Critical care ultrasound-guided fluid resuscitation versus early goal-

directed therapy in patients with septic shock: A systematic review

and Meta-analysis
Zhe-Yuan Chen
China Medical University
Xiao Han
China Medical University
Ying Liu
General Hospital of Northern Theater Command
Meng-Jun Wang
China Medical University
Bei-Bei Wang
General Hospital of Northern Theater Command
Ling Wang
General Hospital of Northern Theater Command
Hong-Xu Jin (  hongxuj@126.com )
General Hospital of Northern Theater Command

Research Article

Keywords: septic shock, ultrasonography, fluid therapy, resuscitation, mortality, meta-analysis, systematic review

Posted Date: June 6th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-1711004/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

Version of Record: A version of this preprint was published at Emergency and Critical Care Medicine on May 9th, 2023. See the published
version at https://doi.org/10.1097/EC9.0000000000000088.

Page 1/13
Abstract
Background: Fluid resuscitation is a vital therapy for patients with septic shock. With the widespread application of ultrasound in critical care
medicine, it is also used in the fluid resuscitation of critical patients. However, the effect of critical care ultrasound-guided fluid resuscitation
(CCUGFR) in patients with septic shock needs further research.

Methods: We searched PubMed, Embase, Cochrane library, Web of Science, and Registers for randomized controlled trials from inception to
April 2022, evaluating the prognosis of CCUGFR in patients with septic shock. Data were pooled by risk ratio (RR) or mean difference (MD) with
their 95% confidence interval (CI) and estimated using fixed-effects or random-effects models.

Results: Twelve randomized controlled studies with a total of 947 participants were included, of which 473 used CCUGFR. CCUGFR in patients
with septic shock was associated with reduced mortality (RR 0.78; 95%CI, 0.65, 0.94; P=0.007), with low heterogeneity (I2=0%, P=0.45), and 24-
hour fluid volume (MD -1.02; 95%CI, -1.28, -0.75; P<0.001), with low heterogeneity (I2=0%, P=1.00). Increased norepinephrine dose (MD 0.07;
95%CI, 0.02, 0.11; P=0.002), with low heterogeneity (I2=45%, P=0.18), and dobutamine dose (MD 2.2; 95%CI, 0.35, 4.04; P=0.02), with low
heterogeneity (I2=0%, P=0.61). There was no reduction in the risk of dobutamine users (RR 1.67; 95%CI, 0.52, 5.36; P=0.39), with low
heterogeneity (I2=0%, P=0.86), and no difference in duration of vasopressin infusion (MD -5.46; 95%CI, -38.78, 27.86; P=0.75), with high
heterogeneity (I2=97%, P<0.001). But taking left ventricular outflow tract velocity time integral (LVOT-VTI), passive leg raising test, inferior vena
cava (IVC) related measures, or only IVC-related measures to evaluate fluid responsiveness was advantageous in the duration of vasopressin
infusion. Subgroup analyses showed IVC-related measures and using passive leg raising test combined with echocardiography to assess fluid
reactivity reduced hospital stay (MD -2.91; 95%CI, -5.2, -0.62; P=0.01) with low heterogeneity (I2=8%, P=0.34) and ICU length of stay (MD -2.77;
95%CI, -4.51, -1.02; P=0.002), with low heterogeneity (I2=0%, P=0.57).

Conclusion: Our findings suggested that in patients with septic shock receiving CCUGFR is beneficial. CCUGFR and fluid responsiveness using
LVOT-VTI, passive leg raising test, and IVC-related measures may be preferable.

Trial registration: PROSPERO, CRD42022326566, Registered 10 May 2022

Background
Sepsis is a dysfunctional state of the host caused by a dysregulated reaction to the infection [1]. Severe sepsis and septic shock have attracted
extensive attention due to high morbidity and mortality—the current estimates of 30 million episodes and 6 million deaths per year [2]. Therapy
of severe sepsis and septic shock is complex and challenging. However, a deeper understanding of pathogenesis and treatment for septic
shock has been gained with scholars' in-depth research on severe sepsis. In 2003, critical care and infectious diseases professors developed
management guidelines for severe sepsis and septic shock to improve outcome [3].

Fluid resuscitation is one of the most basic treatments for septic shock. According to the Surviving Sepsis Guideline (SSC) in 2004, early goal-
directed therapy (EGDT) was proposed to be administered within the first 6 hours after the septic shock is identified [3]. EGDT is a means of
improving tissue perfusion by observing hemodynamic parameters along with responses to fluid resuscitation and vasopressor medications
[4]. Nevertheless, some studies indicated that EGDT did not improve outcome [5, 6]. More and more studies have found that early
administration of large amounts of crystalloids does not improve prognosis because of complications, and restrictive fluid resuscitation has
reduced the use of vasoactive drugs and mechanical ventilation [7–9]. The 2021 SSC guidelines recommended that at least 30 mL/kg of
crystalloid should be given intravenously within 3 hours of initial resuscitation. The use of non-invasive tools to assess the hemodynamic
status, including echocardiography, was also recommended [10]. However, controversy still exists over whether ultrasonography is accurate
and effective as the indicator for monitoring [11].

