Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427

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Best Practice & Research Clinical

Anaesthesiology
journal homepage: www.elsevier.com/locate/bean

Haemodynamic coherence d The relevance of

fluid therapy
Philip Arnemann, MD, Resident in Anaesthesiology *,
Laura Seidel, MD, Resident in Anaesthesiology,
Christian Ertmer, MD, PhD, Associate Professor of
Anaesthesiology
Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster,
Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany

Keywords:
The ultimate goal of fluid therapy is to improve the oxygenation of
haemodynamic coherence
cells by improving the cardiac output, thus improving microcir-
fluid therapy
resuscitation culation by optimizing macrocirculation. This haemodynamic
microcirculation coherence is often altered in patients with haemorrhagic shock
haemorrhagic shock and sepsis. The loss of haemodynamic coherence is associated with
sepsis adverse outcomes. It may be influenced by the mechanisms of the
underlying disease and properties of different fluids used for
resuscitation in these critically ill patients. Monitoring microcir-
culation and haemodynamic coherence may be an additional tool
to predict the response to fluid administration. In addition,
microcirculatory analysis may support the clinician in his decision
to not administer fluids when microcirculatory blood flow is pre-
served. In future, the indication, guidance and termination of fluid
therapy may be assessed by bedside microvascular analysis in
combination with standard haemodynamic monitoring.
© 2016 Elsevier Ltd. All rights reserved.

The rationale for fluid therapy

The administration of fluids as a therapeutic approach dates back at least to the 19th century when
Thomas Latta infused a fluid into a woman suffering from cholera and associated hypovolemic shock

Abbreviations: HES, hydroxyethyl starch.

* Corresponding author.
E-mail addresses: arnemann@anit.uni-muenster.de (P. Arnemann), Laura.Seidel@ukmuenster.de (L. Seidel), ertmer@anit.
uni-muenster.de (C. Ertmer).

http://dx.doi.org/10.1016/j.bpa.2016.11.003
1521-6896/© 2016 Elsevier Ltd. All rights reserved.
420 P. Arnemann et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427

who ‘had apparently reached the last moments of her earthly existence’ [1]. Although his efforts showed
only transient beneficial effects and his patient did not survive, fluid therapy became an essential part
of supportive therapy for patients with critical illness. Presently, administration of fluids is recom-
mended in various international guidelines for life-threatening haemodynamic conditions such as
sepsis [2] and haemorrhagic shock [3]. These conditions are assumed to be mainly caused by oxygen
deficiency leading to cell dysfunction [4]. Therefore, the ultimate goal of fluid therapy and other
haemodynamic interventions is to restore and maintain oxygen delivery to the individual cell to ensure
organ function.
Fluid administration aims to improve the stroke volume of the heart and thereby increase the
cardiac output via the FrankeStarling mechanism (i.e. by optimizing pre-load) [5]. Notably, research
from the last decades repeatedly demonstrates that despite haemodynamic optimization, organ
function and microcirculation may not improve [6]. Ince [7] defines haemodynamic coherence as the
situation in which an improvement in macrohaemodynamic variables (e.g. cardiac output) correlates
with the beneficial effects of microcirculation and vice versa. If macrohaemodynamic optimization and
microcirculation do not respond in the same direction, haemodynamic coherence is lost. Thus,
improvement of macrohaemodynamics is a condition to enable haemodynamic coherence. In this
context, Pottecher et al. showed that in patients with sepsis and septic shock in need of volume
expansion, passive leg raising test and pulse pressure variation predicted an improvement in micro-
circulation [8].
The present review summarizes the current data on fluid therapy and its impact on haemodynamic
coherence. Blood products are not addressed because they are discussed in another article in this issue.

