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  • Review
  • Open Access

Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data

Critical Care201418:696

https://doi.org/10.1186/s13054-014-0696-5

  • Published:

Abstract

Fluid bolus therapy (FBT) is a standard of care in the management of the septic, hypotensive, tachycardic and/or oliguric patient. However, contemporary evidence for FBT improving patient-centred outcomes is scant. Moreover, its physiological effects in contemporary ICU environments and populations are poorly understood. Using three electronic databases, we identified all studies describing FBT between January 2010 and December 2013. We found 33 studies describing 41 boluses. No randomised controlled trials compared FBT with alternative interventions, such as vasopressors. The median fluid bolus was 500 ml (range 100 to 1,000 ml) administered over 30 minutes (range 10 to 60 minutes) and the most commonly administered fluid was 0.9% sodium chloride solution. In 19 studies, a predetermined physiological trigger initiated FBT. Although 17 studies describe the temporal course of physiological changes after FBT in 31 patient groups, only three studies describe the physiological changes at 60 minutes, and only one study beyond this point. No studies related the physiological changes after FBT with clinically relevant outcomes. There is a clear need for at least obtaining randomised controlled evidence for the physiological effects of FBT in patients with severe sepsis and septic shock beyond the period immediately after its administration.

‘Just as water retains no shape, so in warfare there are no constant conditions’

Sun Tzu (‘The Art of War’)

Keywords

  • Septic Shock
  • Severe Sepsis
  • Cardiac Index
  • Continuous Renal Replacement Therapy
  • Fluid Responsiveness

Introduction

All critically ill patients receive intravenous (IV) fluids, which are given to maintain physiological homeostasis, or as a vehicle for drug administration, or as direct therapeutic administration to correct perceived haemodynamic instability [1]-[4]. In these situations, where there is a perceived reduction in venous return and cardiac output secondary to vasodilatation and/or hypovolaemia, using IV fluid to increase intravascular volume is believed to effectively compensate for these changes in vascular tone by increasing stroke volume in accordance with the Frank-Starling principle [5]-[10].

Several mechanisms for delivering IV fluids, both diagnostically and therapeutically under such circumstances, have been described. These include Weil’s central venous pressure (CVP)-guided fluid challenge technique [10]-[13], the timed and rapid infusion methods favoured by Shoemaker [7],[8],[14]-[16] and, more recently, techniques involving echocardiographic or ultrasonographic assessment of fluid responsiveness following low-volume IV infusion [17]. However, the current standard of care in the management of septic, hypotensive, tachycardic and/or oliguric patients is fluid bolus therapy (FBT), where IV fluid is rapidly administered in discrete boluses [18]-[21]. While the ideal fluid bolus would be a discrete volume of a specific fluid administered at a specified rate, accounting for individual patient features and with a defined aim (Figure 1) [11], there is no current agreement regarding exactly what defines a fluid bolus. Moreover, although strong overall consensus regarding the importance of FBT exists [18]-[20], there appears to be little randomized controlled information on the magnitude and duration of its physiological effects, or on the direct positive impact of FBT on patient outcome in sepsis as an independent intervention [22].
Figure 1
Figure 1

Describing the concept of idealised fluid bolus therapy. (A) Diagram describing the key criteria defining the concept of a fluid bolus. (B) Diagram describing the idealised concept of fluid bolus therapy in critical care, including purpose, triggers, end-points and purported physiological effects of such resuscitation.

In contrast, an expanding body of evidence suggests that FBT may contribute to a positive fluid balance, which, in turn, is independently associated with a variety of adverse outcomes in the critically ill [23]-[28]. Recent experimental evidence suggests rapid fluid infusion can also damage the endothelial glycocalyx [29],[30], a structure already at risk in patients with sepsis [31], leading to endothelial disruption and organ dysfunction [32],[33]. It appears that we need a better understanding of both the current evidence base for FBT and how best to apply it in the clinical setting [34],[35].

Accordingly, we systematically reviewed the contemporary literature to determine current practice and to identify the independent effects of FBT on both physiological and patient-centred outcomes in the management of severe sepsis and septic shock in critical care practice.

Methods

We interrogated the MEDLINE, CENTRAL and EMBASE electronic reference databases using a combination of search terms (Figure 2). The reference lists of retrieved articles were examined for additional studies of potential relevance. The search was carried out in December 2013. To achieve contemporary relevance results were arbitrarily limited to this decade (2010 to 2013) and to English language studies in humans. Paediatric studies were excluded. This search defined a set of records of studies of fluid administration or haemodynamic optimization in patients with severe sepsis or septic shock.
Figure 2
Figure 2

Electronic search strategy. Diagrammatic representation of the search strategy combining terms representing fluid resuscitation, sepsis and clinical studies, along with predetermined limitations.

The abstracts of these records were examined to identify those studies of potential relevance. These manuscripts were retrieved and examined manually in accordance with our inclusion criteria. The studies to be included in the review were checked to ensure they had not been retracted subsequent to their publication.

Study inclusion criteria

Population of included studies

We considered clinical studies of any type describing a population of patients suffering from severe sepsis or septic shock. We also included those studies of shock or circulatory failure where either the majority of patients, or a defined subgroup of patients, had severe sepsis or septic shock.

Intervention - fluid bolus administration

For the purposes of this study a fluid bolus was a defined volume of a defined fluid administered over a defined time period. We recognised that most studies do not describe FBT in ideal terms (Figure 1) and therefore studies describing at least two of the three criteria were included in the review.

Comparator - alternatives to fluid administration

Any studies comparing FBT with the initiation of vasoactive medication, the increase of such medication or observation as an alternative to the administration of FBT were included in the review.

Between groups analysis

Where studies included in the review assigned patients to multiple treatment arms, each treatment group was treated as an individual group.

Outcome - physiological effects of bolus administration

Subsets of studies were selected from those describing FBT. The first included those reporting changes in cardiac output, heart rate, mean arterial pressure, central venous pressure, venous oxygen saturation, blood lactate concentration, urine output or haemoglobin concentration following FBT; for the purposes of inclusion, studies could describe changes in any or all of the haemodynamic parameters listed, but the direction, magnitude and duration of the change had to be extractable from tables or figures contained in the paper. The second group included those reporting non-physiological, patient-centred outcomes. Our primary outcome of interest was mortality at all reported time points. Secondary outcomes of interest included duration of ICU and hospital stay, duration of mechanical ventilation, and need for continuous renal replacement therapy (CRRT). We did not contact authors for additional information or individual patient data.