Ultrasound has been used in critical care medicine for more than 30 years due to its simple operation, non-invasiveness, and sustainable
monitoring [12]. In recent years, critical care ultrasound technology has rapidly developed and applied in intensive care unit (ICU), forming
ultrasound-guided interventional radiology, hemodynamic monitoring, and organ perfusion assessment [13–17]. Of course, critical care
ultrasound has also been used to guide fluid resuscitation in patients with septic shock, such as lung ultrasound B-line scores to guide fluid
management in patients with extravascular pulmonary water [18]. Patient's cardiac function and fluid responsiveness can be assessed by
monitoring the size of the cardiac structure, the left ventricular ejection fraction, and left ventricular outflow tract velocity time integral (LVOT-
VTI) [14, 19, 20]. Furthermore, fluid responsiveness can be more accurately assessed by inferior vena cava (IVC) diameter and degree of
morphological variability [21].

So far, there is no consistent conclusion about the initial fluid resuscitation guided by critical care ultrasound in patients with septic shock
because the results of clinical studies were controversial. To obtain reliable evidence, we conducted a systematic review and meta-analysis to

Page 2/13
compare critical care ultrasound guidance with early goal-directed therapy in patients with septic shock.

Methods
This systematic review and meta-analysis was registered on PROSPERO (CRD42022326566) and conducted following the PRISMA guidelines
[22].

Search strategy
We searched PubMed, Embase, Cochrane Library, and Web of Science databases from the establishment to April 16, 2022, without restriction
on language, country, or region. We also searched the Cochrane Central Register of Controlled Trials and the Chinese Clinical Trials Registry.
The following terms were searched: "Fluid Therapy"; "Resuscitation"; "Resuscitation Orders"; "Ultrasonography"; "Diagnostic Imaging";
"Ultrasonography, Doppler"; "Ultrasonography, Interventional"; "Echocardiography"; "Echocardiography, Doppler, Pulsed"; "Echocardiography,
Doppler, Color"; "Echocardiography, Doppler"; "Echocardiography, Transesophageal"; "Heart-Lung Machine"; "Lung"; "Vena Cava, Inferior";
"Sepsis"; "Shock, Septic"; "Randomized Controlled Trial". The literature was managed by EndNote X9.

Inclusion and Exclusion Criteria

Inclusion criteria were as follows: (1) randomized controlled trials (RCTs); (2) adult patients (over 18 years of age) with a definitive diagnosis of
septic shock; (3) initial fluid resuscitation in the emergency room or ICU; (4) the intervention group was evaluated by ultrasound during initial
resuscitation, including hemodynamics, fluid responsiveness, and cardiopulmonary function, etc. ; (5) the control group received the initial
resuscitation method recommended by the guidelines for SSC; and (6) other treatments between the two groups should be comparable. Case
reports, retrospective studies, observational studies, animal studies, repeated studies, and studies irrelevant to our outcomes of interest were
excluded.

Study selection
Two authors (Z-YC and XH) independently screened the titles and abstracts of the articles and further evaluated the eligible articles. If there
was any dispute, they would discuss it with the third author (B-BW).

Data extraction and assessment

Two authors (Z-YC and XH) extracted all data independently, and the third person (B-BW) checked the data. These data included first author,
year of publication, country, type of study design, number of cases, treatment versus control group, and primary outcome data. Relevant data
−

were collected using Excel tables. Quantitative data were expressed as mean and standard deviation (mean ± SD, X ±S), and binary data were
expressed as frequency or percentage. Medians and quartiles were converted to mean and standard deviation using the method provided by
Sean McGrath et al. [23]. The quality of the included studies was evaluated in terms of the method of random allocation, concealment of the
allocation scheme, blinding, incomplete outcome data, selective reporting of outcomes, and other sources of bias by the Cochrane
Collaboration recommended. It was classified as low, moderate, and high quality and was shown in green, yellow and red [24].

Outcomes
The primary outcome was mortality during the study period. Secondary outcomes included 24-hour fluid volume, vasoactive drug dose or
duration, length of hospital stay, ICU stay, and others.

Statistical and analysis

Dichotomous and continuous data were calculated using Mantel-Haenszel (M-H) risk ratios (RR), and Inverse-Variance (IV) mean differences
(MD), respectively, with 95% confidence intervals (CI), and estimates of effects were summarized by forest plots. Except for adverse events, all
results were evaluated in the meta-analysis. Heterogeneity among studies was assessed by using Cochran Q-statistic (P < 0.10 considered
statistically significant), I2, and visual inspection of forest plots. A fixed-effects model was performed when I2 < 50%; otherwise, the random-
effects model was used. In addition, funnel plots were used to assess for potential publication bias across outcomes over 10 studies.
Subgroup analysis was performed according to different ultrasound strategies with significant heterogeneity. Qualitative analysis was
performed when it was challenging to perform subgroup analysis. In addition, a sensitivity analysis was performed. All relevant data were
analyzed using RevMan 5.4.1 (The Cochrane Collaboration, 2020) and STATA 17.0 (StataCorp, 2021).