Basic considerations in fluid therapy and microcirculation

Because physiology suggests that fluid therapy increases microcirculatory blood flow only if global
blood flow is increased (i.e. cardiac output), macrocirculatory fluid responsiveness is essential to
improve microcirculation with fluids. There are four distinct scenarios in critically ill patients. In the
first scenario, macro- and microcirculation are stable, and no change in haemodynamic management is
indicated. In the second scenario, which is probably common, macrohaemodynamics are unstable (e.g.
a certain drop in blood pressure), but microcirculatory analysis (e.g. sublingual) suggests maintained
microvascular blood flow. In this setting, it can be hypothesized that cardiac output is sufficient and
blood pressure is at least appropriate for the index tissue in which the microcirculation is monitored. If
blood pressure is thought to be too low in other areas (e.g. the carotid area), then a vasopressor may be
the treatment of choice. In the third scenario, macro- and microcirculation are both impaired (e.g. in
untreated haemorrhagic shock), and haemodynamic interventions (fluid therapy, catecholamines,
transfusion, etc.) will determine whether haemodynamic coherence persists after macro-
haemodynamic stabilization. In the (probably most interesting) fourth scenario, macro-
haemodynamics have been stabilized, but microcirculation remains impaired. As a first approach,
macrohaemodynamic fluid responsiveness may be assessed. If the patient is fluid responsive, the
associated increase in cardiac output may or may not improve the microcirculation. In the authors
experience, the administration of fluids rarely improves microcirculation in this setting. In contrast,
other interventions such as red blood cell transfusion, vasodilators and antioxidants may prove
effective in improving microcirculation [9,10]. However, all these interventions are experimental; they
will be effective only on an individual patient basis and necessitate a close and concomitant monitoring
of the microcirculation.

Fluid therapy and haemodynamic coherence in patients with haemorrhagic shock

Patients with haemorrhagic shock are usually treated by optimizing the intra-vascular volume
through fluid or blood administration after the bleeding is controlled [3]. Haemorrhagic shock reduces
microvascular flow and capillary density [11]. Usually, microvascular analysis shows a homogeneous
reduction of convection and diffusion due to low cardiac output and anaemia. From a physiological
point of view, fluid therapy should restore microvascular perfusion by increasing cardiac output,
 P. Arnemann et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427 421

provided that a certain haematocrit is maintained. However, results of experimental and clinical
studies in this context vary concerning haemodynamic coherence associated with fluid therapy.
Wu et al. showed in a rat model of haemorrhagic shock that despite restoring mean arterial pressure
by fluid therapy with 0.9% sodium chloride solution, there was no haemodynamic coherence after
resuscitation. Intestinal blood flow remained compromised [12]. In a hamster window chamber model
of haemorrhagic shock, Villela et al. found that functional capillary density improved after resuscitation
with Ringer's lactate solution [13]. In a clinically relevant paediatric large animal model in pigs,
Gonz! alez et al. investigated the impact of 0.9% saline solution and different preparations of 5% albumin
solutions on sublingual microcirculation. They found no differences between the fluids, but an
improved microvascular flow and perfused vessel density was observed after resuscitation [14]. In
addition, in an porcine model of haemorrhagic shock, Guerci et al. found that sublingual microvascular
flow and tissue oxygen tension improved after fluid resuscitation [15]. In a prospective observational
study, in patients suffering from haemorrhagic shock, Tachon et al. showed that haemodynamic
coherence between macrocirculation and sublingual microcirculation was initially impaired after
controlling bleeding and restoring macrocirculation [16]. Microcirculation remained altered for the
next 72 h and then normalized.
From the results of the above-mentioned studies, it appears that although in haemorrhagic shock
the vasculature and endothelium are not a primary part of the pathophysiology, microcirculation is not
essentially restored with fluid resuscitation. Reasons for these varying findings may be the use of
different fluids or amounts of fluids in the treatment of patients with haemorrhagic shock (see also
section on haemodynamic coherence and type of fluid). In addition, the frequently accompanying
inflammatory response following haemorrhagic shock alters microcirculation. These alterations are
based on neutrophil interactions with the endothelium [17], leading to reactive oxygen species pro-
duction, vascular leakage and ultimately organ failure [18]. Early resuscitation may lead to haemo-
dynamic coherence but (too) late initiation of resuscitation does not because of inflammatory
alterations of microcirculation. Unfortunately, no conclusive evidence is available to answer this
question yet. In addition, masked hypovolaemia, e.g. due to endogenous or exogenous vasopressors,
may lead to good macrohaemodynamic data but leaves the microcirculation impaired [19]. Venous
congestion may also lead to compromised haemodynamic coherence by diminishing the driving
pressure of capillaries. This is supported by the findings of Vellinga et al. that high central venous
pressure may impair microvascular blood flow [20]. The authors hypothesized that high central venous
pressure may serve as an obstructive outflow resistance. More research is needed on the timing of
resuscitation in patients with haemorrhagic shock and the link between inflammation and haemo-
dynamic coherence in patients with haemorrhagic shock.