Data collection

We collected data on study type, study setting and location, study population and the aims of the study. Due to our acceptance of multiple types of study, we chose not to adopt a methodological scoring system. We examined the definition of a fluid bolus in each study fulfilling our criteria and recorded the type and volume of fluid used, as well as the rate of administration. We identified the trigger and end-points for fluid bolus administration, the number of boluses administered and the use of red cell transfusions and vasoactive medication as part of the experimental protocol. We identified the demographic group in which subsequent observations were recorded. In those studies describing the physiological effects of bolus administration, we recorded the absolute change in cardiac output, heart rate, mean arterial pressure, venous oxygen saturation, blood lactate concentration, urine output and haemoglobin concentration. In those studies reporting patient-centred outcomes we recorded mortality at all reported time points, duration of ICU and hospital stay, duration of mechanical ventilation, and need for CRRT.

Statistical analysis

We expected grossly heterogeneous results across different study types and study protocols. A meta-analysis approach could not be applied. Results are therefore presented as crude medians with full ranges. These exclude alternative units of measure, which are reported separately - for example, the median may be given in millilitres, followed by individual reporting of ml/kg.

Results

Electronic search

Our search strategy identified 2,956 articles over the period 2010 to 2013. Of these, 2,875 were excluded as duplicates, irrelevant, paediatric research or having been published in a language other than English. Of the 81 potentially relevant publications identified, 33 met our inclusion criteria (Figure 3) [36]-[68]. In total, 17 of these described the physiological changes occurring following FBT [36],[39],[40],[45],[46],[48],[50],[53]-[55],[57],[59],[60],[62],[63],[65],[66] and seven studies described patient-orientated outcome measures [37],[42],[43],[49],[58],[59],[64].
Figure 3
Figure 3

Study selection. Flow diagram of the study selection process and detailed description of study exclusions. FBT, fluid bolus therapy.

Relevant contemporary studies

The study details, population, size and aims are presented in Table 1. We identified 22 prospective observational studies, four retrospective observational studies, two quasi-experimental studies, and five randomised controlled trials (RCTs). Of the five RCTs, none compared FBT with a control intervention; two actually reported the impact of blood volume analysis on protocolized resuscitation [64],[67]; two compared hypertonic versus isotonic fluids [51],[65]; and one actually compared two vasopressors and reported fluid data as an addendum [38]. Additional study data can be found in the electronic supplemental material (Additional file 1: Table S1).
Table 1

Study settings, size, population and aims

First author

Journal

Year

Aims of study

Location

Institution(s)

Study type

Population size

Bihari [36]

Shock

2013

Investigation of the use and effects of fluid boluses in septic patients following primary resuscitation

Australia

Single centre, academic ICU

Prospective observational study

50 patients with severe sepsis or septic shock

Castellanos-Ortega [37]

Critical Care Medicine

2010

Evaluation of the impact of a standardised EGDT response to sepsis

Spain

Single centre, academic ICU

Quasi-experimental study

480 patients with septic shock

De Backer [38]

New England Journal of Medicine

2010

Assessing the effect of noradrenaline as first-line vasopressor on mortality

Europe

8 centres, mixed ICUs

Randomised clinical trial

1,679 patients with shock requiring vaspressor therapy. 1,044 patients with sepsis

Dong [39]

World Journal of Emergency Medicine

2012

Investigating the relationship between stroke volume index and passive leg raising and fluid responsiveness

China

2 centres, general ICUs

Prospective observational study

32 mechanically ventilated patients with septic shock

Freitas [40]

British Journal of Anaesthesia

2013

Evaluation of the predictive value of automated PPV for fluid responsiveness in patients with sepsis and low tidal volumes

Brazil

Single centre, academic ICU

Prospective observational study

40 patients with low tidal volume ventilation and severe sepsis or septic shock requiring a fluid challenge

Gaieski [41]

Critical Care Medicine

2010

Evaluation of the impact of a standardised EGDT response to sepsis on time to antibiotic administration and survival

USA

Single centre, academic ICU

Retrospective observational study

261 patients with severe sepsis and septic shock undergoing EGDT

Hamzaoui [42]

Critical Care

2010

Evaluation of the cardiac consequences of early administration of noradrenaline

France

Single centre, academic ICU

Prospective observational study

105 patients with septic shock requiring vasopressor commencement following initial fluid resuscitation

Hanzelka [43]

Supportive Care in Cancer

2013

Evaluation of the impact of a standardised EGDT response to sepsis

USA

Single centre, academic ED

Retrospective observational study

200 patients with cancer and severe sepsis or septic shock presenting to ED

Jacob [44]

Critical Care Medicine

2012

Evaluation of the impact of early monitored sepsis management

Uganda

2 centres, medical/treatment centres

Prospective observational study

671 patients with severe sepsis presenting within office hours

Khwannimit [45]

European Journal of Anaesthesiology

2012

Comparing SVV by Vigileo with PPV by monitor to predict fluid responsiveness

Thailand

Single centre, academic ICU

Prospective observational study

42 patients with septic shock who were mechanically ventilated with tidal volumes >8 ml/kg requiring fluid resuscitation

Lakhal [46]

Intensive Care Medicine

2013

Identification of fluid responsiveness from IABP and NIBP

France

3 centres, academic ICU

Prospective observational study

130 patients with circulatory failure requiring a fluid challenge. 58 patients with septic shock

Lanspa [47]

Journal of Critical Care

2012

Assessment of CVP and shock index to predict haemodynamic response to volume expansion when compared with CVP alone

USA

Single centre, academic ICU

Prospective observational study

25 patients with septic shock over 14 years of age

Machare-Delgado [48]

Journal of Intensive Care Medicine

2011

Predicting fluid responsiveness by comparing SVV and inferior vena caval respiratory variation by ECHO during mechanical ventilation

USA

Single centre, medical academic ICU

Prospective observational study

25 mechanically ventilated vasopressor-dependent patients who required a fluid challenge. 22 patients with severe sepsis or septic shock

MacRedmond [49]

Quality and Safety in Health Care

2010

Evaluation of the impact of implementing a quality initiative on the management of severe sepsis and septic shock