Results
Study selection
Page 3/13
There were 1309 papers initially obtained after searching, and 23 relevant studies were also searched from the clinical trial registration website.
A total of 89 papers were duplicated and excluded. After reading the article titles and abstracts, 1218 irrelevant studies were excluded. After
reading the complete text, four similar studies were published by the same research team, two studies without relevant endpoints, one study in
children, three studies without critical care ultrasound-guided fluid resuscitation, one study without septic shock, and two studies without
comparing the ultrasound guidance with early goal-directed therapy were further excluded. Finally, 12 studies were included (Fig. 1).

Study characteristics
A total of 947 participants, of whom 473 were treated with critical care ultrasound-guided fluid resuscitation, were included [19, 20, 25–34]
(Table 1).

Nine studies reported fluid volume, of which six reported 24-hour fluid volume as mean ± SD [27, 28] and median with interquartile range [20,
25, 29, 33], one reported 24-hour fluid balance [32], one reported target titration of fluids [30], and one reported 6-hour infusion volumes [26].
Three studies reported the dose of norepinephrine by "µg/kg/h" [27, 30] and the maximum dose [26], one reported the duration of
norepinephrine [29], and one reported the total dose of norepinephrine over 24 hours [28]. Two studies respectively reported the dose of
dobutamine [27, 30] and the number of participants [26, 33]. Three studies reported the duration of vasopressin [26, 27, 30], one reported
without infusion duration [20], and one reported the participants who infusion it in the first 6 hours [25].

Length of stay was expressed as a mean ± SD in two studies [19, 30] and median with interquartile range in three studies [20, 25, 27]. Length of
ICU stay was expressed as median with interquartile range in three studies [26, 27, 29], the median in one study [32], and mean ± SD in one
study [30]. Length of stay free ICU admission was reported in two studies [20, 33].

Page 4/13
 Table 1
The characteristics of studies included
Country, No. of Intervention Male Mean APACHE II / Primary outcome / Primary end‑points
age SOFA 3 score
SC / Patients (%) at baseline
MC 1 (years)

Alhabashy Ireland 87 CCUGFR 57.1 42.33 ± (A) 23.95 ± 30-day mortality

8.96 3.45
(2021) SC EGDT2 51.1
44.44 ± 24.76 ± 4.26
7.65

Elsayed Egypt 60 CCUGFR 56.7 38.6 ± (A) 25.4 ± 3.7 30-day mortality
3.3
(2020) SC EGDT 53.3 25.5 ± 3.7
39.4 ±
3.7

Garg India 36 CCUGFR 55.6 37.39 ± (A) 21.38 ± IVCCI <20%;

15.53 9.61
(2016) SC EGDT 44.4 MAP of ≥ 65 mmHg and CVP >12 mmHg4
44.5 ± 20.66 ± 7.39
18.73

Ismail Egypt 80 CCUGFR 55.0 56 - reach a score of 16 according to the

ultrasound scoring system
(2019) SC EGDT 42.5 58 -
CVP of 8–12 mmHg

Lanspa USA 30 CCUGFR 47.0 69(61– (A)29(23–41) changed in SOFA score at 48 h

77)
(2018) SC EGDT 53.0 33 (31–41)
64(49–
75)

Li China 74 CCUGFR 46.0 62.1 ± - CVP of 8–12 mmHg, MAP ≥ 65 mmHg,

15.3 urine volume ≥ 0.5 mL/kg/h, and ScvO2 5
(2019) SC EGDT 48.6 - ≥ 0.70 within 6 hours
64.2 ±
17.5

Li China 94 CCUGFR 49.0 54.5 ± (A) 20.8 ± 8.2 28-day mortality

15.2
(2021) SC EGDT 62.2 21.8 ± 6.7
56.7 ±
11.0

Musikatavorn Thailand 202 CCUGFR 52.5 65.3 ± - 30-day mortality

20.1
(2021) SC EGDT 62.4 -
63.7 ±
16.8

Qi China 68 CCUGFR 77.8 65.5(50– (A) 18(18- in-hospital mortality rate, 90-day survival
72) 20.5) rate
(2020) SC EGDT 75
67(50.5– 19.5(18-24.5)
73)

Sricharoenchai Thailand 90 CCUGFR - - (SO) 4(3–6) the 30-day all-cause mortality

(2019) SC EGDT - - 4(3–6)

All results are present in mean (median if not reported).

1 MC: multicenter, SC: single-center.

2 CCUGFR: critical care ultrasound-guided fluid resuscitation, EGDT: early goal directed therapy.

3 (A) –APACHE II, acute physiology and chronic health evaluation II, (SO)–SOFA score, Sepsis-related Organ Failure score.

