
24.1%; *p* = 1.00).

Forty-four studies (35.4%) investigated the reliability
of a dynamic index in predicting fluid responsiveness.
Comparing the two considered decades, no differences
were found in the rate of FC administration [17 min (17-
25) vs. 29 min (13–33) *p* = 0.42], or in the rate of fluid
responders [53% (41–62) vs. 50% (44–56) *p* = 0.81], or
in the threshold of increase in CO or surrogates adopted
to define fluid responsiveness (10% over 15%) (78.5% vs.
66.67 *p* = 0.42), as compared to studies in the decade
2000–2010. On the contrary, in the decade 2010-2021
we adopted more frequently crystalloids (21.4% vs. 60.0%
*p* = 0.024).

Fluid challenge characteristics and haemodynamic
monitoring

Overall, the included studies infused 6,333 fluid chal-
lenges. The median (IQR) proportion of fluid responders
was 52 (44–62)% (Table 2).

In 19 studies (15.3%), the volume of the fluid challenge
was reported in mL/kg, with a median (IQR) of 7 (6–8)
mL/kg (Table 2). A fixed volume of 500 mL was admin-
istered in 95 (76.6)% of the included studies. The median
(IQR) of the dispensed volume of fluid was 500 (500–500)
mL, infused in a median (IQR) of 18 (11–30) min. Then,
the median (IQR) infusion rate was 25 (17–33) mL/min.

CO/CI was used as target variables in 78 (62.9%) stud-
ies, while SV/SVI was used in 40 (32.2%) studies. The
other six studies (4.8%) adopted SV surrogates (ABF in 4
studies and VTI in two studies). In 88 (70.9%) studies, the
<figure><img src="image_3.png" /></figure>

threshold adopted to define the fluid responsiveness was an increase of the considered variable ≥ 15% from baseline (Table 2).

Three studies (2.4%) [25–27] did not report the type of fluid used for the fluid challenge. Among the others, crystalloids were used in 68 (56.6)% studies, colloids in 52 (43.3) %, and blood in one (0.8)% (Table 2).

The majority of the studies [49 (39.5%)] used transpulmonary thermodilution/dye dilution calibrated haemodynamic monitoring; 22 (17.7%) studies adopted the pulmonary artery catheter monitoring. Echocardiography (either transthoracic or transoesophageal) was used in 31 (25.0)% of studies, and 5 (4.0%) used oesophageal doppler monitoring. Uncalibrated pulse wave analysis monitoring was used in the other 14 (11.2)% studies (Table 2). Finally, bioreactance was adopted in three

studies (2.4%). Haemodynamic pre-post-fluid challenge variables in responders and non-responders populations are reported in Table 3.

**Trigger of fluid challenge administration.**

Hypotension (i.e., systolic or mean arterial pressure below a fixed value or reduced by a fixed percentage from baseline) was used in 68 (62.4)% of studies. Oliguria (i.e. a drop in urine output below 0.5 mL/h for 2 or 3 consecutive hours) was used in 54 (49.5)% studies, skin mottling or peripheral hypoperfusion in 47 (43.1)% studies, tachycardia (i.e. an increase in heart rate above 100–110 beats/min) in 43 (39.4)%, the need for initiating the infusion or reducing the dose of vasoactive drugs in 41 (37.6)% studies, an increase in blood lactate in 34 (31.2)% studies, a diagnosis of sepsis/septic shock in 12 (11.0)% studies,
<table><caption>**Table 1** Patient characteristics at enrolment</caption><thead><tr><th>General characteristics</th><th>Overall<br>(n=6086)</th><th>% DR</th><th>2011-2021<br>(n=1243)</th><th>2000-2010<br>(n=4843)</th><th>p value**</th></tr></thead><tbody><tr><td>Age (year)</td><td>63 (59-65)</td><td>(95.9)</td><td>63 (59-65)</td><td>63 (58-67)</td><td>0.52</td></tr><tr><td>Male (n, %)</td><td>3552 (58.3)</td><td>(87.1)</td><td>2837 (58.6)</td><td>715 (57.5)</td><td>0.52</td></tr><tr><td>SAPS II (points)</td><td>53 (45-59)</td><td>(39.5)</td><td>55 (45-60)</td><td>53 (40-57)</td><td>0.34</td></tr><tr><td>SOFA (points)</td><td>10 (7-11)</td><td>(22.5)</td><td>10 (7-11)</td><td>11 (9-14)</td><td>0.10</td></tr><tr><td>APACHE (points)</td><td>20 (19-26)</td><td>(22.5)</td><td>24 (19-27)</td><td>19 (12-21)</td><td>0.12</td></tr><tr><td><strong>Data regarding respiratory support</strong></td><td></td><td>(70.9)</td><td></td><td></td><td></td></tr><tr><td>Totally controlled ventilatory support (n; %)</td><td>2658 (56.6)</td><td></td><td>1955 (56.2)</td><td>703 (57.9)</td><td>0.29</td></tr><tr><td>PCV (n; %)</td><td>150 (3.2)</td><td></td><td>128 (3.6)</td><td>22 (1.8)</td><td></td></tr><tr><td>VCV (n; %)</td><td>2428 (51.7)</td><td></td><td>1747 (50.2)</td><td>681 (56.1)</td><td></td></tr><tr><td>APRV (n; %)</td><td>80 (1.7)</td><td></td><td>80 (2.3)</td><td>0 (0-0)</td><td></td></tr><tr><td>Partially controlled ventilatory support (n; %)</td><td>1503 (32.0)</td><td></td><td>1161 (33.4)</td><td>342 (28.1)</td><td>0.05</td></tr><tr><td>ACV (n; %)</td><td>1256 (26.7)</td><td></td><td>990 (28.4)</td><td>266 (21.9)</td><td></td></tr><tr><td>PSV (n; %)</td><td>247 (5.3)</td><td></td><td>171 (4.9)</td><td>76 (6.2)</td><td></td></tr><tr><td>Spontaneously breathing (n; %)</td><td>530 (10.1)</td><td></td><td>362 (10.4)</td><td>168 (13.8)</td><td>0.001</td></tr><tr><td>V<sub>T</sub> (mL/Kg ideal body weight)</td><td>7 (7-8)</td><td>(70.9)</td><td>7 (6-8)</td><td>8 (7-9)</td><td>0.03</td></tr><tr><td><strong>Type of patients*</strong></td><td></td><td>(91.9)</td><td></td><td></td><td></td></tr><tr><td>Sepsis/septic shock (%)</td><td>3546 (50.6)</td><td></td><td>2823 (50.5)</td><td>723 (51.2)</td><td>0.63</td></tr><tr><td>Haemorrhagic/hypovolemic shock (%)</td><td>344 (4.9)</td><td></td><td>252 (13.9)</td><td>92 (6.5)</td><td>&lt;0.0001</td></tr><tr><td>Trauma (%)</td><td>120 (1.7)</td><td></td><td>101 (1.8)</td><td>19 (1.3)</td><td>0.25</td></tr><tr><td>ARDS/pneumonia (%)</td><td>1741 (24.8)</td><td></td><td>1428 (25.5)</td><td>313 (22.2)</td><td>0.009</td></tr><tr><td>Postoperative optimization (%)</td><td>1005 (14.3)</td><td></td><td>780 (13.9)</td><td>225 (15.9)</td><td>0.06</td></tr><tr><td>Cardiogenic (%)</td><td>193 (2.7)</td><td></td><td>160 (2.8)</td><td>33 (2.3)</td><td>0.31</td></tr><tr><td>Other (%)</td><td>53 (0.7)</td><td></td><td>47 (2.8)</td><td>6 (0.5)</td><td>0.12</td></tr></tbody></table>