Canada

Single centre, ICU

Quasi-experimental study

74 patients with severe sepsis or septic shock admitted via ED

Mahjoub [50]

Intensive Care Medicine

2012

Assessment of the impact of volume expansion on patients with left ventricular dysfunction

France

Single centre, academic ICU

Prospective observational study

83 mechanically ventilated patients with sepsis-induced circulatory failure

McIntyre [51]

Journal of Critical Care

2012

Feasibility study comparing the effects of 5% albumin versus 0.9% saline for resuscitation in septic shock

Canada

6 centres, academic ED and ICU

Randomised clinical trial

50 patients with refractory hypotension and sepsis

Monnet [52]

Critical Care

2010

Comparing haemodynamic changes induced by noradrenaline and volume expansion using Vigileo and PiCCO

France

Single centre, academic medical ICU

Prospective observational study

80 patients with sepsis-induced circulatory failure

Monnet [53]

Critical Care Medicine

2011

Assessing the effects of noradrenaline on haemodynamics in sepsis

France

Single centre, academic medical ICU

Prospective observational study

25 patients with sepsis-induced fluid-responsive acute circulatory failure with DBP <40 mmHg, or requiring noradrenaline

Monnet [54]

Critical Care Medicine

2013

Comparing ScvO2 and markers of anaerobic metabolism as predictors of unfavourable changes in oxygen extraction

France

Single centre, academic medical ICU

Prospective observational study

51 patients with acute circulatory failure undergoing transpulmonary thermodilution monitoring, 40 patients with septic shock

Monnet [55]

Critical Care Medicine

2011

Investigation of the utility of pulse pressure as a surrogate for changes in cardiac output

France

Single centre, academic medical ICU

Prospective observational study

373 patients with acute circulatory failure requiring a fluid challenge or the introduction or dose increase of noradrenaline. 338 patients with septic shock

O’Neill [56]

Journal of Emergency Medicine

2012

Evaluation of the most difficult elements of a SSC protocol to implement in a community-based ED

USA

Single centre, community ED

Retrospective observational study

79 with severe sepsis or septic shock remaining hypotensive following 2,000 ml of fluid resuscitation

Ospina-Tascon [57]

Intensive Care Medicine

2010

Evaluation of the effects of fluid administration on microcirculatory alterations in sepsis

Belgium

Single centre, academic ICU

Prospective observational study

60 patients with severe sepsis requiring fluid challenge. 37 within 24 hours of diagnosis, 23 after 48 hours

Patel [58]

Annals of Pharmacotherapy

2010

Investigation of the implementation and effects of introducing the SSC guidelines

USA

Single centre, community ICU

Prospective observational study

112 patients with sepsis or septic shock

Pierrakos [59]

Intensive Care Medicine

2012

Evaluation of the correlation between changes in MAP and CI following fluid challenge

Belgium

Single centre, academic ICU

Prospective observational study

51 patients with septic shock undergoing invasive haemodynamic monitoring and requiring a fluid challenge

Pottecher [60]

Intensive Care Medicine

2010

Assessment of sublingual microcirculatory changes in response to fluid challenge

France

2 centres, academic ED

Prospective observational study

25 mechanically ventilated patients with severe sepsis or septic shock within 24 hours of ICU admission demonstrating pre-load dependency

Sanchez [61]

Anaesthesia and Intensive Care

2011

Measuring the response to a fluid load in patients with and without septic shock

Spain

Single centre, academic ICU

Prospective observational study

32 patients requiring invasive monitoring. 18 patients with septic shock

Schnell [62]

Critical Care Medicine

2013

Assessment of the effects of a fluid challenge on Doppler-based renal resistive index in critically ill patients

France

3 centres, academic ICUs

Prospective observational study

35 mechanically ventilated patients with real-time cardiac monitoring requiring a fluid challenge. 30 patients with sepsis

Sturgess [63]

Anaesthesia and Intensive Care

2010

Comparison of aortic corrected flow time, BNP and CVP as predictors of fluid responsiveness

Australia

Single centre, private ICU

Prospective observational study

10 patients with septic shock requiring a fluid challenge

Trof [64]

Critical Care Medicine

2012

Comparison of volume-guided and pressure-guided hemodynamic management in shocked patients

Netherlands

2 centres, academic, ICU

Randomised clinical trial

120 patients with shock requiring invasive haemodynamic monitoring and >48 hours of ICU admission. 72 patients with sepsis

van Haren [65]

Shock

2012

Evaluation of the effects of hypertonic versus isotonic fluid administration in patients with septic shock

Netherlands

Single centre, academic ICU

Randomised clinical trial

24 patients with septic shock enrolled within 24 hours of admission

Wacharasint [66]

Journal of the Medical Association of Thailand

2012

Evaluation of the effectiveness of three dynamic measures of fluid responsiveness in septic shock patients

Thailand

Single centre, medical ICU

Prospective observational study

20 patients with sepsis and acute circulatory failure with invasive haemodynamic monitoring stable for 15 minutes prior to inclusion

Yu [67]

Shock

2011

Evaluation of the effects of blood volume analysis compared with pulmonary artery catheter monitoring

North America

Single centre, academic ICU

Randomised clinical trial

100 patients requiring resuscitation for shock. 69 patients with severe sepsis or septic shock

Zhang [68]

Journal of Critical Care

2012

Investigation of the association between plasma protein levels and subsequent pulmonary oedema

China

Single centre, academic ICU

Retrospective observational study

62 patients with sepsis undergoing transpulmonary thermodilution assessment requiring fluid

BNP, B-type natriuretic peptide; CI, cardiac index; CVP, central venous pressure; DBP, diastolic blood pressure; ECHO, echocardiogram; ED, Emergency Department; EGDT, early goal directed therapy; IABP, intra-arterial blood pressure; MAP, mean arterial blood pressure; NIBP, non-invasive blood pressure; PiCCO, pulse contour cardiac output monitoring; PPV, pulse pressure variation; ScvO2, central venous oxygen saturation; SSC, Surviving Sepsis Campaign; SVV, stroke volume variation.