4 IVCCI: Inferior vena cava collapsibility index, MAP: mean arterial pressure, CVP: central venous pressure.

Page 5/13
 Country, No. of Intervention Male Mean APACHE II / Primary outcome / Primary end‑points
age SOFA 3 score
SC / Patients (%) at baseline
MC 1 (years)

Yu China 86 CCUGFR 71.4 54.1 ± (A) 22.2 ± 6.1 the lactate clearance rate (LCR) at 6 h
15.4
(2022) SC EGDT 63.6 23.6 ± 5.5
57.8 ±
15.7

Zhuang China 40 CCUGFR 40.0 71.6 ± (SO) 12.2 ± 6-hour blood pressure achieved rate (MAP
11.3 5.1 ≥ 65 mmHg), 24-hour resuscitation fluid
(2020) SC EGDT 55.0 volume
71.6 ± 14.3 ± 5.0
19.2

All results are present in mean (median if not reported).

1 MC: multicenter, SC: single-center.

2 CCUGFR: critical care ultrasound-guided fluid resuscitation, EGDT: early goal directed therapy.

3 (A) –APACHE II, acute physiology and chronic health evaluation II, (SO)–SOFA score, Sepsis-related Organ Failure score.

4 IVCCI: Inferior vena cava collapsibility index, MAP: mean arterial pressure, CVP: central venous pressure.

5 ScvO2: Systemic central venous blood oxygen saturation.

Primary Outcome
The mortality was analyzed using a fixed-effects model (Fig. 2). Critical care ultrasound-guided fluid resuscitation was associated with lower
mortality (RR 0.78; 95% CI, 0.65, 0.94; P = 0.007). The heterogeneity between studies was low (I2 = 0%, P = 0.45). The funnel plot analysis
indicated no significant publication bias for mortality (Supplementary Fig. 6). The sensitivity analysis showed that the mortality was reliable
(Supplementary Fig. 7).
Secondary Outcomes and Subgroup Analysis
The 24-hour fluid volume was analyzed using a fixed-effects model (Fig. 3a). The fluid volume at 24 hours was significantly reduced in critical
care ultrasound-guided fluid resuscitation (MD -1.02; 95%CI, -1.28, -0.75; P < 0.001) with low heterogeneity (I2 = 0%, P = 1.00).

Norepinephrine dose was analyzed using a fixed-effect model (Fig. 3b). The dose of norepinephrine was increased in critical care ultrasound-
guided fluid resuscitation (MD 0.07; 95%CI, 0.02, 0.11; P = 0.002). The heterogeneity was low (I2 = 45%, P = 0.18). The dobutamine dose was
analyzed using a fixed-effects model (Fig. 3c). The dobutamine dose was increased (MD 2.2; 95% CI, 0.35, 4.04; P = 0.02). The heterogeneity
with low (I2 = 0%, P = 0.61). The number of dobutamine users was analyzed using a fixed-effects model (Fig. 3d). Critical care ultrasound-
guided fluid resuscitation did not reduce the risk of dobutamine users (RR 1.67; 95%CI, 0.52, 5.36; P = 0.39). The heterogeneity was low (I2 = 0%,
P = 0.86). The duration of vasopressin infusion was analyzed using a random-effects model (Fig. 3e). The duration of vasopressin infusion
was not significantly changed by critical care ultrasound-guided fluid resuscitation (MD -5.46; 95%CI, − 38.78, 27.86; P = 0.75). The
heterogeneity was high (I2 = 97%, P < 0.001). Due to only a small number of studies included, subgroup analysis was difficult. Thus, a single
study effect analysis was adopted. Taking LVOT-VTI, passive leg raising test, IVC-related measures, or only IVC-related measures to evaluate
fluid responsiveness was able to have an advantage in the duration of vasopressin infusion [26, 27]. A study revealed that using LVOT-VTI
assessing stroke volume and stroke volume variability as fluid responsiveness could not shorten the duration of vasopressin infusion [30].

Length of hospital stay was analyzed using a random-effects model (Fig. 3f). Critical care ultrasound-guided fluid resuscitation did not shorten
the length of hospital stay (MD -2.19; 95%CI, -6.28, 1.91; P = 0.29). The heterogeneity was high (I2 = 91%, P < 0.001). Thus, we performed
subgroup analyses (Figs. 4). According to different ultrasound indicators for monitoring, they were divided into two groups: IVC-related
measures and echocardiography. After removing this factor, the results showed that IVC-related measures could reduce the length of hospital
stay (MD -2.91; 95%CI, -5.2, -0.62; P = 0.01). The heterogeneity was low (I2 = 8%, P = 0.34). However, the heterogeneity in the echocardiography
group was high (I2 = 97%, P < 0.001). Qualitative analysis showed that using passive leg raising test combined with echocardiography to
assess fluid reactivity showed superiority in the length of hospital stay [19]. Length of ICU stay was analyzed using a random-effects model
(Fig. 3g). Critical care ultrasound-guided fluid resuscitation also did not reduce the length of ICU stay (MD -0.71; 95%CI, -4.43, 3.02; P = 0.71).
The heterogeneity was high (I2 = 85%, P < 0.001). We also performed subgroup analyses of the ICU stay by different ultrasound strategies
(Figs. 5). The results showed that IVC-related measures or IVC-related measures combined with others could reduce the length of ICU stay (MD
Page 6/13
-2.77; 95%CI, -4.51, -1.02; P = 0.002), with low heterogeneity (I2 = 0%, P = 0.57). Length of free ICU stay treatment was analyzed using a fixed-
effects model (Fig. 3h). Critical care ultrasound-guided fluid resuscitation did not significantly change the length of free ICU stay (MD 1.5; 95%
CI, − 3.81, 6.81; P = 0.58). The heterogeneity was low (I2 = 0%, P = 0.55).