Data presented as median (25th–75th IQR), as appropriate; % DR, percentage of studies reporting the data indicated, SAPS, simplified acute physiology score; SOFA, sequential organ failure assessment; APACHE, Acute Physiologic Assessment and Chronic Health Evaluation; PCV, pressure-controlled ventilation; VCV, volume-controlled ventilation; APRV, Airway pressure release ventilation; ACV, assisted-controlled ventilation; PSV, pressure support ventilation; ARDS, acute respiratory distress syndrome; V<sub>T</sub>, tidal volume. *The overall number of patients stratified by typology is more significant as compared to the overall number of patients included in the studies because of partial overlapping classification (i.e., sepsis/septic shock and ARDS/pneumonia); **p value refers to the comparison between 2000–2010 versus 2011–2021 subgroups

and renal or hepatic dysfunction in seven (6.4)% studies. Fifteen studies (12.1%) did not report any trigger to start fluid challenge administration.

## Comparison of publication periods 2011–2021 versus 2000–2010

The comparison between the 2000–2010 and 2011–2021 decades is reported in Table 4. The percentage of fluid responders (52% for both the decades) and the volume infused (500 mL) were comparable. On the contrary, the infusion time was lower in the last decade (a median of 15 (10–30) min vs 30 (15–30) min, *p* = 0.03). Crystalloids were used in 61.9% of studies published between 2011–2021 and 34.3% in the 2000–2010 decade (*p* = 0.007) (Figs. 2 and S1 in the Additional file 1).

CO/CI was used in 67% of the studies published in 2011–2021 and in 60% of those published in 2000–2010 (*p* = 0.51). The threshold adopted was an increase in CO or surrogates ≥ 15% in 67.4% of the studies of the

2011–2021 decade and in 81.2% of the studies published in 2000–2010 (*p* = 0.17) (Additional file 1: Figure S1).