Pre-fluid bolus therapy fluid administration

Fluid resuscitation prior to study recruitment and FBT was described in 10 studies. In the five studies describing finite volumes of resuscitation fluid, the median volume administered was 2,200 ml (range 1,000 to 5,060 ml) [38],[47],[51],[53],[58]. The five remaining studies reported weight-dependent volumes of between 20 and 30 ml/kg of resuscitation (Table 2) [41],[43],[49],[56],[57].
Table 2

Description of fluid boluses, triggers, physiological end-points and primary confounders

First author

Year

Initial resuscitation

Bolus fluid type

Bolus fluid volume (ml)

Bolus fluid rate (minutes)

Physiological trigger for fluid administration

Physiological end-point for fluid administration

Number of boluses administered

Vasoactive administration?

Packed red cell transfusion?

Bihari [36]

2013

Undefined

4% albumin

750

<30

Clinician defined

Clinician defined

2

Yes

Not described

Packed red cells

20% albumin

Fresh frozen plasma

4% gelatin

0.9% saline

Castellanos-Ortega [37]

2010

Undefined

Crystalloid

1,000

30

Hypotension

CVP ≥8 mmHg, MAP ≥65 mmHg, ScvO2 ≥ 70%

Not described

Yes

Not described

Colloid

500

De Backer [38]

2010

500 ml colloid or 1,000 ml crystalloid

Crystalloid

1,000

Not defined

MAP <70 mmHg; SBP <100 mmHg, altered mental state; mottled skin; oliguria >1 hour, hyperlactataemia

Not described

Not described

Yes

Not described

Colloid

500

Dong [39]

2012

Undefined

6% HES

500

30

SBP <90 mmHg or >40 mmHg drop or need for vasopressors, oliguria >1 hour; mottled skin; HR >100 bpm

End of infusion.

1

Not described

Not described

Freitas [40]

2012

Undefined

6% HES

7 ml/kg (max 500)

30

Clinician defined

End of infusion

1

Yes

No

Gaieski [41]

2010

20-30 ml/kg

0.9% saline

500

15-20

CVP <8 mmHg

CVP >8 mmHg

Not described

Yes

Yes

Hamzaoui [42]

2010

Undefined

0.9% saline

1,000

Not defined

Undefined

Not described

Not described

Yes

Not described

Hanzelka [43]

2013

20 ml/kg

Undefined

1,000

60

Severe sepsis

SBP >90 mmHg, MAP <65 mmHg

Not described

Yes

No

500

30

Jacob [44]

2012

Undefined

0.9% saline

1,000

60

SBP <100 mmHg or hyperlactataemia

SBP increased by 10 mmHg for 2 consecutive hours to >90 mmHg

Up to 10

No

Not described

500

30

Khwannimit [45]

2012

Undefined

6% HES

500

30

Clinician defined

End of infusion

1

Yes

Not described

Lakhal [46]

2013

Undefined

4% gelatin

500

30

One or more of SBP <90 mmHg, MAP <65 mmHg , requiring vasoactive medication, oliguria, skin mottling, hyperlactataemia

End of infusion

1

Yes

Not described

Lanspa [47]

2012

5,060 ml

Crystalloid (or equivalent colloid)

20 ml/kg

<20

Clinician defined

End of infusion

1.36

Yes

Yes

Machare-Delgado [48]

2011

Undefined

0.9% saline

500

10

Clinician defined

End of infusion

1

Not described

No

MacRedmond [49]

2010

25 ml/kg

0.9% saline

500

<15

MAP <65 mmHg

CVP 8-12; MAP >65 mmHg; ScvO2 > 70%

Not described

Yes

Yes

Mahjoub [50]

2013

Undefined

0.9% saline

500

20

SBP <90 mmHg and/or need for vasoactive drugs and/or persistent lactic acidosis

End of infusion

1

Yes

Not described

McIntyre [51]

2012

2,400 ml

0.9% saline or 4% albumin

500

STAT

Undefined

Not described

6

Yes

Not described

Monnet [52]

2010

Undefined

0.9% saline

500

30

SBP <90 mmHg, SBP drop >50 mmHg if HT, and one or more of HR >100, skin mottling or oliguria

End of infusion

1

Yes

Not described

Monnet [53]

2011

2,200 ml

0.9% saline

500

10

SBP <90 mmHg, SBP drop >50 mmHg if HT, and one or more of HR >100, skin mottling or oliguria

End of infusion

1

Yes

Not described

Monnet [54]

2013

Undefined

0.9% saline

500

30

SBP <90 mmHg, SBP drop >50 mmHg if HT, and one or more of HR >100, skin mottling or oliguria

End of infusion

1

Yes

Yes

Monnet [55]

2011

Undefined

0.9% saline

500

20

SBP <90 mmHg, SBP drop >50 mmHg if HT, and one or more of HR >100, skin mottling or oliguria

End of infusion

1

Yes

Not described

O’Neill [56]

2012

20 ml/kg

0.9% saline

500

15

CVP <8 mmHg; MAP <65 mmHg; ScvO2 < 70%

CVP 8-12; MAP >65 mmHg; ScvO2 > 70%

0.68

Yes

Not described

Ospina-Tascon [57]

2010

Undefined

CSL

1,000

30

MAP <65 mmHg

End of infusion

1

Yes

Not described

4% albumin

400

Patel [58]

2010

2,000 ml

Normal saline

Undefined

30

SBP <90 mmHg; MAP <65 mmHg

Not described

1

Yes

Not described

Pierrakos [59]

2012

Undefined

CSL

100

30

Clinician defined

End of infusion

1

Yes

Not described

6% HES

500

Pottecher [60]

2010

Undefined

HES 6% or 0.9% saline

500

30

MAP <65 mmHg, skin mottling or oliguria

End of infusion

1

Yes

Not described

Sanchez [61]

2011

Undefined

Crystalloid

1,000

Undefined

Hypotension with perfusion abnormalities

 

Not described

Yes

No

Colloid

500

ITBVI >900 ml/ml or EVLWI >10 ml/kg

Schnell [62]

2013

Undefined

0.9% saline

500

15-30

Clinician defined

End of infusion

1

Yes

Not described

Sturgess [63]

2010

Undefined

4% albumin

250

15

Clinician defined

End of infusion

1

Yes

No

Trof [64]

2012

Undefined

HES or 4% gelatin

250-500

30

EVLWI <10 ml/kg or >10 ml/kg with GEDVI <850 ml/m2; PAOP >18 mmHg; MAP <65 mmHg, HR >100, SvO2 < 65% or ScvO2 < 70%; oliguria; peripheral perfusion deficits, hyperlactatemia