Fluid therapy and haemodynamic coherence in patients with sepsis and septic shock

Microcirculation in patients with sepsis and septic shock is known to be impaired because of in-
flammatory processes that lead to shunting and vascular leakage. In fact, sepsis has often been labelled
as a ‘disease of the microcirculation’ [21]. One of the main problems in sepsis is the extreme hetero-
geneity in microvascular perfusion of different organs or even within the same organ [22]. Fluid
therapy is an important supportive therapeutic approach recommended by the guidelines for sepsis
treatment [2]. The common goal of all haemodynamic interventions (not only) in sepsis is to improve
microcirculation. Fluid therapy improves microcirculation by the optimization of stroke volume and
cardiac output. Clinical experience and evidence show that the heart is often volume responsive in
sepsis, i.e. stroke volume increases after fluid challenge. Haemodynamic coherence is required to
translate these changes in global blood flow to changes in microvascular blood flow. Notably, a large
body of evidence suggests that haemodynamic coherence is absent, dependent, e.g. on the time point
in the course of sepsis, or differs in various organs.
van Genderen et al. found that haemodynamic coherence, as measured by microvascular flow and
capillary density, was absent in an experimental pig model of endotoxaemic shock in the early phase of
shock, whereas in the late hyperdynamic phase, microcirculation seemed to improve along with the
macrohaemodynamics [23]. In an experimental ovine model of endotoxaemia, Dubin et al. investigated
the impact of fluid therapy on macro- and microcirculation. The results of their study demonstrated
422 P. Arnemann et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427

