Bennett et al.

Critical Care (2018) 22:74

https://doi.org/10.1186/s13054-018-1993-1

REVIEW Open Access

Effects of Fluids on the Macro- and

Microcirculations
Victoria A. Bennett*, Alexander Vidouris and Maurizio Cecconi

this is lost in some disease states. This overview explores

Abstract the effects of the fluid on the macro- and microcircula-
This article is one of ten reviews selected from the tions and how we can monitor these effects.
Annual Update in Intensive Care and Emergency
Medicine 2018. Other selected articles can be found Indications for Fluid
online at https://www.biomedcentral.com/collections/ Classically, the need for fluid therapy is identified using
annualupdate2018. Further information about the Annual information from the clinical history, examination,
Update in Intensive Care and Emergency Medicine is measurement of hemodynamic variables and markers of
available from http://www.springer.com/series/8901. tissue hypoperfusion [7]. Markers of hypoperfusion may
include lactate, prolonged capillary refill time and skin
Background mottling [6]. A fluid challenge is given when tissue hy-
Intravenous fluid administration is one of the most poperfusion is suspected [7]. Fluid is given to optimize
frequently performed interventions in the intensive care cardiovascular status with the aim of ensuring adequate
unit (ICU) and in hospital in general. In fact, most inpa- end-organ perfusion and improving oxygen delivery to
tients will receive fluids at some point during their the tissues. Fluid is given as a fluid challenge so that re-
hospital stay [1]. In critically ill patients, fluid resuscita- sponse can be assessed and the need for ongoing fluid
tion is a vital component of patient management. It has therapy ascertained. To mitigate against the risk of fluid
been shown that both too little and too much fluid can overload in those who do not require additional intra-
be detrimental. A positive cumulative fluid balance on vascular volume, the smallest volume that provides an
day four of a critical care admission has been associated effective challenge of the cardiovascular system should
with increased morbidity [2, 3]. Both perioperatively and be used [8].
during sepsis, a U-shaped curve has been described for Most often, measures of the macrocirculation are used
volume of fluid administered and morbidity. Higher to assess and treat hemodynamic compromise in the
mortality is observed at both extremes of volume of fluid critically ill patient and measures of the microcirculation
given [4, 5]. are not routinely used at the bedside. Resuscitation
However, despite extensive research in the field, con- based on macrocirculatory endpoints is expected to re-
troversy remains regarding the best approach to fluid sult in parallel improvement in the microcirculation [9].
therapy. The FENICE study focused on the fluid
challenge and found wide disparity in practice; from fluid Macrocirculation
choice to method of administration and clinician response The macrocirculatory response to intravenous fluid
to the result [6]. To help guide decision making around administration is based on the principles of the Frank-
fluid administration, the effects, both desirable and poten- Starling law of the heart. Venous return is always equal
tially detrimental ones, need to be considered. This can be to cardiac output. The Frank-Starling principle describes
considered at both the macrocirculatory and the microcir- how the heart is able to accommodate increased venous
culatory level. Whilst in health coherence between the return and then eject the increased volume from the
macrocirculation and microcirculation can be assumed, heart, with an increase in stroke volume. Increased
venous return increases ventricular filling, which results
in increased stretch of the cardiac myocyctes. This in-
* Correspondence: [email protected]
Department of Intensive Care Medicine, St George’s University Hospital NHS creased stretch results in increased contractility, or in
Foundation Trust, London, UK other words, the increased diastolic expansion results in