MAP >65 mmHg, ScvO2 > 70%, lactate clearance, diuresis >0.5 ml/kg/hour, restoration of peripheral perfusion deficits

3.48

Yes

Not described

van Haren [65]

2012

Undefined

6% HES in 0.9% saline

500

15

Septic shock

End of infusion

1

Yes

Not described

250

15

6% HES in 7.2% saline

Wacharasint [66]

2013

Undefined

HES 6%

500

30

SBP <90 mmHg or requirement for vasopressors

End of infusion

1

Yes

Not described

Yu [67]

2011

30 ml/kg in 1,000 ml increments

Crystalloid or colloid

250-500

Undefined

PAOP <12 mmHg or 12-17 mmHg with

SBP >100 mmHg, HR <100 bpm, UO >0.5 ml/kg/hour, lactate clearance, SmvO2 > 70%

Not described

Not described

Yes

SBP <100; HR >100 bpm UO <0.5 ml/kg/hour; hyperlactataemia; SvO2 > 70% or equivalent blood volume goals

Zhang [68]

2012

Undefined

Crystalloid or colloid

250-500

30

SBP <90 mmHg; HR >100 bpm; GEDVI <700 ml/m2; CVP <12 mmHg (PEEP dependent)

Pre-defined rise in CVP

Not described

Yes

Not described

CSL, compound sodium lactate solution; CVP, central venous pressure; EVLWI, extra-vascular lung water index; HES, hydroxyethyl starch; HR, heart rate; HT, hypertensive; GEDVI, global end diastolic volume index; ITBVI, intrathoracic blood volume index; MAP, mean arterial blood pressure; PAOP, pulmonary artery occlusion pressure; PEEP, positive end-expiratory pressure; SBP, systolic blood pressure; ScvO2, central venous oxygen saturation; SmvO2, mixed venous oxygen saturations; STAT, statim/immediately; SvO2, venous oxygen saturation; UO, urine output.

Initiation and cessation of fluid bolus therapy

Across the 33 studies, 19 predetermined clinical or physiological features triggered FBT. In the remaining 14 studies, FBT was triggered by clinical judgment in eight, by ‘hypotension’ in two, simply by the diagnosis of severe sepsis or septic shock in two, and remained unspecified in two (Table 2).

In the majority of studies (18 of 33) FBT ceased at the end of the bolus in question; 10 studies used predetermined immediate changes in physiological variables as end-points; four studies did not define the physiological end-points of fluid resuscitation (Table 2).

Defining fluid bolus therapy

Overall, 41 forms of FBT were described, fully or in part, in 33 studies. They are presented in Table 2. In 20 studies, the fluid type was fixed; in 13 more than one fluid type was used. In six studies the fluid type was not identified beyond the generic ‘crystalloid or colloid’. The fluid most commonly used as a bolus was 0.9% saline (17 studies), followed by 6% hydroxyethyl starch (eight studies). On the other hand, 4% albumin was used in only four studies [38],[53],[59],[65], 4% gelatin in only three [38],[48],[66], physiological lactated solutions in only two [59],[61], and 20% albumin and blood products in only one [38].

The median amount of fluid administered as a finite volume was 500 ml (range 100 to 1,000 ml). However, 20 ml/kg and 7 ml/kg were individually reported as weight-dependent boluses. The median number of boluses (24 studies) was 1 (range 0.68 to 10). Rates of administration were defined for 31 of 41 boluses with a median rate of 30 minutes (range 10 to 60 minutes).

Haemodynamic changes after fluid bolus therapy

Comparing different interventions

No RCTs compared the haemodynamic changes induced by FBT with ‘observation’ or ‘vasopressor administration’ or ‘inotropic drug administration’ or ‘continuous low dose IV fluid infusion’ or any combination of the above. The only study comparing FBT with an alternative intervention was a single, non-randomized, prospective, observational study that compared acute circulatory failure patients treated with FBT (500 ml of saline) or with increased norepinephrine dose according to clinician preference [55]. The two groups had clearly different baseline characteristics and were not directly compared.

Temporal trends in physiological changes following fluid bolus therapy

The temporal change in physiological parameters following FBT is described in 31 different groups across 17 studies (Table 3).
Table 3

Physiological effects grouped by measurement time

First author

Fluid given

Group

Time from completion of fluid administration until physiological measurement (minutes)

Measure of central tendency

Change in cardiac output estimation

Change in heart rate (bpm)

Change in mean arterial pressure (mmHg))

Change in central venous pressure (mmHg)

Change in venous oxygen saturation (%)

Change in blood lactate concentration (mmol/l)

Change in urine output

Change in haemoglobin concentration (g/L)

Haemodynamic indices measured immediately following fluid bolus administration

Machare-Delgado [48]

500 ml of 0.9% saline over 10 minutes

Responders: >10% SVI increase

0

Mean

+3.99 ml/m2/beat

       
 

500 ml of 0.9% saline over 10 minutes

Non-responders: >10% SVI increase

0

Mean

+0.57 ml/m2/beat

       

Dong [39]

500 ml of 6% HES over 30 minutes

Responders: >15% SVI increase

0

Mean

+600 ml/min/m2

-1.5

+15.2

+3.2

    
 

500 ml of 6% HES over 30 minutes

Non-responders: <15% SVI increase

0

Mean

+300 ml/min/m2

-1.2

+4.8

+2.3

    

Khwannimit [45]

500 ml of 6% HES over 30 minutes

Responders: >15% SVI increase

0

Mean

+1300 ml/min/m2

-3.3

+9.5

+3.4

    
 

500 ml of 6% HES over 30 minutes

Non-responders: <15% SVI increase

0

Mean

+200 ml/min/m2

-0.9

+3.9

+5.2

    

Lakhal [46]

500 ml of 4% gelatin over 30 minutes

Responders: >15% SVI increase

0

Mean

+900 ml/min/m2

-6

+14

+3

    
 

500 ml of 4% gelatin over 30 minutes

Non-responders: <15% SVI increase

0

Mean

+0 ml/min/m2

-3

+7

+4.5

    

Mahjoub [50]

500 ml of 0.9% saline over 20 minutes

Responders: >10% SV increase

0

Mean

+1,000 ml/min

-4

+7

+2.6

    
 