## Discussion

The results of this review, including research studies investigating the fluid challenge effect in critically ill adult patients receiving haemodynamic monitoring, may be summarised as follows: 1) fluid challenge is usually performed infusing a bolus of 500 mL of fluid, most often a crystalloid, in less than 20 min; 2) the response to fluid challenge is usually defined as a CI or CO increase ≥ 15% as compared to baseline; 3) positive response to fluid challenge is reported in about 50% of ICU patients; 4) the most common trigger for fluid challenge administration is usually the occurrence of hypotension, followed by oliguria and clinical signs of hypoperfusion; 5) the comparison between the 2000–2010 and 2011–2021 decades of publication showed no difference in the percentage of fluid responders (52% on average for both the decades), the volume infused (500 ml), and the criteria defining fluid responsiveness. On the contrary,
<table><caption>**Table 2** Fluid challenge characteristics and haemodynamic monitoring in the included studies</caption><thead><tr><th>References</th><th>Year</th><th>Vol (ml)</th><th>Vol (ml/kg)</th><th>Time (min)</th><th>Rate (ml/min)</th><th>Responsiveness cut-off</th><th>Type of fluid</th><th>Monitoring device</th><th>% R</th></tr></thead><tbody><tr><td>Mahjoub et al. [35]</td><td>2010</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>CARDIOQ</td><td>76</td></tr><tr><td>Feissel et al. [37]</td><td>2004</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CO ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>41</td></tr><tr><td>Marik et al. [39]</td><td>2013</td><td>500</td><td>–</td><td>10</td><td>50</td><td>SVI ≥ 10%</td><td>CRYS—Saline</td><td>NICOM</td><td>53</td></tr><tr><td>Wyffels et al. [41]</td><td>2007</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>62</td></tr><tr><td>Jozwiak et al. [43]</td><td>2017</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>50</td></tr><tr><td>Monnet et al. [45]</td><td>2009</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>70</td></tr><tr><td>Monnet et al. [47]</td><td>2012</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>55</td></tr><tr><td>Vaquer et al. [20]</td><td>2020</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>34</td></tr><tr><td>Chen et al. [49]</td><td>2021</td><td>500</td><td>–</td><td>40</td><td>13</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO2</td><td>60</td></tr><tr><td>Abdullah et al. [49]</td><td>2021</td><td>500</td><td>–</td><td>10</td><td>50</td><td>SVI ≥ 15%</td><td>CRYS—Saline</td><td>UNCAL—FLOWTRAC/ VIGILEO</td><td>46</td></tr><tr><td>Messina et al. [52]</td><td>2021</td><td>500</td><td>–</td><td>10</td><td>50</td><td>SVI ≥ 10%</td><td>CRYS—Ringer A/L</td><td>UNCAL—MOSTCARE</td><td>48</td></tr><tr><td>Taccheri et al. [54]</td><td>2021</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 10%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>50</td></tr><tr><td>Kaur et al. [56]</td><td>2021</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CO ≥ 15%</td><td>CRYS—Ringer A/L</td><td>UNCAL—FLOWTRAC/ VIGILEO</td><td>67</td></tr><tr><td>Biasucci et al. [58]</td><td>2019</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>60</td></tr><tr><td>Gavaud et al. [60]</td><td>2019</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CO ≥ 10%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>90</td></tr><tr><td>Dépret et al. [62]</td><td>2019</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>50</td></tr><tr><td>Messina et al. [64]</td><td>2019</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>UNCAL—MOSTCARE</td><td>66</td></tr><tr><td>Vistisen et al. [66]</td><td>2018</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SV ≥ 10%</td><td>CRYS—Saline</td><td>NICOM</td><td>23</td></tr><tr><td>Xu et al. [68]</td><td>2017</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CI ≥ 15%</td><td>COLL—Gelatine</td><td>PAC</td><td>45</td></tr><tr><td>Preau et al. [69]</td><td>2017</td><td>–</td><td>6</td><td>30</td><td>–</td><td>SVI ≥ 10%</td><td>COLL—Gelatine</td><td>CAL—PiCCO2</td><td>55</td></tr><tr><td>Machare-Delgado et al. [71]</td><td>2011</td><td>–</td><td>6</td><td>10</td><td>–</td><td>SVI ≥ 10%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>32</td></tr><tr><td>Monnet et al. [73]</td><td>2013</td><td>–</td><td>7</td><td>30</td><td>–</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>49</td></tr><tr><td>Monnet et al. [74]</td><td>2007</td><td>500</td><td>–</td><td>8</td><td>67</td><td>ABF ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>54</td></tr><tr><td>Ishihara et al. [76]</td><td>2013</td><td>250</td><td>–</td><td>20</td><td>13</td><td>CI ≥ 15%</td><td>COLL—Dextran 10%</td><td>CAL—PiCCO</td><td>54</td></tr><tr><td>Monge Garcia et al. [78]</td><td>2012</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CO ≥ 15%</td><td>COLL—HES 6%</td><td>CARDIOQ</td><td>57</td></tr><tr><td>Luzi et al. [80]</td><td>2013</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>50</td></tr><tr><td>Dong et al. [82]</td><td>2012</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>69</td></tr><tr><td>Jabot et al. [84]</td><td>2008</td><td>–</td><td>20</td><td>10</td><td>–</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>100</td></tr><tr><td>Préau et al. [86]</td><td>2010</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SV ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>41</td></tr><tr><td>Monnet et al. [88]</td><td>2006</td><td>500</td><td>–</td><td>10</td><td>50</td><td>ABF ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>52</td></tr><tr><td>Monnet et al. [47]</td><td>2012</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>56</td></tr><tr><td>Monnet et al. [91]</td><td>2013</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>43</td></tr><tr><td>Loupec et al. [93]</td><td>2011</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CO ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>53</td></tr><tr><td>Monnet et al. [95]</td><td>2012</td><td>–</td><td>8</td><td>30</td><td>–</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>44</td></tr><tr><td>Huang et al. [97]</td><td>2008</td><td>–</td><td>7</td><td>40</td><td>–</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>46</td></tr><tr><td>Khwannimit et al. [98]</td><td>2012</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>COLL—HES 6%</td><td>UNCAL—FLOWTRAC/ VIGILEO</td><td>57</td></tr><tr><td>Fischer et al. [100]</td><td>2013</td><td>–</td><td>7</td><td>15</td><td>–</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>71</td></tr><tr><td>Kramer et al. [102]</td><td>2004</td><td>–</td><td>7</td><td>15</td><td>–</td><td>CO ≥ 15%</td><td>Blood</td><td>PAC</td><td>29</td></tr><tr><td>Yazigi et al. [104]</td><td>2012</td><td>–</td><td>10</td><td>20</td><td>–</td><td>SVI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>68</td></tr><tr><td>Wyler von Ballmoos et al. [106]</td><td>2010</td><td>200</td><td>7</td><td>10</td><td>20</td><td>SV ≥ 10%</td><td>COLL—HES 6%</td><td>PAC</td><td>28</td></tr><tr><td>Michard et al. [108]</td><td>2000</td><td>500</td><td>6</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>40</td></tr><tr><td>Lakhal et al. [110]</td><td>2011</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>COLL—Gelatine</td><td>PAC</td><td>40</td></tr><tr><td>Muller et al. [112]</td><td>2012</td><td>500</td><td>–</td><td>15</td><td>33</td><td>VTI ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>50</td></tr><tr><td>Giraud et al. [114]</td><td>2011</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>PAC</td><td>47</td></tr><tr><td>Suehiro et al. [116]</td><td>2012</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>CRYS—Ringer A/L</td><td>UNCAL—FLOWTRAC/ VIGILEO</td><td>48</td></tr></tbody></table>