Sensitivity analyses showed that secondary outcomes, including 24-hour fluid volume, norepinephrine dose, dobutamine dose, number of
dobutamine users, length of hospital stay, length of ICU stay, and free ICU stay were credible (Supplementary Figs. 8–11, 13–15), but not the
duration of vasopressin infusion (Supplementary Fig. 12). Publication bias was not evaluated due to only a small number of studies included
in the secondary outcome.

Discussion
Few meta-analyses have compared critical care ultrasound-guided fluid resuscitation with early goal-directed therapy in patients with septic
shock. This systematic review and meta-analysis of 12 studies comprehensively reviewed RCTs published in recent years, and subgroup
analyses or qualitative assessments were performed for outcomes with more significant heterogeneity.

We found that critical care ultrasound-guided fluid resuscitation in septic shock patients can reduce mortality. In secondary outcomes, critical
care ultrasound-guided fluid resuscitation in patients with septic shock reduced 24-hour fluid volume, increased norepinephrine and
dobutamine doses, and did not reduce the number of patients using dobutamine. Moreover, taking IVC-related measures and passive leg
raising test combined with LVOT-VTI, or IVC-related measures, to evaluate fluid responsiveness had advantageous in reducing the duration of
vasopressin. The increasing dose of vasoactive drugs in the critical care ultrasound-guided fluid resuscitation group, which may maintain
organ tissue perfusion by reducing the amount of fluid, will bring more side effects. Vasoactive drugs also play an essential role in the
treatment of septic shock. In clinical practice, vasoactive drugs are required when blood pressure cannot maintain organ and tissue perfusion
even by adequate fluids. Vasoactive drugs regulate vascular tone through some receptors to improve fluid distribution and tissue perfusion and
avoid fluid overload [35].

There was no significant advantage of critical care ultrasound-guided fluid resuscitation in the length of hospital and ICU stay. However, these
results were heterogeneous, which may be related to different critical care ultrasound strategies. Therefore, we divided the critical care
ultrasound measures into two groups with IVC-related indicators and without these. In subgroup analysis, the critical care ultrasound study
with IVC-related measures could significantly reduce the length of hospital stay and ICU stay, especially using passive leg raising test
combined with others to assess fluid reactivity showing superiority in the length of hospital stay. The use of dynamic indicators, including
echocardiography to guide fluid resuscitation, is weakly recommended in Surviving Sepsis Campaign, and the quality of the evidence is
deficient. Other organ and volume responsiveness indicators for monitoring have not been proposed [10]. Subgroup analysis showed that IVC-
related measures such as the diameter and morphological variability of the IVC combined with others to guide fluid resuscitation had a better
prognosis than echocardiography alone.

Sepsis is a disordered manifestation of the body's systemic inflammatory response to infection, and septic shock is a severe form of sepsis.
Although new therapies have been sought in recent years, the results have mainly been disappointing [36]. Early identification of sepsis,
especially septic shock, and timely treatment are essential to reducing mortality and complications [10]. Compared to the 2016 SSC guideline,
the 2021 SSC guideline did not change the initial fluid resuscitation for patients in septic shock. However, it downgraded the recommendation
of fluid volume for early resuscitation in sepsis from a strong recommendation to a weak recommendation [10, 37]. Initial fluid resuscitation
has been a highly controversial issue, and most of recommendations are based on clinical practice in multiple extensive studies. The need for
early fluid resuscitation in patients with sepsis-induced hypotension or septic shock is based on their pathophysiological changes. The source
of fluid resuscitation is the early hypovolemic state of the patient due to systemic vasodilation and increased vascular permeability. Therefore,
fluid resuscitation can restore intravascular volume, increase cardiac output, and improve oxygen delivery to improve tissue perfusion [38]. It
should make physicians think about using the guideline to individualize therapy. Not all volume expansion effects are as we expect. Due to
individual differences in patients, organ function and volume responsiveness are essential in determining whether fluid resuscitation plays a
therapeutic or detrimental effect [39]. In recent years, critical care ultrasound has played an increasingly important role, running through the
whole process of diagnosis and treatment of critical patients. It has become a part of standard practice in ICU [40]. As a non-invasive
monitoring method, critical care ultrasound can effectively assess patient organ function and volume responsiveness [41]. As a dynamic
indicator for monitoring volume responsiveness, IVC-related measures can represent right atrial pressure and indicator for cardiopulmonary
interaction to guide fluid therapy with higher accuracy. However, it should be noted that IVC-related measures for monitoring are also affected
by many factors, such as diseases affecting the return of blood to the right heart, venous thrombosis, and compression of blood vessels [42].
LVOT-VTI is an ultrasound assessment of hemodynamics by Doppler-derived measure of cardiac output and stroke volume [43]. Although it
has been found in several studies to predict fluid responsiveness, it has some drawbacks, particularly in severe aortic regurgitation or
obstruction, arrhythmias, and there will be severe errors in the measurement [44, 45]. Vignon, P et al. compared several ultrasound indicators
for monitoring fluid responsiveness in mechanically ventilated patients and found that the LVOT-VTI has the highest sensitivity and measuring
Page 7/13
the diameter of the superior vena cava and respiratory variability has the highest specificity, which is better than IVC-related measures and
LVOT-VTI [46]. For measurement accuracy, we should take appropriate measures according to its characteristics, even use more than one
measure to assess fluid responsiveness.