500 ml of 0.9% saline over 20 minutes

Non-responders: >10% SV increase

0

Mean

+300 ml/min

-3

+1

+2.9

    

Monnet [53]

500 ml of 0.9% saline over 10 minutes

All patients

0

Mean

+800 ml/min/m2

-7

+8

+5

    

Monnet [55]

500 ml of 0.9% saline over 20 minutes

Responders: >15% CI increase

0

Mean

+800 ml/min/m2

-2

+11

     
 

500 ml of 0.9% saline over 20 minutes

Non-responders: <15% increase in CI

0

Mean

+200 ml/min/m2

-2

+4

     

Monnet [54]

500 ml of 0.9% saline over 30 minutes

Responders: >15% VO2 increase

0

Mean

+1,000 ml/min/m2

-2

+7

 

+1%

-1.9

 

-7

 

500 ml of 0.9% saline over 30 minutes

Non-responders: <15% increase in VO2

0

Mean

+1,000 ml/min/m2

+0

+13

 

+7%

-0.3

 

-6

Schnell [62]

500 ml of 0.9% saline over 15-30 minutes

Responders: >10% increase in aortic blood flow

0

Median

+20 ml/beat

-10

+7

     
 

500 ml of 0.9% saline over 15-30 minutes

Non-responders: <10% increase in aortic blood flow

0

Median

+8 ml/beat

-1

+6

     

Sturgess [63]

250 ml of 4% albumin over 15 minutes

All patients

0

Mean

+7.5% ml/beat

       

Haemodynamic indices measured 30 minutes after fluid bolus administration

Freitas [40]

7 ml/kg, maximum 500 ml, of 6% HES over 30 minutes

Responders: >15% CO increase

30

Mean

+2,100 ml/min

-2

+11

+3

+8%

-0.1

  
 

7 ml/kg, maximum 500 ml, of 6% HES over 30 minutes

Non-responders: <15% increase in CO

30

Mean

+200 ml/min

+0

+8

+5

-3.5%

-0.2

  

Pierrakos [59]

500 ml of 6% HES or 1,000 ml of CSL over 30 minutes

Responders: >10% increase in CI

30

Mean

+600 ml/min/m2

-4

+8

+3

+3%

   
 

500 ml of 6% HES or 1,000 ml of CSL over 30 minutes

Non-responders: <10% increase in CI

30

Mean

+0 ml/min/m2

-4

+3

+2

+0%

   

Pottecher [60]

Up to 500 ml of 6% HES or 0.9% saline over 30 minutes

All patients

30

Mean

+1,400 ml/min

-2

+7

     

Wacharasint [66]

500 ml of 6% HES over 30 minutes

All patients

30

Mean

+470 ml/min/m2

+0.3

+9.2

+5.25

    

van Haren [65]

250 ml of 6% HES in 7.2% saline over 15 minutes

Hypertonic bolus

30

Mean

+300 ml/min/m2

-11

+4

+2

 

-0.2

 

-8

 

500 ml of 6% HES in 0.9% saline over 15 minutes

Isotonic bolus

30

Mean

-400 ml/min/m2

-1

+5

+4

 

-0.1

 

-9

Haemodynamic indices measured 60 minutes after fluid bolus administration

Bihari [36]

500-750 ml of 4% albumin, blood, 20% albumin FFP, 0.9% saline, 4% gelatin or platelets administered over less than 30 minutes

All patients

60

Median

 

+0

+2

+2

+0.4%

-0.2

No change

-6

Ospina-Tascon [57]

400 ml of 4% albumin or 1,000 ml of CSL over 30 minutes

Patients with early sepsis

60

Median

+300 ml/min/m2

+2

+2

+3

+2%

-0.2

  
 

400 ml of 4% albumin or 1,000 ml of CSL over 30 minutes

Patients with late sepsis

60

Median

+300 ml/min/m2

-9

+7

+1

+1%

+0.1

  

van Haren [65]

250 ml of 6% HES in 7.2% saline over 15 minutes

Hypertonic bolus

60

Mean

+400 ml/min/m2

-11

+6

+1

 

-0.3

 

-9

 

500 ml of 6% HES in 0.9% saline over 15 minutes

Isotonic bolus

60

Mean

-300 ml/min/m2

-1

+3

+3

 

-0.1

 

-12

Haemodynamic indices measured greater than 60 minutes after fluid bolus administration

van Haren [65]

250 ml of 6% HES in 7.2% saline over 15 minutes

Hypertonic bolus

120

Mean

+300 ml/ml/m2

-7

+7

+2

 

0.0

+13

-6

 

500 ml of 6% HES in 0.9% saline over 15 minutes

Isotonic bolus

120

Mean

-300 ml/min/m2

+0

+1

+2

 

-0.3

-30

-9

 

250 ml of 6% HES in 7.2% saline over 15 minutes

Hypertonic bolus

180

Mean

+100 ml/min/m2

-3

+6

+3

 

-0.3

 

-9

 

500 ml of 6% HES in 0.9% saline over 15 minutes

Isotonic bolus

180

Mean

+0 ml/min/m2

+3

+5

+3

 

-0.2

 

-6

 

250 ml of 6% HES in 7.2% saline over 15 minutes

Hypertonic bolus

240

Mean

+100 ml/min/m2

+1

+3

+3

 

-0.3

-3

-8

 

500 ml of 6% HES in 0.9% saline over 15 minutes

Isotonic bolus

240

Mean

-200 ml/min/m2

+3

+0

+3

 

-0.2

-40

-4

CI, cardiac index; CO, cardiac output; CSL, compound sodium lactate; FFP, fresh frozen plasma; HES, hydroxyethyl starch; SVI, stroke volume index; VO2, oxygen delivery.

Immediately post-infusion

Ten studies reported the physiological state after bolus administration in 18 groups immediately post-administration. In the six studies describing changes in cardiac index immediately post-FBT, cardiac index increased by a median of 800 ml/minute/m2 (range 0 to 1,300 ml/minute/m2). The median reduction in heart rate at the end of a fluid bolus (eight studies) was 2 bpm (range 10 to 0 bpm reduction) and the median increase in mean arterial pressure (eight studies) was 7 mmHg (range 1 to 15.2 mmHg). The median increase in CVP across five studies was 3.2 mmHg (range 2.3 to 5.2 mmHg). Only a single study reported the effect on venous oxygen saturation, blood lactate concentration or haemoglobin concentration. No study reported the effect on urine output.