<table><caption>**Table 2** (continued)</caption><thead><tr><th>References</th><th>Year</th><th>Vol (ml)</th><th>Vol (ml/kg)</th><th>Time (min)</th><th>Rate (ml/min)</th><th>Responsiveness cut-off</th><th>Type of fluid</th><th>Monitoring device</th><th>% R</th></tr></thead><tbody><tr><td>Perner et al. [117]</td><td>2006</td><td>–</td><td>4</td><td>30</td><td>–</td><td>CI ≥ 10%</td><td>COLL—Dextran 6%</td><td>CAL—PiCCO</td><td>47</td></tr><tr><td>Smorenberg et al. [118]</td><td>2013</td><td>250</td><td>–</td><td>15</td><td>17</td><td>SVI ≥ 10%</td><td>COLL—Gelatine</td><td>PAC</td><td>44</td></tr><tr><td>Monnet et al. [119]</td><td>2012</td><td>–</td><td>10</td><td>30</td><td>–</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>42</td></tr><tr><td>Yonis et al. [121]</td><td>2017</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CI ≥ 10%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>33</td></tr><tr><td>Xiao-ting et al. [122]</td><td>2015</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CI ≥ 10%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>70</td></tr><tr><td>Biais et al. [124]</td><td>2009</td><td>500</td><td>–</td><td>15</td><td>33</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>UNCAL—FLOWTRAC/VIGILEO</td><td>67</td></tr><tr><td>Mallat et al. [126]</td><td>2015</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>45</td></tr><tr><td>Maizel et al. [127]</td><td>2007</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CO ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>50</td></tr><tr><td>Lamia et al. [129]</td><td>2007</td><td>500</td><td>–</td><td>15</td><td>33</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>59</td></tr><tr><td>Silva et al. [131]</td><td>2004</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 10%</td><td>COLL—HES 6%</td><td>PAC</td><td>63</td></tr><tr><td>Cecconi et al. [133]</td><td>2012</td><td>250</td><td>–</td><td>5</td><td>50</td><td>SV ≥ 15%</td><td>COLL—HES 6%/Dextran 10%</td><td>CAL—LiDCO</td><td>39</td></tr><tr><td>Georges et al. [135]</td><td>2018</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CO ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>56</td></tr><tr><td>Monnet et al. [137]</td><td>2013</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>52</td></tr><tr><td>Monnet et al. [139]</td><td>2005</td><td>500</td><td>–</td><td>10</td><td>50</td><td>VTI ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>53</td></tr><tr><td>Biais et al. [141]</td><td>2012</td><td>500</td><td>–</td><td>15</td><td>33</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>UNCAL—MOSTCARE</td><td>54</td></tr><tr><td>Lakhal et al. [115]</td><td>2013</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>COLL—Gelatine</td><td>PAC</td><td>37</td></tr><tr><td>Michard et al. [144]</td><td>2003</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>49</td></tr></tbody></table><table><thead><tr><th>References</th><th>Year</th><th>Vol (ml)</th><th>Vol (ml/kg)</th><th>Time (min)</th><th>Rate (ml/min)</th><th>Responsiveness cut-off</th><th>Type of fluid</th><th>Monitoring device</th><th>% R</th></tr></thead><tbody><tr><td>Préau et al. [36]</td><td>2012</td><td>–</td><td>6</td><td>30</td><td>–</td><td>SV ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>44</td></tr><tr><td>Caille et al. [38]</td><td>2008</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CI ≥ 10%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>43</td></tr><tr><td>Mahjoub et al. [40]</td><td>2012</td><td>500</td><td>–</td><td>20</td><td>25</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>71</td></tr><tr><td>Wu et al. [42]</td><td>2014</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CO ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>54</td></tr><tr><td>Fellahi et al. [44]</td><td>2012</td><td>–</td><td>7</td><td>15</td><td>–</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>84</td></tr><tr><td>Smorenberg et al. [46]</td><td>2017</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>COLL—HES 6%</td><td>CAL—LiDCO</td><td>62</td></tr><tr><td>Muller et al. [48]</td><td>2011</td><td>500</td><td>–</td><td>15</td><td>33</td><td>VTI ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>54</td></tr><tr><td>Monnet et al. [28]</td><td>2011</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>62</td></tr><tr><td>Monge Garcia et al. [50]</td><td>2008</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>CRYS—Saline</td><td>UNCAL—FLOWTRAC/VIGILEO</td><td>37</td></tr><tr><td>Natalini et al. [51]</td><td>2006</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>PAC</td><td>59</td></tr><tr><td>Mahjoub et al. [53]</td><td>2009</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SV ≥ 15%</td><td>COLL—Gelatine</td><td>ECO—TT/TE</td><td>66</td></tr><tr><td>Fischer et al. [55]</td><td>2013</td><td>–</td><td>7</td><td>15</td><td>–</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>73</td></tr><tr><td>Vistisen et al. [57]</td><td>2009</td><td>500</td><td>–</td><td>90</td><td>6</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>74</td></tr><tr><td>Kupersztych-Hagege et al. [59]</td><td>2013</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>40</td></tr><tr><td>Monge Garcia et al. [61]</td><td>2009</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>COLL—HES 6%</td><td>UNCAL—FLOWTRAC/VIGILEO</td><td>50</td></tr><tr><td>Lakhal et al. [63]</td><td>2012</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>COLL—Gelatine</td><td>PAC</td><td>39</td></tr><tr><td>Soubrier et al. [65]</td><td>2007</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>59</td></tr><tr><td>Fellahi et al. [67]</td><td>2012</td><td>500</td><td>–</td><td>15</td><td>33</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>56</td></tr><tr><td>Osman et al. [22]</td><td>2007</td><td>500</td><td>–</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>43</td></tr><tr><td>Lakhal et al. [70]</td><td>2010</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>COLL—Gelatine</td><td>CAL—PiCCO</td><td>42</td></tr><tr><td>De Oliveira-Costa et al. [72]</td><td>2012</td><td>1000</td><td>–</td><td>30</td><td>33</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>PAC</td><td>46</td></tr><tr><td>Velissaris et al. [23]</td><td>2011</td><td>500</td><td>–</td><td>30</td><td>17</td><td>CI ≥ 10%</td><td>COLL</td><td>PAC</td><td>52</td></tr><tr><td>Monnet et al. [75]</td><td>2011</td><td>500</td><td>–</td><td>10</td><td>50</td><td>CI ≥ 10%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>84</td></tr><tr><td>Muller et al. [77]</td><td>2010</td><td>500</td><td>–</td><td>30</td><td>17</td><td>SVI ≥ 10%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>72</td></tr></tbody></table>