Of course, this systematic review and meta-analysis also has some limitations. Most RCTs are single-center studies, lacking higher-quality
RCTs. In addition, there is heterogeneity among some of the included studies, and the same outcome may be expressed in different ways. It is
challenging to combine them, resulting in fewer studies for some secondary outcomes and limited certainty.

Conclusion
This systematic review and meta-analysis, as we know, is the most comprehensive to date, describing a comparison of critical care ultrasound-
guided fluid resuscitation with early goal-directed therapy in patients with septic shock. Critical care ultrasound-guided fluid resuscitation in
septic shock patients can reduce mortality and 24-hour fluid volume and increase vasoactive drugs' dose. The critical care ultrasound strategy
with IVC-related measures can reduce the length of hospital and ICU stay. Taking LVOT-VTI, passive leg raising test, IVC-related measures, or
only IVC-related measures to evaluate fluid responsiveness was advantageous. Therefore, critical care ultrasound-guided fluid resuscitation
can improve the prognosis of patients with septic shock. Using ultrasound strategies, including IVC-related measures, LVOT-VTI, and passive
leg raising test guiding fluid resuscitation may be more effective.

Abbreviations
SSC: Surviving Sepsis Guideline; EGDT: Early goal-directed therapy; CCUGFR: Critical care ultrasound-guided fluid resuscitation; ICU: Intensive
care unit; IVC: Inferior vena cava; IVCCI: Inferior vena cava collapsibility index; LVOT-VTI: Left ventricular outflow tract velocity time integral;
RCTs: Randomized controlled trials; mean±SD: Mean and standard deviation; M-H: Mantel-Haenszel; RR: Risk ratios; IV: Inverse-Variance; MD:
Mean differences; CI: Confidence intervals; MC: Multicenter; SC: Single-center; A: APACHE II, acute physiology and chronic health evaluation II;
SO: SOFA score, Sepsis-related Organ Failure score; MAP: Mean arterial pressure; CVP: Central venous pressure; ScvO2: Systemic central
venous blood oxygen saturation

Declarations
Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Competing interests

All authors declare no competing interests.

Funding

This research received no funding.

Authors' contributions

Z-YC conceived the study, participated in the design, acquired data, and drafted the manuscript. XH conceived the study, extracted data, and
performed the statistical analysis. YL and M-JW participated in data interpretation and final drafting of the manuscript. B-BW worked on
collecting data and designing the study. LW contributed to the study's design, and H-XJ edited and examined the manuscript. All authors read
and approved the final manuscript.

Acknowledgements

Page 8/13
The authors' gratitude Xing-shun Qi, MD, for giving consultations about this study.