Thirty minutes post-administration

Five studies reported the physiological effects of FBT 30 minutes after administration. Cardiac index increased by a median of 300 ml/minute/m2 (range -400 to 600 ml/minute/m2) in three studies. The median reduction in heart rate (five studies) was 2 bpm (range 11 bpm reduction to 0.3 bpm increase) and the median increase in mean arterial pressure (five studies) was 7.5 mmHg (range 3 to 11 mmHg). The median increase in CVP across four studies was 3 mmHg (range 2 to 5.25 mmHg). There was a median increase in central venous saturation of 2% (range 4% reduction to 8% increase) across two studies. Changes in other indices are reported in Table 3.

Sixty minutes post-administration

Only three studies reported the physiological effects of FBT 60 minutes after administration (Figure 4) [36],[57],[65]. Cardiac index increased by a median of 300 ml/minute/m2 (range -300 to 400 ml/minute/m2) in two studies. The median reduction in heart rate 60 minutes after a fluid bolus (three studies) was 1 bpm (range 11 bpm reduction to 2 bpm increase) and the median increase in mean arterial pressure (three studies) was 3 mmHg (range 2 to 7 mmHg). The median increase in CVP across three studies was 2 mmHg (range 1 to 3 mmHg). There was a median increase in central venous saturation of 1% (range 0.4% to 2% increase) across two studies.
Figure 4
Figure 4

Physiological effects of fluid bolus therapy over time. Multi-panel figure of the haemodynamic effects of fluid bolus therapy (FBT) as reported in studies with observation periods of 60 minutes or more. (A) Changes in heart rate over time. (B) Changes in cardiac index over time. (C) Changes in mean arterial pressure over time. (D) Changes in central venous pressure (CVP) over time. Each solid black line represents a patient group and the average physiological response to FBT over the observation period. Lines terminate when measurements were discontinued in the study from which the group was taken.

Beyond 1 hour post-fluid bolus therapy

Only one study reported the effects of BFT at 120, 180 and 240 minutes after administration (Figure 4) [65].

Comparing responders and non-responders

Overall, 10 studies compared the physiological responses to FBT administration between groups defined by changes in a physiological variable. Patients were defined as either responders or non-responders depending on the response exhibited. Different variables are used in different studies: stroke volume index (five studies), cardiac index or output (three studies), increase in oxygen consumption (one study) or aortic blood flow rate (one study). All reported changes only within 30 minutes of FBT completion (Additional file 1: Table S2).

In the six studies describing changes in cardiac index, cardiac index increased by a median of 850 ml/minute/m2 (range 600 to 1,300 ml/minute/m2) in fluid responders compared with 200 ml/minute/m2 (range 0 to 1,000 ml/minute/m2) in non-responders. The median increase in mean arterial pressure (10 studies) in responders was 9.5 mmHg (range 7 to 15.2 mmHg) versus 4.8 mmHg (range 1 to 13 mmHg) in non-responders. Similarly, the median increase in central venous pressure (six studies) was 3 mmHg (range 2.6 to 3.4 mmHg) in responders versus 3.7 mmHg (range 2 to 5.2 mmHg) in non-responders. The median decrease in heart rate (nine studies) was 3.3 bpm in responders (range 1.5 to 10 bpm decrease) and 1.2 bpm in non-responders (range 0 to 4 bpm decrease). Information on changes in venous oxygen saturation, blood lactate concentration, and blood haemoglobin concentration in the few studies reporting such data are presented in Additional file 1: Table S2.

Additional comparisons

The physiological effects of FBT grouped by speed of FBT delivery (Additional file 1: Table S3) and by class of fluid administered (Additional file 1: Table S4) have also been presented. There is no consistent pattern demonstrated across or between groups.

Relationship between physiological changes after fluid bolus therapy and clinical outcome

Overall, seven studies described clinically orientated outcomes [37],[43],[44],[49],[58],[59],[64]. All reported the effects of complex interventions, such as early goal-directed therapy. No studies examined the relationship between FBT and outcome directly (Tables 4 and 5).
Table 4

Clinically orientated primary outcomes

First author

Journal

Year

Control group

ICU mortality

Hospital mortality

Other

Intervention group

ICU mortality

Hospital mortality

Other

MacRedmond [ [49]]

Quality and Safety in Health Care

2010

Before protocolised resuscitation

19/37

  

After protocolised resuscitation

10/37

  

Pierrakos [ [59]]

Intensive Care Medicine

2012

Responders (>10% increase in CI)

13/25

  

Non-responders (<10% increase in CI)

11/26

  

Patel [ [58]]

Annals of Pharmacotherapy

2010

Pre-intervention

 

32/53

 

Post-intervention, significantly more fluid and less vasoactives

 

12/59

 

Castellanos-Ortega [ [37]]

Critical Care Medicine

2010

Pre-intervention

51/96

55/96

 

Post-intervention, significantly more fluid

117/384

144/384

 

Trof [ [64]]

Critical Care Medicine

2012

Pulmonary artery catheter-guided resuscitation

13/34

15/34

 

Transpulmonary thermodilution-guided resuscitation

17/38

21/38

 

Hanzelka [ [43]]

Supportive Care in Cancer

2013

Pre-intervention

  

28-day: 38/100

Post-intervention, significantly quicker resuscitation

  

28-day: 20/100

Jacob [ [44]]

Critical Care Medicine

2012

Pre-intervention

  

30-day: 126/245

Post-intervention, significantly quicker resuscitation with significantly larger volumes of fluid at 6 and 24 hours

  

30-day: 257/426

CI, cardiac index.