that despite improvement in cardiac output and global organ perfusion, such as mesenteric blood flow,
microcirculation improved only heterogeneously [24]. Sublingual and serosal intestinal microvascular
flow improved, whereas mucosal intestinal perfusion remained impaired, leading to intra-mucosal
acidosis.
Heterogeneity of haemodynamic coherence was also demonstrated by Edul et al. in patients with
abdominal sepsis. The investigators found that sublingual microcirculation correlated with cardiac
output and improved after a fluid challenge [25]. However, intestinal microcirculation did not react in
the same manner and stayed deteriorated. Boerma et al. showed that in patients with abdominal
sepsis, heterogeneity in haemodynamic coherence is also time dependent [26]. One day after treat-
ment initialization, macrocirculation was improved, but there was no correlation with sublingual or
intestinal microcirculation; moreover, both the microcirculation sites did not correlate with each other.
Two days later, microcirculatory correlation between sublingual and intestinal region was restored, and
sublingual microcirculation correlated with the cardiac index. Time dependency of haemodynamic
coherence in sepsis is supported by the results of Ospina-Tascon et al. who studied patients with severe
sepsis. In their study, contrary to the findings of Boerma et al., fluid resuscitation improved micro-
circulation within the first 24 h after the diagnosis of sepsis but not after 48 h, independent of mac-
rohaemodynamic variables and their changes [27]. At first glance, the different findings may be
explained by the fact that Boerma et al. investigated the correlation between macro- and microcir-
culation at different time points regardless of fluid therapy, whereas Ospina-Tascon et al. investigated
the effects of a fluid challenge on microcirculation. These data support the pragmatic notion that early
fluid therapy is likely to be beneficial, whereas late fluid therapy is rather adverse [28].
There are also studies demonstrating haemodynamic coherence in patients with sepsis. For
example, Dubin et al. demonstrated that protocolized fluid resuscitation improved microcirculation by
increasing the cardiac output in patients with severe sepsis [29].
Loss of haemodynamic coherence in sepsis is associated with adverse outcomes. This has been
demonstrated by Edul et al. who showed that patients with septic shock who had more severe al-
terations in microcirculation had an inferior rate of survival [30]. Sakr et al. also showed that micro-
circulation in non-survivors in septic shock did not improve as good as it did in survivors [31]. Findings
by Trzeciak et al. support these results by demonstrating that in patients with loss of haemodynamic
coherence, organ failure occurred more often [32].
These heterogeneous findings on haemodynamic coherence in patients with sepsis and septic shock
may be explained by various mechanisms. Activation of coagulation plays a role in this context, leading
to microvascular thrombosis and altering microcirculation [33]. Oedema formation and subsequent
organ failure due to impairment of the glycocalyx are amongst other reasons that contribute to
microvascular disorder [34]. In addition, the induction and local alteration of nitric oxide species and
nitric oxide synthase in inflammation in sepsis contributes to microcirculatory alterations [35]. Het-
erogeneity in microvascular flow and capillary density may also contribute to the ambivalent results.
As microcirculation is not uniformly impaired in every compartment of an organ, resuscitation may
also lead to hyperdynamic flow in regions with normal microcirculation, thus diminishing cellular
metabolism and oxygen supply. Haemodynamic coherence in patients with sepsis may also be influ-
enced by a number of other factors such as the time-point in the individual course of disease, the organ
in which microcirculation is measured and the variables of microcirculation that reflect microcircu-
lation best. It is still unknown which variables have to be measured to arrive at conclusive therapeutic
decisions.

Type of fluid and haemodynamic coherence

Various experimental and clinical data suggest that the type of fluid may also influence the inci-
dence of haemodynamic coherence. Different types of fluid with theoretical and practical advantages
and disadvantages are available for use in fluid resuscitation. Fluids can be classified as crystalloid and
colloid solutions and as balanced and unbalanced solutions. A more comprehensive review of available
fluids has been thoroughly described before [36].
 P. Arnemann et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427 423