References
1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM et al:
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315(8):801-810.
2. Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S: Recognizing Sepsis as a Global Health Priority - A WHO Resolution.
The New England Journal of Medicine 2017, 377(5):414-417.
3. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM et al: Surviving Sepsis
Campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicine 2004, 32(3):858-873.
4. van Drumpt A, van Bommel J, Hoeks S, Grüne F, Wolvetang T, Bekkers J, Ter Horst M: The value of arterial pressure waveform cardiac
output measurements in the radial and femoral artery in major cardiac surgery patients. BMC Anesthesiology 2017, 17(1):42.
5. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SAR et al: Goal-directed
resuscitation for patients with early septic shock. The New England Journal of Medicine 2014, 371(16):1496-1506.
6. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF et al: Trial of early, goal-
directed resuscitation for septic shock. N Engl J Med 2015, 372(14):1301-1311.
7. Saoraya J, Wongsamita L, Srisawat N, Musikatavorn K: The effects of a limited infusion rate of fluid in the early resuscitation of sepsis on
glycocalyx shedding measured by plasma syndecan-1: a randomized controlled trial. Journal of Intensive Care 2021, 9(1).
8. Corl KA, Prodromou M, Merchant RC, Gareen I, Marks S, Banerjee D, Amass T, Abbasi A, Delcompare C, Palmisciano A et al: The Restrictive
IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study. Crit Care Med 2019, 47(7):951-959.
9. Self WH, Semler MW, Bellomo R, Brown SM, deboisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE et al: Liberal Versus
Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Annals of Emergency Medicine 2018,
72(4):457-466.
10. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC et al:
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine 2021,
49(11):e1063-e1143.
11. Brown SM, Kasal J: Bedside Ultrasound in the Intensive Care Unit: Where Is the Evidence? Seminars In Respiratory and Critical Care
Medicine 2015, 36(6):878-889.
12. Shenoy MM, Dhala A, Khanna A: Transesophageal echocardiography in emergency medicine and critical care. The American Journal of
Emergency Medicine 1991, 9(6):580-587.
13. Lichtenstein DA: BLUE-protocol and FALLS-protocol: two applications of lung ultrasound in the critically ill. Chest 2015, 147(6):1659-1670.
14. Vieillard-Baron A, Millington SJ, Sanfilippo F, Chew M, Diaz-Gomez J, McLean A, Pinsky MR, Pulido J, Mayo P, Fletcher N: A decade of
progress in critical care echocardiography: a narrative review. Intensive Care Medicine 2019, 45(6):770-788.
15. Ñamendys-Silva SA, Garrido-Aguirre E, Romero-González JP, Mena-Arceo RG, Rojo Del Moral O, González-Chon O: Pulmonary Ultrasound: A
New Era in Critical Care Medicine. Ultrasound Q 2018, 34(4):219-225.
16. Nicolaou S, Talsky A, Khashoggi K, Venu V: Ultrasound-guided interventional radiology in critical care. Critical Care Medicine 2007, 35(5
Suppl):S186-S197.
17. Corradi F, Brusasco C, Via G, Tavazzi G, Forfori F: Renal Doppler-Based Assessment of Regional Organ Perfusion in the Critically Ill Patient.
Shock (Augusta, Ga) 2021, 55(6):842-843.
18. Rusu D-M, Grigoras I, Blaj M, Siriopol I, Ciumanghel A-I, Sandu G, Onofriescu M, Lungu O, Covic AC: Lung Ultrasound-Guided Fluid
Management versus Standard Care in Surgical ICU Patients: A Randomised Controlled Trial. Diagnostics 2021, 11(8).
19. Li G, Wei F, Zhang G, Sun L, Lian R: Clinical value of early liquid resuscitation guided by passive leg-raising test combined with
transthoracic echocardiography in patients with septic shock. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2019, 31(4):413-417.
20. Yu K, Zhang S, Chen N, Chen M, Zhang W, Xia Q, Lei Q, Gao Z, Wu L, Jin C et al: Critical care ultrasound goal-directed versus early goal-
directed therapy in septic shock. Intensive Care Medicine 2022, 48(1):121-123.
21. Huan C, Lu C, Song B, Li PC, Ren HS, Chu YF, Min D, Wang YP, Wang P, Wang CT: The shape change index (SCI) of inferior vena cava (IVC)
measuring by transabdominal ultrasound to predict the presence of septic shock in intensive care unit (ICU) patients. European Review For
Medical and Pharmacological Sciences 2019, 23(6):2505-2512.