Table 5

Clinically orientated secondary outcomes

First author

Journal

Year

Control group

LOS in ICU (days)

LOS in hospital (days)

MV (days)

CRRT

Intervention group

LOS in ICU (days)

LOS in hospital (days)

MV (days)

CRRT

MacRedmond [ [49]]

Quality and Safety in Health Care

2010

Before protocolised resuscitation

8

   

After protocolised resuscitation

7

   

Castellanos-Ortega [ [37]]

Critical Care Medicine

2010

Pre-intervention

9.9

26.5

  

Intervention group, significantly more receive fluid

9.1

30.6

  

Hanzelka [ [43]]

Supportive Care in Cancer

2013

Pre-intervention

5.1

10.3

  

Post-intervention, significantly quicker resuscitation

2.5

8.1

  

Trof [ [64]]

Critical Care Medicine

2012

Pulmonary artery catheter-guided resuscitation

15

25

13

 

Transpulmonary thermodilution-guided resuscitation

11

27

10

 

Patel [ [58]]

Annals of Pharmacotherapy

2010

Pre-intervention

6

9.5

7.5

8/53

Post-intervention, significantly more fluid and less vasoactives

5

9

7

0/59

CRRT, continuous renal replacement therapy; LOS, length of stay; MV, mechanical ventilation.

Discussion

We examined the contemporary literature on FBT in severe sepsis and septic shock and identified 33 original studies describing the characteristics of a fluid bolus, 17 of which also describe the associated physiological changes. We found heterogeneity of triggers, amount, fluid choice and speed of delivery for FBT, which was administered to achieve heterogeneous physiological targets. We similarly found heterogeneity of physiological changes after FBT. In addition, no RCTs compared FBT with an alternative intervention. Finally, no study related physiological changes after FBT to clinically relevant outcomes.

FBT is a widespread intervention in the management of the critically ill septic patient, despite lack of a consistent definition or use of terminology. Our study demonstrates that no contemporary RCTs exist that compare FBT with alternative interventions. The only study comparing FBT to an alternative intervention was a single, non-randomized, prospective, observational study that compared acute circulatory failure patients treated with FBT (500 ml of saline) or with increased norepinephrine dose according to clinician preference. The two groups had clearly different baseline characteristics and were not directly compared [55]. Alternative interventions to FBT may include a diagnostic low-volume FBT [17], classic fluid challenge [11],[12], low-volume FBT and low-dose vasopressor therapy, or cardiac output-guided therapy. Despite the availability of such strategies and the availability of non-invasive cardiac output monitoring, these alternative approaches have not been studied.

Understanding which patient will be fluid responsive is a vital part of rationalising fluid therapy [69]. However, there are multiple different definitions of fluid responsiveness, each dependent on different interventions and different measurements. It would appear that there is little evidence to suggest a consistently different response to FBT based on pre-intervention physiology, as fluid responsiveness is often tautologically and retrospectively defined by participants’ responses to the therapy. A full review of this topic is beyond the scope of this review, though this information is available elsewhere [69],[70].

The contribution of FBT to a positive fluid balance remains poorly understood. In a recent observational study, Bihari and colleagues [36] found that a median of 52.4% of fluid balance on the first, 30.8% on the second and 33.2% on the third study day consisted of FBT. In the Fluid and Catheter Treatment Trial [27] and Sepsis Occurrence in Acutely Ill Patients [71] studies, increasing fluid balance was associated with increased risk of acute kidney injury and mortality. In a retrospective study of septic shock patients in a North American university hospital, non-survivors had a significantly greater positive net fluid balance than survivors over the first 24 hours from onset [34]. Our study also shows little or no evidence for any persisting beneficial physiological changes following FBT. These observations suggest the need for RCTs comparing FBT with alternative interventions and well-defined triggers and physiological outcomes.

This review has several strengths. To our knowledge this is the first review of the contemporary literature on FBT in critically ill patients with severe sepsis.

We are the first to explore the contemporary features of a FBT, and the first to produce a summary of the physiological changes associated with FBT in septic, critically ill patients, including data from RCTs, and observational and quasi-experimental studies. Our wide search criteria, use of three separate sources and hand searching references reduced the risk of inclusion bias and makes it unlikely that we missed relevant studies.

Our study also has some limitations. Our assessments of physiological changes are necessarily limited to the measures of central tendency provided in tables and graphs in the studies identified. We have only provided crude median results in an attempt to provide a rough estimate of possible effect. We limited our search to the present evolving decade. It is unlikely that current clinical practice is better reflected by earlier studies. Indeed, in comparing our results with similar, earlier studies, the reported physiological changes are similar [14],[71]-[75]. We did not account for the effect of vasoactive medications beyond noting their administration. It appears obvious that the mixed and differential inotropic/vasopressor/lusitropic/chronotropic effects of different vasoactive medications are likely to have an effect on the physiological changes reported, as would the administration of blood products. Inadequate information was provided in the studies to make such adjustments possible. FBT is normally part of a complex intervention - the resuscitation of the critically ill patient. As well as the initiation and manipulation of vasoactive medications, analyses must contend with the impact of the use of mechanical ventilation, CRRT, and antibiotic administration. These confounders were not reliably reported in the studies identified and could not be evaluated. In addition, the perceived haemodynamic success of an intervention often depends on the trajectory of the patient’s clinical course. Unfortunately no such information was available from the studies reviewed.

Conclusion

FBT in severe sepsis and septic shock is described in 33 articles in the contemporary literature. Only 17 of these studies report the physiological changes associated with FBT. Evidence regarding the efficacy of FBT compared with alternative interventions is lacking. Crucially, no studies relate the physiological changes after FBT to clinically relevant outcomes. In light of recent studies highlighting the association between FBT and fluid administration in general and harm, there is a clear need for at least obtaining randomised controlled evidence for the physiological effects of FBT over the immediate (0 to 4 hours) post-intervention period in patients with severe sepsis and septic shock.

Author’s contributions

NJG: study design, electronic search design, literature search, study selection, data extraction, data handling/analysis, manuscript preparation, manuscript revision, and manuscript submission. GME: literature search, study selection, manuscript revision, and manuscript submission. RB: study design, electronic search design, data analysis, manuscript preparation, manuscript revision, and manuscript submission. All authors read and approved the final manuscript.

Additional file

Abbreviations

CRRT: 

Continuous renal replacement therapy

CVP: 

Central venous pressure

FBT: 

Fluid bolus therapy

IV: 

Intravenous

RCT: 

Randomised controlled trial

Declarations

Authors’ Affiliations

(1)
Department of Intensive Care, Austin Hospital, Melbourne 3084, Victoria, Australia
(2)
Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, 3004, Victoria, Australia
(3)
School of Nursing and Midwifery, Faculty of Health, Deakin University, Burwood, 3125, Victoria, Australia

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