<table><caption>**Table 2** (continued)</caption><thead><tr><th>References</th><th>Year</th><th>Vol (ml)</th><th>Vol (ml/kg)</th><th>Time (min)</th><th>Rate (ml/min)</th><th>Responsiveness cut-off</th><th>Type of fluid</th><th>Monitoring device</th><th>% R</th></tr></thead><tbody><tr><td>Muller et al. [79]</td><td>2008</td><td>500</td><td>-</td><td>30</td><td>17</td><td>SVI ≥ 15%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>51</td></tr><tr><td>Heenen et al. [81]</td><td>2006</td><td>500</td><td>-</td><td>30</td><td>17</td><td>CO ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>43</td></tr><tr><td>De Backer et al. [83]</td><td>2005</td><td>500</td><td>-</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>PAC</td><td>55</td></tr><tr><td>Le Dorze et al. [85]</td><td>2018</td><td>250</td><td>-</td><td>5</td><td>50</td><td>SV ≥ 10%</td><td>CRYS—Saline</td><td>CARDIOQ</td><td>35</td></tr><tr><td>Wu et al. [87]</td><td>2018</td><td>250</td><td>-</td><td>15</td><td>17</td><td>SVI ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>45</td></tr><tr><td>Si et al. [89]</td><td>2018</td><td>250</td><td>-</td><td>30</td><td>8</td><td>SVI ≥ 15%</td><td>COLL—Albumine</td><td>CAL—PiCCO</td><td>63</td></tr><tr><td>Pouska et al. [90]</td><td>2018</td><td>-</td><td>5</td><td>20</td><td>-</td><td>SVI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>49</td></tr><tr><td>Xu et al. [92]</td><td>2017</td><td>250</td><td>-</td><td>10</td><td>25</td><td>SV ≥ 10%</td><td>CRYS—Saline</td><td>NICOM</td><td>41</td></tr><tr><td>Soussi et al. [94]</td><td>2017</td><td>500</td><td>-</td><td>15</td><td>33</td><td>CI ≥ 15%</td><td>CRYS—Ringer A/L</td><td>CAL—PiCCO2</td><td>31</td></tr><tr><td>Mallat et al. [96]</td><td>2016</td><td>500</td><td>-</td><td>15</td><td>33</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>52</td></tr><tr><td>Aya et al. [32]</td><td>2016</td><td>250</td><td>-</td><td>5</td><td>50</td><td>CO ≥ 10%</td><td>CRYS—Ringer A/L</td><td>CAL—LiDCO</td><td>50</td></tr><tr><td>Hamimy et al. [99]</td><td>2016</td><td>500</td><td>-</td><td>15</td><td>33</td><td>SV ≥ 10%</td><td>CRYS—Saline</td><td>CARDIOQ</td><td>89</td></tr><tr><td>Liu et al. [101]</td><td>2016</td><td>500</td><td>-</td><td>20</td><td>25</td><td>CO ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>54</td></tr><tr><td>Guérin et al. [103]</td><td>2015</td><td>500</td><td>-</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>50</td></tr><tr><td>Airapetian et al. [105]</td><td>2015</td><td>500</td><td>-</td><td>15</td><td>33</td><td>CO ≥ 10%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>49</td></tr><tr><td>Messina et al. [107]</td><td>2015</td><td>500</td><td>-</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>UNCAL—MOST-CARE</td><td>-</td></tr><tr><td>Cecconi et al. [109]</td><td>2015</td><td>250</td><td>-</td><td>8</td><td>33</td><td>CO ≥ 10%</td><td>COLL—Gelatine</td><td>CAL—PiCCO</td><td>50</td></tr><tr><td>Soliman et al. [111]</td><td>2015</td><td>500</td><td>-</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>COLL—HES 6%</td><td>ECO—TT/TE</td><td>56</td></tr><tr><td>Nunes et al. [113]</td><td>2014</td><td>500</td><td>-</td><td>30</td><td>17</td><td>CI ≥ 15%</td><td>CRYS—Ringer A/L</td><td>PAC</td><td>65</td></tr><tr><td>Lakhal et al. [115]</td><td>2013</td><td>500</td><td>-</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>COLL—Gelatine</td><td>PAC</td><td>37</td></tr><tr><td>Monge García et al. [21]</td><td>2015</td><td>500</td><td>-</td><td>30</td><td>17</td><td>CO ≥ 10%</td><td>0,COLL—Gelatine</td><td>CARDIOQ</td><td>67</td></tr><tr><td>Cecconi et al. [26]</td><td>2013</td><td>250</td><td>-</td><td>5</td><td>50</td><td>CO ≥ 10%</td><td>-</td><td>CAL—LiDCO</td><td>43</td></tr><tr><td>Hu et al. [24]</td><td>2013</td><td>300</td><td>-</td><td>20</td><td>15</td><td>CI ≥ 10%</td><td>COLL—HES 6%</td><td>CAL—PiCCO</td><td>52</td></tr><tr><td>Schnell et al. [120]</td><td>2013</td><td>500</td><td>-</td><td>23</td><td>22</td><td>ABF ≥ 10%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>49</td></tr><tr><td>Pranskunas et al. [27]</td><td>2013</td><td>500</td><td>-</td><td>30</td><td>17</td><td>SV ≥ 10%</td><td>-</td><td>CAL—VIGILANCE</td><td>68</td></tr><tr><td>Elsayed et al. [123]</td><td>2021</td><td>-</td><td>4</td><td>15</td><td>-</td><td>CO ≥ 15%</td><td>CRYS—Ringer A/L</td><td>ECO—TT/TE</td><td>35</td></tr><tr><td>Bataille et al. [125]</td><td>2021</td><td>500</td><td>-</td><td>15</td><td>33</td><td>SV ≥ 15%</td><td>CRYS—Ringer A/L</td><td>ECO—TT/TE</td><td>50</td></tr><tr><td>De Santis et al. [25]</td><td>2021</td><td>500</td><td>-</td><td>30</td><td>17</td><td>CI ≥ 10%</td><td>-</td><td>CAL—PiCCO</td><td>58</td></tr><tr><td>Kumar et al. [128]</td><td>2021</td><td>-</td><td>10</td><td>30</td><td>-</td><td>CI ≥ 10%</td><td>CRYS—Saline</td><td>UNCAL—FLOWTRAC/VIGILEO</td><td>64</td></tr><tr><td>Braun et al. [130]</td><td>2020</td><td>500</td><td>-</td><td>15</td><td>33</td><td>SV ≥ 15%</td><td>CRYS—Ringer A/L</td><td>CAL—PiCCO</td><td>43</td></tr><tr><td>Huette et al. [132]</td><td>2020</td><td>500</td><td>-</td><td>10</td><td>50</td><td>SV ≥ 15%</td><td>CRYS—Ringer A/L</td><td>ECO—TT/TE</td><td>77</td></tr><tr><td>Abdelfattah et al. [134]</td><td>2020</td><td>500</td><td>-</td><td>15</td><td>33</td><td>CO ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>55</td></tr><tr><td>Jacquet-Lagrèze et al. [136]</td><td>2019</td><td>500</td><td>-</td><td>20</td><td>25</td><td>CI ≥ 15%</td><td>CRYS—Ringer A/L</td><td>CAL—PiCCO</td><td>38</td></tr><tr><td>Beurton et al. [138]</td><td>2019</td><td>500</td><td>-</td><td>10</td><td>50</td><td>CI ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO2</td><td>60</td></tr><tr><td>Roger et al. [140]</td><td>2019</td><td>500</td><td>-</td><td>10</td><td>50</td><td>SV ≥ 15%</td><td>CRYS—Ringer A/L</td><td>ECO—TT/TE</td><td>53</td></tr><tr><td>Mukhtar et al. [142]</td><td>2019</td><td>500</td><td>-</td><td>16</td><td>31</td><td>SV ≥ 15%</td><td>COLL—Albumine</td><td>ECO—TT/TE</td><td>68</td></tr><tr><td>Trifi et al. [143]</td><td>2019</td><td>500</td><td>-</td><td>15</td><td>33</td><td>SV ≥ 15%</td><td>CRYS—Saline</td><td>ECO—TT/TE</td><td>70</td></tr><tr><td>Giraud et al. [145]</td><td>2018</td><td>500</td><td>-</td><td>10</td><td>50</td><td>CO ≥ 15%</td><td>CRYS—Saline</td><td>CAL—PiCCO</td><td>45</td></tr></tbody></table>