In a rodent model of haemorrhagic shock, Wu et al. found that fluid resuscitation with 0.9% saline
was not as effective in restoring intestinal microcirculation compared to hypertonic saline solution, 4%
succinylated gelatin and 6% hydroxyethyl starch (HES) 130/0.4. However, more reactive oxygen species
were found in the kidney after resuscitation with either colloid. All fluids improved microcirculation
[37]. Supporting these findings, the same group demonstrated in another experimental study that
resuscitation of haemorrhagic shock with 0.9% saline did not improve intestinal microcirculation [12].
In a rodent model of haemorrhagic shock and resuscitation, Aksu et al. compared the impact of
balanced versus 0.9% saline-based fluids. Although macrocirculation improved in both groups, the
balanced fluid improved renal oxygen utilization compared to 0.9% saline [38]. Pascual et al. showed in
mice suffering from haemorrhagic shock that resuscitation with hypertonic saline solution reduces
vascular leakage compared to resuscitation with balanced crystalloid solution (Ringer's lactate),
thereby improving microcirculation [39]. Villela et al. found that resuscitation of haemorrhagic shock
in hamsters using Ringer's lactate solution with increased viscosity increased functional capillary
density compared to normal Ringer's solution [13].
In an experimental ovine model of abdominal sepsis, Orbegozo et al. found that using 0.9% saline for
resuscitation did not improve microcirculation to the same extent as when using two balanced crys-
talloid solutions [40]. In a rodent model of endotoxaemia, Scha €per et al. demonstrated that fluid
therapy with colloids, namely 6% HES 130/0.4 and 4% succinylated gelatin, preserved intestinal
microcirculation compared to fluid therapy with 0.9% saline [41]. In patients with severe sepsis, Dubin
et al. showed that fluid resuscitation with 6% HES 130/0.4 was superior to that with 0.9% saline solution
in improving sublingual microcirculation [29].
The influence of the type of fluid on haemodynamic coherence may be explained by their
biochemical properties and interactions with the endothelium. From the results of the above-
mentioned studies, 0.9% saline seems to be the least effective in recruiting the microcirculation in
coherence with the macrocirculation. Although 0.9% saline is the most commonly used resuscitation
fluid worldwide [42], it has some less favourable effects. The high chloride content in 0.9% saline is
known to induce hyperchloridaemic acidosis, thus triggering the formation of active nitrogen species
that cause vasodilatation and induce vascular leakage [43]. In the kidney, high chloride concentrations
reduce the rate of glomerular filtration by activating the tubuloglomerular feedback mechanism that
alters the afferent glomerular and thereby microvascular blood flow of the kidney [44]. These mech-
anisms may also explain the association of hyperchloridaemic acidosis with adverse outcomes in
critically ill patients [45], possibly due to the loss of haemodynamic coherence. Other effects of fluids
that may explain their different behaviour in haemodynamic coherence include the differing intra-
vascular volume effect, particularly when comparing crystalloid and colloid solutions. Infusion of
colloid solutions leads to decreased oedema formation because of greater intra-vascular volume effect
compared to infusion of crystalloid solutions. Interstitial oedema increases the diffusion distance at a
microcirculatory level, thus impairing oxygen delivery to the cells [7]. Several other characteristics
influence microcirculatory variables, particularly when HES-based solutions are used. HES solutions
increase blood viscosity [46] and reduce platelet aggregation and clot firmness [47]. Influence of blood
viscosity on microcirculation was shown by Villela et al. as explained above [13]. In addition, decreased
neutrophil recruitment and transmigration after infusion of HES-based solutions have been reported
and may lead to decreased inflammation [48], thereby potentially improving the microcirculation.

Monitoring microcirculation as the predictor of success and guidance of fluid therapy

The monitoring of microcirculation as a tool to guide fluid therapy has been proposed by Ince [49].
The rationale for fluid administration should be low convective flow in the microcirculation. Thus,
improvement of microcirculatory flow is the goal of fluid therapy. This concept also integrates when to
stop giving fluids: if fluid therapy begins to dilute the oxygen-carrying red blood cells such that oxygen
delivery to the cells is diminished, it has to be stopped. Fluids should be administered as long as
haemodynamic coherence is present and should be stopped as soon as haemodynamic coherence is
lost. Recently, other authors also suggested to add microcirculation as an end point for resuscitation,
424 P. Arnemann et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427

e.g. as a general monitoring tool [50], more specifically in patients with sepsis [51] and hypovolaemic
shock [52].
As shown above, haemodynamic coherence is associated with less organ failure [32], and its loss is
associated with adverse outcomes [30,31]. In a murine model of haemorrhagic shock, Hutchings et al.
showed that preserved microcirculation in the early phase of resuscitation predicts shock reversal as
shown by better lactate clearance compared to impaired microcirculation at that time point [53].
Tachon et al. also identified the proportion of perfused vessels as a predictor of the probability for organ
failure in haemorrhagic shock and resuscitation patients [16]. Pranskunas et al. investigated changes in
microvascular blood flow and clinical signs of impaired organ perfusion in response to fluid challenge
in patients with impaired organ perfusion in an intensive care unit. They found that low initial
microvascular blood flow was a predictor for improvement in microvascular flow and organ function
after fluid challenge [54]. In addition, Klijn et al. observed that in patients with sepsis, tissue
oxygenation and microvascular blood flow predicted fluid responsiveness after initial resuscitation
[55]. In summary, there is good evidence that observation of microcirculation and its changes due to
fluid therapy may be able to predict patient outcome.
The notion that the effects of fluid administration on the microcirculation should be monitored to
identify when to stop administering fluids is supported by Ospina-Tugson whose study showed good
improvement of microcirculation in the early phase of sepsis but not in the late phase [27]. Over-
resuscitation (administration of too much fluid) leads to haemodilution and oedema formation.
Konrad et al. showed in pigs that haemodilution led to oedema formation in the kidney and impaired
renal microvascular oxygenation [56]. Ferrara et al. were also able to demonstrate in sheep that hae-
modilution may lead to microvascular shunting, thereby reducing oxygen delivery to cells [57].
Despite the possible advantages of regulating fluid therapy by observing microcirculation and its
changes, only one experimental study by Xu et al. examined the effects of a microcirculation surrogate-
guided fluid therapy and compared them with those of conventional fluid therapy. In a porcine model,
the authors induced haemorrhagic shock and resuscitated using a balanced crystalloid solution to
target arterial blood pressure, in one group, and microcirculatory function as determined by sublingual
partial pressure of carbon dioxide. They found that despite a markedly reduced requirement of fluid
volume in the microcirculatory-guided group, no differences were observed between the groups
regarding myocardial and neurological function and in microcirculation and survival [58].