© Bennett et al. 2018

Bennett et al. Critical Care (2018) 22:74 Page 2 of 6

increased systolic contraction [10, 11]. Administration of this patient is fluid responsive. At C, although an ad-
fluid aims to challenge this and assess whether a patient equate fluid challenge is given, as demonstrated by an
can accommodate an increased preload with an in- increase in Pmsf, no significant increase in stroke
creased stroke volume. volume is seen at point D – this patient is not fluid re-
The hemodynamic response to a fluid challenge can sponsive. If an inadequate fluid challenge, of too small a
be understood by considering the effects at different volume to increase Pmsf, is given at point A, an increase
points on the cardiovascular system. The first change in stroke volume is not seen at point E and the patient
seen is an expansion of the intravascular volume. Intra- would incorrectly be labeled as non-responsive to fluid.
vascular volume can be divided into stressed and Cecconi et al. demonstrated that a change in the pres-
unstressed volumes. The unstressed volume fills the ves- sure gradient of venous return, defined as the difference
sels but does not generate any pressure. The stressed between the Pmsf and central venous pressure (CVP),
volume causes stretch of the vessel walls and increases following a fluid challenge was seen in responders but
the pressure within the vessels. Mean systemic filling not in non-responders. In the non-responders, the in-
pressure (Pmsf ) is the measurement of the pressure crease in Pmsf was mirrored by an increase in CVP [14].
when there is no flow in the vessels, or in circulatory In those that respond, the maximal change in cardiac
arrest. Whilst Pmsf cannot be measured under the output is seen one minute after completion of the fluid
circumstances with which it was initially described, alter- challenge. The increase in cardiac output is a transient
native techniques have been validated [12]. If an effective response; a return to baseline values is seen ten minutes
fluid challenge is given, it will, at least transiently, in- post-fluid administration [13].
crease the stressed volume and cause a rise in Pmsf. This The decision to give fluids should be based on whether
increases cardiac preload, which ultimately increases an increase in cardiac output is likely to occur with fluid
cardiac output in preload-responsive patients. The re- loading and whether it would be likely to improve tissue
sponse to the increase in cardiac preload can be explained perfusion. These are clinical questions that the clinician
by the Frank-Starling principle. should ask before considering giving fluids. A patient
In a patient who is fluid responsive, an effective fluid who is non-responsive is unlikely to benefit from further
challenge will result in a significant increase, of more fluid loading. Not all patients who are responsive to fluid
than 10%, in the stroke volume or cardiac output. If a require the additional volume [8]. For example, in a
fluid challenge is given, which is effective in significantly study of healthy volunteers, by definition not in shock, a
increasing Pmsf, but no subsequent increase in cardiac significant increase in stroke volume was seen following
output is seen, the patient is labeled as non-responsive a head down tilt (mimicking a fluid challenge). Despite
[13]. This is demonstrated in Fig. 1: an adequate fluid being fluid responsive these healthy volunteers were
challenge administered at point A, increases Pmsf and a unlikely to need fluid resuscitation or have evidence of
significant increase in stroke volume is seen at point B – tissue hypoperfusion [15].

Fig. 1 Assessment of fluid responsiveness using a fluid challenge; effects on mean systemic filling pressure (Pmsf) and stroke volume, explained
using the Frank Starling Curve. See text for explanation
Bennett et al. Critical Care (2018) 22:74 Page 3 of 6