COLL, colloids; CRYS, crystalloids; HES 6%, hydroxyethyl starch 6%; Ringer A/L, ringer acetate\lactate; CAL, thermodilution/chemodilution calibrated device; UNCAL, pulse wave analysis uncalibrated device; ABF, aortic blood flow; CO, cardiac output; CI, cardiac index; SV, stroke volume; SVI, stroke volume index; VTI, velocity-time integral; CardioQ, Deltex Medical Ltd, Chichester, UK; ECO-TT/TE, transthoracic\transoesophageal echocardiography; FLOWTRAC/VIGILEO, Edwards Lifescience Corporation, Irvine, Ca, USA; LIDCO, LIDCO group plc, London, UK; MOSTCARE, Pressure Recording Analytical Method, PRAM, Vytech Health®, Padova, Italy; NICOM, Non-Invasive Continuous Cardiac Output, Imedex, France; PAC, pulmonary artery catheter; PiCCO/ProAQT/PICCO2, PULSION Medical Systems; R, responders; Vol, volume
<table><caption>**Table 3** Haemodynamic parameters before and after fluid challenge administration in responders and non-responders</caption><thead><tr><th>Haemodynamic variable</th><th>% DR</th><th>Pre FC</th><th>Post FC</th><th>% change pre<br>versus post FC</th><th>p value–pre FC<br>R versus NR</th><th>p value<br>pre FC<br>versus<br>post FC</th></tr></thead><tbody><tr><td>CI (L/min/m²)</td><td>44.3</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>2.8 (2.5–3.2)</td><td>3.6 (3.0–4.1)</td><td>29 (23–33)</td><td>0.0003</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>3.3 (2.7–3.6)</td><td>3.4 (2.9–3.7)</td><td>5 (0–6)</td><td></td><td>0.09</td></tr><tr><td>SVI (ml/m²)</td><td>22.6</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>29 (26–33)</td><td>39 (36–42)</td><td>29 (25–38)</td><td>0.0001</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>36 (31–41)</td><td>37 (31–42)</td><td>3 (– 1; 7)</td><td></td><td>0.05</td></tr><tr><td>MAP (mmHg)</td><td>73.4</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>70 (68–74)</td><td>82 (77–85)</td><td>14 (10–18)</td><td>0.005</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>74 (70–80)</td><td>78 (75–85)</td><td>6 (4–8)</td><td></td><td>&lt; 0.0001</td></tr><tr><td>SAP (mmHg)</td><td>33.9</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>104 (99–108)</td><td>123 (113–129)</td><td>17 (12–22)</td><td>0.002</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>109 (105–118)</td><td>116 (109–123)</td><td>5 (4–8)</td><td></td><td>&lt; 0.0001</td></tr><tr><td>PAOP (mmHg)</td><td>14.5</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>11 (10–12)</td><td>15 (12–16)</td><td>28 (18–45)</td><td>0.05</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>13 (10–14)</td><td>16 (13–18)</td><td>28 (15–37)</td><td></td><td>0.005</td></tr><tr><td>CVP (mmHg)</td><td>42.7</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>9 (7–11)</td><td>11 (10–13)</td><td>30 (19–41)</td><td>0.03</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>10 (8–12)</td><td>13 (10–15)</td><td>26 (15–38)</td><td></td><td>&lt; 0.0001</td></tr><tr><td>HR (beats/min)</td><td>75.8</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>98 (88–105)</td><td>94 (86–101)</td><td>– 3 (– 4; – 1)</td><td>0.03</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>94 (86–101)</td><td>91 (84–98)</td><td>– 2 (– 3; – 1)</td><td></td><td>&lt; 0.0001</td></tr><tr><td>PPV (%)</td><td>30.6</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>15 (12–18)</td><td>9 (5–11)</td><td>– 42 (– 53; – 29)</td><td>&lt; 0.0001</td><td>&lt; 0.0001</td></tr><tr><td>NR</td><td></td><td>8 (6–10)</td><td>7 (5–9)</td><td>– 15 (– 28; 0)</td><td></td><td>0.0002</td></tr><tr><td>SVV (%)</td><td>14.5</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>R</td><td></td><td>14 (12–17)</td><td>10 (6–12)</td><td>– 36 (– 45; – 30)</td><td>&lt; 0.0001</td><td>0.0002</td></tr><tr><td>NR</td><td></td><td>11 (8–13)</td><td>9 (6–11)</td><td>– 22 (– 33; – 9)</td><td></td><td>0.002</td></tr></tbody></table>