Summary

Fluid therapy is a common therapeutic intervention in critically ill patients. Its main objective is to
optimize cardiac output, thereby aiming to restore oxygen supply to the individual organs and their
cells. Haemodynamic coherence is the pre-requisite condition in which the microcirculation follows
the macrocirculation for achieving this goal.
In patients with haemorrhagic shock and those with sepsis and septic shock, haemodynamic
coherence is influenced by various factors. In patients with haemorrhagic shock, the induction of
inflammation by the insult may influence haemodynamic coherence. In patients with sepsis, the
heterogeneity of microcirculatory disorders is mediated by the infection triggering inflammation,
subsequently altering endothelial functioning and oedema formation.
The choice of fluid for therapy also influences the occurrence of haemodynamic coherence in
different situations. Alterations in haemodynamic coherence may be due to the various characteristics
of these fluids, such as their influence on endothelial barrier function, blood flow mediation in organs
such as kidney or intestine, alteration of blood flow by rheological properties and manipulation of
inflammatory reactions. However, 0.9% saline is probably the least effective solution in
microcirculation.
Impaired microcirculation is associated with organ failure and adverse outcomes. It also predicts
positive response to fluid administration. Therefore, monitoring microcirculation and haemodynamic
coherence is a potential end point for fluid resuscitation in critically ill patients. It can be hypothesized
that microcirculation can also be used to determine the indication, guidance and termination of fluid
therapy.
 P. Arnemann et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 419e427 425

Practice Points

! Fluid responsiveness is a pre-requisite for microcirculatory improvement by fluid therapy. In

patients with fluid responsiveness and haemodynamic coherence, fluid administration will
increase microvascular blood flow.
! Loss of haemodynamic coherence is associated with adverse outcomes.
! Monitoring microcirculation in haemorrhagic shock and sepsis may help in guiding fluid
therapy.
! The choice of fluid for resuscitation should be made individualized on the basis of the pa-
tient's disease and current macrohaemodynamic and microcirculatory condition; 0.9% saline
may have no indication as a resuscitation fluid.

Research Agenda

! The impact of the timing of fluid administration and volume of administered fluid on
microcirculation and associated outcomes in haemorrhagic shock needs to be investigated.
! Therapeutic approaches to improve sustained microcirculatory impairment despite macro-
circulatory stabilization are desperately needed.
! Whereas a correlation between impaired microcirculation and adverse outcomes has
repeatedly been shown, protocols for fluid therapy that improve both the microcirculation
and patient outcomes should now be investigated.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial or
non-profit sectors.

Conflicts of interest

Philip Arnemann received research grants from Fresenius Kabi Germany. Laura Seidel has no pro-
prietary interests to declare. Christian Ertmer received travel reimbursement and research grants from
Fresenius Kabi Germany.

Acknowledgements

Not applicable.

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