Other hemodynamic parameters, used more historically, upon smooth muscle. They respond to physical stimuli in
include static endpoints, such as heart rate. However, a the microcirculation, such as increased blood pressure,
change in heart rate in response to fluid administration is causing constriction in the arterioles of the microcircula-
not a sensitive marker of fluid responsiveness and can be tion. Some of the molecules that are active in the vascula-
influenced by numerous other factors [13]. ture of the microcirculation are released from the
CVP has historically also been used to guide fluid ad- endothelial wall including prostaglandins, nitric oxide
ministration. Targeting a CVP of 8–12 cmH2O was part (NO) and endothelin, which are released as a result of
of several optimization protocols in the past [16, 17]. The shear stress on the vessels. NO release can also be stimu-
role of CVP in predicting fluid responsiveness has since lated by other vasoactive peptides. Metabolic stimuli, such
been refuted. Use of the CVP as an indicator of fluid as adenosine, hydrogen ions, carbon dioxide and oxygen
responsiveness has been shown to be unreliable [18, 19]. tension, generated in tissues also control blood flow in the
It does not provide accurate information about blood microcirculation via dilation of the vessels [9]. The func-
volume [20]. Monitoring trends in CVP over time may tion of the microcirculation is also controlled by the per-
provide information about cardiovascular function but meability of the capillaries, their structure, the osmotic
should not be used alone to guide fluid resuscitation [21]. and diffusion gradients across the cell membranes and the
transport systems across the vessel walls.
Microcirculation and Hemodynamic Coherence There may be a lack of hemodynamic coherence in
In health, hemodynamic coherence is assumed to exist. disease states. States of shock, inflammation and infec-
This means changes within the macrocirculation are re- tion can interfere with the sensing and homeostatic
flective of changes in the microcirculation. As described control mechanisms of the microcirculation [22]. Coher-
earlier, the macrocirculation is generally used to guide ence is often altered in states of hemorrhagic shock or
fluid resuscitation, although ultimately the target is septic shock [24]. The loss of hemodynamic coherence
normalization of the microcirculation and maintenance can be the result of physiological changes in the environ-
of end-organ perfusion. However, although optimization ment resulting in nitrosative and oxidative mechanisms
of fluid status may result in normalization of macrocir- affecting regulation of the vasculature, changes in cell
culatory hemodynamics, such as blood pressure, this function or through changes in barrier mechanisms and
does not always translate to paralleled improvements or concentration gradients, all of which will inhibit normal
normalization of the microcirculation, or guarantee tissue perfusion. Hemodynamic coherence has been
adequate tissue perfusion. In these conditions, a lack of shown to vary in different tissue types dependent upon
hemodynamic coherence is described. This means that the disease state present [25].
targeting the normalization of macrocirculatory variables Coherence can be lost between different tissues in a sin-
may not be effective in restoring perfusion of end organs gle organ system. In a pig model, resuscitation with fluids
and tissues [22]. was successful in improving perfusion of the microcircula-
Under normal physiological conditions, the macrocir- tion in the mucosa of the gut, but not effective in the villi
culation regulates the distribution of blood and thus [26]. It was observed that the NO synthase (NOS) enzyme
end-organ perfusion. Systemic responses occur to alter was not homogenously distributed, which caused variable
macrovascular factors in order to compensate for hypo- and abnormal blood flow regulation in the microcircula-
volemia, hypoxia or other nutrient delivery insufficien- tion [27]. NOS enzymes form NO from L-arginine, which
cies and to ensure removal of waste products. The acts to decrease response to vasoactive agents. One such
macrocirculation is controlled by the central nervous enzyme, NOS 3 is also utilized in the maintenance of
system via the sympathoadrenomedullary axis and the vascular tone. NO is pivotal in the formation of cyclic
parasympathetic nervous system. The renin-angiotensin- guanosine monophosphate (cGMP), which induces
aldosterone axis, vasopressin, natriuretic peptides and smooth muscle relaxation through various mechanisms.
adipocytokines are also important in the control of These include activation of potassium ion channels in the
blood volume and blood pressure [23]. These pathways cell membrane and reduction in the intracellular concen-
and hormones affect the blood supply to the microcircu- tration of calcium ions. These enzymes are activated in
lation via modulation of the function of the heart, the disease states with high cytokine and endotoxin release,
tone of the vasculature and the volume, viscosity and such as sepsis. This results in increased NO production,
composition of the blood. and subsequent dilation of the vasculature and both
The microcirculation has a hugely important role in macrocirculatory and microcirculatory dysfunction, to
maintaining homeostasis of end organs and regulating varying degrees in different tissues [28]. Inappropriate
tissue perfusion and also in thermoregulation by control- vasodilation, vasoconstriction or microcirculatory tam-
ling cutaneous blood flow. Local mechanisms regulate ponade induced by increased venous pressure can result
vascular tone at the microcirculatory level by acting in decreased oxygenation of the tissues.
Bennett et al. Critical Care (2018) 22:74 Page 4 of 6