Page 9/13
22. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
International Journal of Surgery (London, England) 2010, 8(5):336-341.
23. McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A: Estimating the sample mean and standard deviation from commonly reported
quantiles in meta-analysis. Stat Methods Med Res 2020:962280219889080.
24. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA: Cochrane handbook for systematic reviews of interventions:
John Wiley & Sons; 2019.
25. Musikatavorn K, Plitawanon P, Lumlertgul S, Narajeenron K, Rojanasarntikul D, Tarapan T, Saoraya J: Randomized Controlled Trial of
Ultrasound-guided Fluid Resuscitation of Sepsis-Induced Hypoperfusion and Septic Shock. West J Emerg Med 2021, 22(2):369-378.
26. Li L, Ai Y, Wang X, Zhang H, Ma X, Huang L, Ai M, Peng Q, Zhang L: Effect of focused cardiopulmonary ultrasonography on clinical
outcome of septic shock: a randomized study. The Journal of international medical research 2021, 49(5):3000605211013176.
27. Alhabashy WS, Shalaby OM, Elgebaly AS, El Ghafar MSA: Echocardiography-guided hemodynamic management of severe sepsis and
septic shock in adults: A randomized controlled trial. Anaesthesia, Pain and Intensive Care 2021, 25(6):722-732.
28. Yan Z, Linfeng D, Lu C, Jun L, Yinghao P, Jian W: Inferior vena cava diameter combined with lung ultrasound B-line score to guide fluid
resuscitation in patients with septic shock. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020, 32(11):1356-1360.
29. Qi B, Yang W, Zhang H, Li G, Cai J, Zhang X, Jiang F: Clinical application of inferior vena cava inspiratory collapsibility in early goal-
directed therapy of septic shock. Chinese Journal of Respiratory and Critical Care Medicine 2020, 19(3):246-250.
30. Elsayed Afandy M, El Sharkawy SI, Omara AF: Transthoracic echocardiographic versus cardiometry derived indices in management of
septic patients. Egyptian Journal of Anaesthesia 2020, 36(1):312-318.
31. Sricharoenchai T, Saisirivechakun P: Clinical outcomes of C-guided versus static central venous pressure-guided fluid resuscitation in
patients with sepsis and/or septic shock in Thammasat University Hospital. Intensive Care Medicine Experimental 2019, 7.
32. Ismail RM, Dahroug AH, Zaytoun TM: Determination of end point of fluid resuscitation using simplified lung ultrasound protocol in
patients with septic shock. Egyptian Journal of Chest Diseases and Tuberculosis 2019, 68(1):102-107.
33. Lanspa MJ, Burk RE, Wilson EL, Hirshberg EL, Grissom CK, Brown SM: Echocardiogram-guided resuscitation versus early goal-directed
therapy in the treatment of septic shock: a randomized, controlled, feasibility trial. Journal of Intensive Care 2018, 6.
34. Garg M, Sen J, Goyal S, Chaudhry D: Comparative evaluation of central venous pressure and sonographic inferior vena cava variability in
assessing fluid responsiveness in septic shock. Indian Journal of Critical Care Medicine 2016, 20(12):708-713.
35. Li Y, Xiaozhu Z, Guomei R, Qiannan D, Hahn RG: Effects of vasoactive drugs on crystalloid fluid kinetics in septic sheep. PloS one 2017,
12(2):e0172361.
36. Angus DC, van der Poll T: Severe sepsis and septic shock. The New England Journal of Medicine 2013, 369(9):840-851.
37. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME et al: Surviving Sepsis
Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Medicine 2017, 43(3):304-377.
38. Bakker J, Kattan E, Annane D, Castro R, Cecconi M, De Backer D, Dubin A, Evans L, Gong MN, Hamzaoui O et al: Current practice and
evolving concepts in septic shock resuscitation. Intensive Care Medicine 2022, 48(2):148-163.
39. Monnet X, Marik PE, Teboul J-L: Prediction of fluid responsiveness: an update. Annals of Intensive Care 2016, 6(1):111.
40. Wilson JG, Breyer KEW: Critical Care Ultrasound: A Review for Practicing Nephrologists. Advances In Chronic Kidney Disease 2016,
23(3):141-145.
41. Shokoohi H, Boniface KS, Pourmand A, Liu YT, Davison DL, Hawkins KD, Buhumaid RE, Salimian M, Yadav K: Bedside Ultrasound Reduces
Diagnostic Uncertainty and Guides Resuscitation in Patients With Undifferentiated Hypotension. Critical Care Medicine 2015, 43(12):2562-
2569.
42. Kaptein MJ, Kaptein EM: Inferior Vena Cava Collapsibility Index: Clinical Validation and Application for Assessment of Relative
Intravascular Volume. Advances In Chronic Kidney Disease 2021, 28(3):218-226.
43. Navaratnam M, Punn R, Ramamoorthy C, Tacy TA: LVOT-VTI is a Useful Indicator of Low Ventricular Function in Young Patients. Pediatric
Cardiology 2017, 38(6):1148-1154.
44. Ma G-G, Xu L-Y, Luo J-C, Hou J-Y, Hao G-W, Su Y, Liu K, Yu S-J, Tu G-W, Luo Z: Change in left ventricular velocity time integral during
Trendelenburg maneuver predicts fluid responsiveness in cardiac surgical patients in the operating room. Quantitative imaging in medicine
and surgery 2021, 11(7):3133-3145.
45. Blanco P: Rationale for using the velocity-time integral and the minute distance for assessing the stroke volume and cardiac output in
point-of-care settings. Ultrasound J 2020, 12(1):21.
46. Vignon P, Repessé X, Bégot E, Léger J, Jacob C, Bouferrache K, Slama M, Prat G, Vieillard-Baron A: Comparison of Echocardiographic
Indices Used to Predict Fluid Responsiveness in Ventilated Patients. American journal of respiratory and critical care medicine 2017,

Page 10/13
 195(8):1022-1032.

Figures

Figure 1

Flowchart of the search strategy in this systematic review and Meta-analysis.

Page 11/13
Figure 2

The mortality of septic shock patients based on the critical care ultrasound-guided fluid resuscitation treatment. The pooled effects were
calculated by the M-H method with the fixed-effects model.

Figure 3

24h fluid administration (a), norepinephrine dose (b), dobutamine dose (c), the number of dobutamine users (d), duration of vasopressin
infusion (e), the length of hospital stay (f), ICU stay (g), and free ICU stay (h) of septic shock patients based on the critical care ultrasound-
guided fluid resuscitation treatment. The pooled effects were calculated by the M-H or IV method with the fixed-effects or random-effects
model.

Page 12/13
Figure 4

The subgroup in total length of hospital stay in septic shock patients based on the critical care ultrasound-guided fluid resuscitation treatment.
The pooled effects were calculated by the IV method with the random-effects model.

Figure 5

The subgroup in ICU stay in septic shock patients based on the critical care ultrasound-guided fluid resuscitation treatment. The pooled effects
were calculated by the IV method with the random-effects model.

Supplementary Files
This is a list of supplementary files associated with this preprint. Click to download.

SupplementaryFiguresinCriticalcareultrasoundguidedfluidresuscitationinpatientswithsepticshockAsystematicreviewandMetaanalysis.docx

Page 13/13