Data are presented as median (25th–75th interquartile) in responders (R) and non-responders (NR), n = 21; FC, fluid challenge; CI, cardiac index; SVI, stroke volume index; MAP, mean arterial pressure; SAP, systolic pressure variation; HR, heart rate; PPV, pulse pressure variation; SVV, stroke volume variation; CVP, central venous pressure; PAOP, pulmonary artery occluded pressure; %DR, percentage of data reported in the studies

<table><caption>**Table 4** Comparison between 2011–2021 and 2000–2010 decades regarding the modality of fluid challenge administration</caption><thead><tr><th>General characteristics</th><th>2011–2021</th><th>2000–2010</th><th>p value</th></tr></thead><tbody><tr><td>Fluid responders (%)</td><td>52 (45–60)</td><td>52 (43–62)</td><td>0.32</td></tr><tr><td>Crystalloids versus colloids (n. of studies)</td><td>57 versus 32</td><td>11 versus 20</td><td>0.007</td></tr><tr><td>Volume (ml)</td><td>500 (500–500)</td><td>500 (500–500)</td><td>0.32</td></tr><tr><td>Time of infusion (min)</td><td>15 (10–30)</td><td>30 (15–30)</td><td>0.03</td></tr><tr><td>Threshold 10% versus 15% (n. of studies)</td><td>30 versus 62</td><td>6 versus 26</td><td>0.17</td></tr><tr><td>CO/CI versus SV/SVI (n. of studies)</td><td>61 versus 30</td><td>18 versus 12</td><td>0.51</td></tr></tbody></table>

CO, cardiac output; CI, cardiac index; SV, stroke volume; SVI, stroke volume index

compared to the 2000–2010 decade, in the period 2011–2021, the fluid challenge infusion time was lower, and crystalloids were more frequently used.

**Fluid challenge characteristics**

Among the included studies, the fluid challenge usually consisted of a median volume of 500 mL administered over a 20-min period and defined as a positive response
<figure><img src="image_4.png" /></figure>

by an increase ≥ 15% of CO or surrogate. These characteristics and responsiveness definition are to be considered good practice, for the response of CO to a fluid bolus is poorly followed by the simultaneous changes in arterial pressure [28, 29] or heart rate [30]. However, this is not the case in clinical practice, where the fluid challenge effect is often assessed by a rise in arterial blood pressure [16].

Interestingly, 500 mL was also the median volume fluid challenge used in the FENICE study (an observational study including 311 centres across 46 countries) [16], whereas a fluid challenge of 250 mL is usually adopted in high-risk surgical patients undergoing goal-directed therapy optimisation [31]. The use of large volumes for fluid challenge optimisation should be balanced to the detrimental risk of fluid overload [9], primarily if safety limits (i.e., increase in CVP) dynamically indicate fluid nonresponsiveness are rarely used [19]. Since fluid challenge volume should be at least 4 mL/kg [32], smaller fluid challenge volumes may be considered for repetitive tests.