In sepsis, neutrophil adhesion and a hypercoagulable state the microcirculation [34]. However, the changes seen in
may lead to capillary occlusion, alongside other capillaries the microcirculation in distributive shock are the most
with normal blood flow. This results in heterogeneous marked. Disruption occurs, with adjacent small vessels
blood flow through the microcirculation, with subsequent often exhibiting markedly different patterns of flow. Much
hypoperfusion and tissue hypoxia. Oxidative stress also oc- of the research on the effects of fluids on the microcircula-
curs, in which endothelial dysfunction and capillary fluid tion has therefore focused on patients with sepsis [29].
and protein leaks occur. There is a loss of cellular barriers The changes within the microcirculation that pre-date
and tight junctions leading to worsening tissue edema [29]. fluid administration must be considered to help predict
Another area in which hemodynamic coherence may be the possible consequences of fluid administration.
affected is in hemorrhagic shock. Permissive hypotension Several mechanisms by which fluids exert their effects
and low volume fluid resuscitation are sometimes used in on the microcirculation have been described. The first,
the initial stages of treatment and over time these can lead and arguably most important, is via increased flow. The
to insidious microcirculatory hypoperfusion. This may effect of a fluid challenge on the macrocirculation, as
disrupt both coherence and cause a reperfusion injury. If previously described, increases filling within the system.
this occurs, then monitoring and restoring the macrocir- In the volume-responsive patient this increases flow,
culation will not result in benefit to the microcirculation which will increase microcirculatory perfusion by in-
[30]. Loss of hemodynamic coherence has been associated creasing pressure at the level of the capillaries.
with poor outcomes [24, 31]. Secondary effects relate to decreased viscosity secondary
As previously discussed, intravenous fluids are given to hemodilution from fluid administration. The decreased
to improve end-organ perfusion and oxygen delivery. viscosity will promote flow. In the hemoconcentrated pa-
Macrocirculatory parameters are used to deduce infor- tient this desirable feature will likely predominate; however,
mation about what is occurring at the microcirculatory it may be that the hemodilution decreases oxygen carriage
level. However, as a lack of coherence may exist between and cause shunting within the microcirculation [34].
the macro- and the microcirculation there is increasing Other adverse effects of fluid administration can be
evidence in favor of monitoring the effects of fluid at the clearly demonstrated through direct vision of the micro-
microcirculatory level [22]. circulation. Leakage of fluid extravascularly with in-
The microcirculation can be observed using a hand- creased tissue edema can be visualized and objectively
held camera at the patient’s bedside. There are currently monitored, as the vessel density will decrease. This re-
four generations of technology available. Through re- sults in increased diffusion distance from red blood cells
cording short video sequences of the microcirculation, to the tissues and decreased efficiency of oxygen delivery
information regarding fluid status can be ascertained. with subsequent hypoxia [29].
The images obtained can be scored and a number of Measurement of flow within the microcirculation, at
measurements made. The microcirculation consensus baseline, can be used to predict those that may benefit
meeting of 2007 described the following scoring systems: from a fluid challenge. Optimization of fluid status using
vessel density measurement including total vessel density macrocirculatory parameters does not always equate to
and perfused vessel density and vessel perfusion assess- improvement in clinical markers of hypoperfusion.
ment using proportion of perfused vessels and microcir- Pranskunas et al. demonstrated that, in those with nor-
culatory flow index (MFI). These parameters can be mal microcirculatory flow, no clinical benefit was gained
used to monitor the effects of fluid on the microcircula- by a fluid challenge, neither from the perspective of im-
tion [32]. Due to the limited availability of monitoring provement in clinical markers of hypoperfusion nor an
equipment and the need for offline analysis of images increase in MFI. In those with a low MFI, a significant
acquired, at present microcirculation measurement improvement in MFI and clinical signs of hypoperfusion
remains primarily a research tool [33]. were seen following a fluid challenge [35]. Periopera-
The effect of intravenous fluid on the microcirculation tively, patients who develop postoperative complications
varies depending on the underlying disease state. Shock have been shown to be more likely to have had micro-
can be broadly divided into four different classes: hypo- vascular flow abnormalities [36]. Those patients with a
volemic, distributive, cardiogenic and obstructive shock. low MFI could not be identified by observing macrocir-
Hypovolemic, cardiogenic and obstructive shock are culatory parameters. Additionally, an increase in MFI
associated with a low cardiac output. However, in sepsis, did not correlate well with those who responded with an
a form of distributive shock, cardiac output may be ei- increase in stroke volume. The authors hypothesized this
ther low or high. In cardiogenic and obstructive shock may be related to the fact that not all those who respond
there is increased afterload, with an expansion of the to a fluid challenge need the additional volume [35].
volume of the microcirculation. Hypovolemic and dis- The effect of fluid administration on the microcircula-
tributive shock are both characterized by impaired flow in tion has been shown to vary dependent on the stage of
Bennett et al. Critical Care (2018) 22:74 Page 5 of 6

the illness. In early sepsis, total vessel density, small Passive leg raise has gained increasing popularity as a
vessel density and MFI all increased with fluid adminis- method of assessing fluid responsiveness. It provides ap-
tration. The same effect was not seen in patients in the proximately 300 ml of fluid as a challenge, increasing
later stages of sepsis, defined as patients more than 48 h preload, from which fluid responsiveness can be deter-
after diagnosis. These changes are not mirrored in the mined. The technique can be reliably used in both venti-
macrocirculation [37]. lated and spontaneously ventilating patients. It provides
a challenge of preload without the need to give intraven-
Predicting Response to Fluids ous fluids in patients who are then shown to be non-
There are a number of different methods that can be responsive. However, it has its own limitations: for prac-
used to try and predict which patients will be fluid re- tical reasons it may not always be possible to perform
sponsive, prior to administering any fluid. Pulse pressure and its reliability in the presence of intraabdominal
variation (PPV) and stroke volume variation (SVV) hypertension has also been questioned [42].
compare beat-to-beat variations, with a variation of As previously discussed it is important to try and predict
more than 12% used as a marker of fluid responsiveness the likely response to fluid administration prior to actually
[38, 39]. These methods are only validated for use in giving fluids. Figure 2 provides a simple flow chart of the
ventilated patients, with tidal volumes of more than possible decision pathway that a clinician may follow
8 ml/kg and with no significant alteration in chest wall when considering fluid prescription for a patient in shock.
compliance. They can also only be used in patients in
sinus rhythm [40]. Conclusion
Another predictor is vena cava collapsibility index. The decision to give intravenous fluid to a patient is a
Variation in the diameter of the inferior vena cava (IVC) clinical one. The clinical assessment of each patient
on transthoracic echocardiography is reasonably predict- should include a prediction of whether it is likely that
ive of fluid responsiveness; however, measurement of the he/she will respond to additional volume and whether
collapsibility of the superior vena cava on transesopha- he/she requires and will benefit from it. Fluid adminis-
geal echocardiography is more reliable. Measurement of tration is in general guided by the changes seen within
the vena cava has the same limitations related to ventila- the macrocirculation. Historically, this was presumed to
tion as PPV or SVV. It can, however, be used in patients represent the microcirculation; however, in illness, it has
with arrhythmias [40]. been shown that coherence may not exist. There are still
The end-expiratory occlusion test can also be used in pa- many uncertainties regarding the effects of fluids on the
tients receiving mechanical ventilation. Interruption of ven- microcirculation. The effects vary depending on the
tilation at end-expiration for at least 15 s causes an increase disease process and indeed the stage of the disease. At
in preload. If cardiac output increases by more than 5% in this stage, the effects of fluids on the microcirculation
response then this is predictive of fluid responsiveness [41]. remain a focus of ongoing study and research.

Fig. 2 Flow chart to demonstrate the possible decision-making process in fluid administration in shock. PPV: pulse pressure variation; SVV: stroke
volume variation
Bennett et al. Critical Care (2018) 22:74 Page 6 of 6

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