Moreover, the FENICE study reported a median of 24 min of infusion time and a rate of 17 mL/min [16]. Hence, the volume and rate of administration seem comparable between clinical and research settings. On the contrary, the infusion time was lower in the last decade (a median of 15 min vs 30 min, *p* = 0.03), indicating a trend towards the increase in the infusion rate in more recent studies. This global inception cohort study evaluated the clinical use of the fluid challenge in daily practice, whereas our review considered only research papers adopting the fluid challenge as a part of a protocol, limiting the comparison with the results of the FENICE. Moreover, in contrast with a previous metanalysis, including ICU studies up to 2014 [19], crystalloids are used in most studies. Crystalloids have

been used in two-thirds of the studies from 2011 to 2021, compared to one-third from 2000 to 2010. These data indicate an alignment between research studies, recent guidelines, and metanalyses [13, 14].

## Limitations

Limitations of our review have to be considered when extrapolating the results to clinical practice. First, the present study does not report any outcome endpoints. A recent large randomised-controlled trial showed no difference in mortality rate among ICU patients receiving different fluid bolus infusion rates [33]. However, the faster rate adopted in this study (5.5 mL/min) is below the median rate found in the studies included in the present review (25 mL/min) [33]. The administration of aliquots of fluids at a slow rate should not probably be indicated as a fluid challenge. Moreover, all the included studies are research papers whose aim was to evaluate the haemodynamic changes after the fluid challenge infusion or assess the reliability of indexes or functional haemodynamic tests in predicting the response to a fluid challenge. We did not include studies on the fluid challenge clinical use in ICU patients.

Another potential source of bias is related to the different haemodynamic monitorings used to assess fluid challenge responsiveness. When considering the median cut-off value identifying responders from non-responders, the accuracy of measurement of the changes in CO, or its surrogates, is undoubtedly relevant. Additionally, the reliability of different monitorings in tracking the dynamic trends of CO may not be consistent and may be below the boundaries of accuracy and precision of the Critchley–Critchley criteria [34]. Hence, the reproducibility of CO measurements obtained by the different monitoring systems may be limited. Moreover, cut-off values and measurement techniques potentially induce heterogeneity in response to the fluid challenge administration. As confirmed, responders ranged from 23 to 100% across the included studies (Table 2). The use of echocardiography is associated with high proportions of fluid responders compared to other haemodynamic monitoring devices. The operator-dependent bias may affect the evaluation of SV changes after fluid challenge.

We excluded studies in which the fluid challenge response has been assessed without haemodynamic monitoring and, hence assessing changes in systemic arterial pressures, potentially limiting the whole comparability of the technique in the two considered decades. Finally, the overall number of patients enrolled in the trials of the two considered decades was considerably
different. This could bias the comparisons between the two groups if weighted for study size.

## Conclusions

This systematic review, including research studies on fluid challenge use in critically ill adult patients receiving haemodynamic monitoring, showed a positive response in 52% of the patients. This test was usually performed infusing a bolus of 500 mL fluid, more often a crystalloid, in less than 20 min, and fluid responsiveness was generally indicated as a CI or CO increase ≥ 15% compared to baseline. Fluid challenge administration is usually triggered by hypotension. In the 2011–2021, the infusion time was shorter, and crystalloids were more frequently used than in the 2000–2010 decade.

## Abbreviations

CI: Cardiac index; SVI: Stroke volume index; CO: Cardiac output; SV: Stroke volume; ICU: Intensive care unit; CVP: Central venous pressure; VTI: Velocity-time integral in the left ventricular outflow tract; ABF: Aortic blood flow.

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13054-022-04056-3.

**Additional file 1. Table S1.** PRISMA-DTA checklist. **Table S2.** Extracted data in each study assessed for eligibility. **Table S3.** Full-text articles excluded, not fitting eligibility criteria. **Table S4.** Studies on functional haemodynamic tests or dynamic indexes of fluid responsiveness. **Figure S1.** Characteristics of fluid challenge administration and monitoring along the considered years.

## Acknowledgements

We are thankful to Dr. Katerina Negri for the linguistic revision of this manuscript.

## Author contributions

AM designed the study, performed data analysis, and drafted the manuscript; EM: helped in data analysis and manuscript preparation; LC, LP, AL, AS, and DR substantially contributed to data collection and interpretation; MC, XM, and GE substantially contributed to data interpretation and manuscript draft. All the authors approved the final version of the paper and agreed to be accountable for all aspects of the work, thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

## Funding

This work has not been funded by an external source.

## Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

## Declarations

**Humans ethics statement, adult consent to participate written and human accordance statement**

Not applicable.

## Consent for publication

Not applicable.

## Competing interests

Dr. Messina received travel expenses and registration for meetings, congresses, and courses and lecture fees from Vygon, Edwards, Philips, and Getinge. Xavier Monnet is a member of the medical advisory board of Pulsion Medical Systems (Getinge), and has given lectures for Baxter. Prof. Cecconi is a consultant of Edwards Lifesciences (Directed Systems Consultancy).

## Author details

¹Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center—IRCCS, Via Alessandro Manzoni, 56, 20089 Rozzano, Milano, Italy. ²Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, Italy. ³Università del Piemonte Orientale, Vercelli, Italy.

⁴Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Santiago, Chile. ⁵Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Medical Intensive Care Unit, Le Kremlin-Bicêtre, F-94270 Paris, France. ⁶Université Paris-Saclay, AP-HP, Service de médecine intensive-réanimation, Hôpital de Bicêtre, Paris, France. ⁷DMU CORREVE, Inserm UMR S_999, FHU SEPSIS, Groupe de Recherche Clinique CARMAS, Le Kremlin-Bicêtre, Paris, France.

Received: 1 April 2022 Accepted: 7 June 2022

Published online: 21 June 2022

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