REVIEW

CURRENT
OPINION Monitoring coherence between the macro and
microcirculation in septic shock
Jan Bakker a,b,c,d and Can Ince a

Purpose of review
Currently, the treatment of patients with shock is focused on the clinical symptoms of shock. In the early
phase, this is usually limited to heart rate, blood pressure, lactate levels and urine output. However, as the
ultimate goal of resuscitation is the improvement in microcirculatory perfusion the question is whether these
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currently used signs of shock and the improvement in these signs actually correspond to the changes in the
microcirculation.
Recent findings
Recent studies have shown that during the development of shock the deterioration in the macrocirculatory
parameters are followed by the deterioration of microcirculatory perfusion. However, in many cases the
restoration of adequate macrocirculatory parameters is frequently not associated with improvement in
microcirculatory perfusion. This relates not only to the cause of shock, where there are some differences
between different forms of shock, but also to the type of treatment.
Summary
The improvement in macrohemodynamics during the resuscitation is not consistently followed by subsequent
changes in the microcirculation. This may result in both over-resuscitation and under-resuscitation leading to
increased morbidity and mortality. In this article the principles of coherence and the monitoring of the
microcirculation are reviewed.
Keywords
endpoints, hemodynamics, lactate, perfusion, peripheral perfusion, resuscitation, shock

INTRODUCTION The clinical definition of circulatory dysfunc-

Circulatory dysfunction is a frequent reason for tion or failure varies and is usually defined by macro-
admission to the ICU. The principal role of the hemodynamic parameters like blood pressure (BP),
circulation is to deliver nutrients (oxygen and fuel) biomarkers in arterial and (central) venous blood
to the organs and remove waste product. This is and parameters of organ function. Where shock is
mainly accomplished by the delivery of red blood the worst form of circulatory failure, its definition is
cells (RBC) into the microcirculation and the passive not really usable at the bedside [1] so that one has to
diffusion of oxygen from the RBCs to the tissue cells. rely on the same parameters and biomarkers for its
When requirements are not met, first organ func- recognition. Not only the use of these, sometimes
tion decreases before ultimately failing. Therefore,
the goal in treating circulatory dysfunction is to
restore adequate perfusion of the microcirculation. a
Department of Intensive Care Adults, Erasmus MC University Medical
The oxygen content [hemoglobin (Hb) and Hb sat- Center, Rotterdam, The Netherlands, bDepartment of Pulmonary and
uration] are factors that also determine the ultimate Critical Care, New York University School of Medicine, cDivision of
amount of oxygen delivered to the organs. However, Pulmonary, Allergy, and Critical Care Medicine, Columbia University
College of Physicians & Surgeons, New York, New York, USA and
in this review we will focus on perfusion as the body d
Department of Intensive Care, Pontificia Universidad Católica de Chile,
has limited ability to improve oxygen content Santiago, Chile
acutely. In addition, in response to changes in oxy- Correspondence to Jan Bakker, MD, PhD, FCCM, FCCP, Department of
gen demand the first response of the circulatory Intensive Care Adults, Erasmus MC University Medical Center, PO Box
system is to improve flow. In situations of stress 2040, Room Ne-415, 3000 CA Rotterdam, The Netherlands.
(shock) the system also influences organ blood flow Tel: +31 10 7030772; e-mail: jan.bakker@erasmusmc.nl
by redirecting flow to more vital organs at the Curr Opin Crit Care 2020, 26:267–272
expense of less the perfusion of less vital organs. DOI:10.1097/MCC.0000000000000729

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Cardiopulmonary monitoring

microcirculation (nailbed, conjunctive, retina) their

KEY POINTS clinical use is thus far limited.
 During the development of shock microcirculatory
perfusion parameters follow the deterioration of
macrocirculatory symptoms and parameters of shock THE IMPORTANCE OF COHERENCE
(coherence). Where the ultimate goal of resuscitation is to restore
microcirculatory perfusion and oxygen exchange,
 Although in some forms of shock coherence is also
present in the resuscitation of shock, especially septic the question is whether the clinically used param-
shock represents a state in which coherence is lost. eters adequately reflect these processes (Fig. 1) [10].
Perceived adequate macrohemodynamics in the
 As the resuscitation is still mainly focused on presence of abnormal microcirculatory perfusion
macrocirculatory parameters, the loss of coherence
has been referred to as microcirculatory shock
may result in both over and under-resuscitation.
[11]. In addition, normal peripheral microcircula-
 Loss of coherence is associated with increased tory perfusion in patients with septic shock is asso-
morbidity and mortality. ciated with a significantly lower mortality in the
&

 Although loss of coherence between the presence of similar macrohemodynamics [12 ]. In

macrocirculation and peripheral perfusion parameters both cases, the lack of coherence could represent a
is also present following initial resuscitation in septic different (clinical) phenotype but could also result
shock, limited research have studied the coherence in either over-resuscitation or under-resuscitation of
between the microcirculation and peripheral circulation. patients. A relevant clinical example of this could be
the use of lactate in the early resuscitation of septic
shock as recommended by the Surviving Sepsis
Campaign Guidelines [13]. In these, fluid adminis-
neither specific nor sensitive markers, might result tration is recommended in patients with increased
in inadequate treatment of the patient. lactate levels as these would mark tissue hypoperfu-
For this review, we define hemodynamic coher- sion with the ultimate goal to normalize lactate
ence as the presence of concordance between levels [13]. Both this assumption and the use of
changes in the macrocirculation and the microcir- normalization have been seriously questioned as
culation. We will mainly focus on sepsis as this a lactate may not (always) indicate tissue hypoperfu-
very frequent cause of circulatory dysfunction in sion and microcirculatory perfusion may be normal
critically ill patients and has been shown to present when lactate levels have not normalized yet [14,15]
a both complex microcirculatory dysfunction and a and coherence may be lost [16]. Both conditions
complex response to its treatment. could lead to over resuscitation with associated risk
of increased morbidity and mortality [17,18].

METHODS TO MONITOR THE

MICROCIRCULATION COHERENCE DURING THE DEVELOPMENT
The methods available to monitor the microcircula- OF CIRCULATORY FAILURE
tion are numerous but relate to the specific micro- In acute models of hemorrhagic shock, tamponade,
circulation of interest. In intact patients this cardiogenic shock and cardiac arrest coherence exists
basically means that access to organs is not possible during the development of shock. In other words,
with the exception of patients with an enteral stoma during the development of shock, as signaled by the
which provides access to gut mucosa. The accessible changes in macrocirculatory parameters, also the
sites are thus mainly limited to skin and the sublin- microcirculation shows abnormal perfusion param-
gual area. In different contexts, the mucosa of the eters [19–27]. Although during the development of
rectum and vagina has been used [2,3]. septic shock, characterized by hypotension and
For the skin the methods available have been decreased cardiac output (CO), hemodynamic coher-
reviewed extensively earlier [4,5] and will not be ence is present [20,28–30]. However, sepsis with
discussed here. The sublingual area provides an easy preserved macrohemodynamics may still show an
opportunity to visualize a true microcirculatory net- abnormal microcirculation [31,32]. In contrast to
work. From its first clinically available device, some other organs, the microcirculation of the brain seems
20 years ago [6], the technique has been further to be preserved during the development of septic,
developed [7], an automated scoring system has cardiogenic and hemorrhagic shock [22,33,34]
&
become available [8 ] and guidelines for the practi- despite significant macrocirculatory abnormalities.
&
cal use and interpretation have been published [9 ]. The study of coherence in human models of
Although other areas can be used to visualize the shock is limited but in models of hypovolemia in

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 Monitoring coherence between the macro and microcirculation Bakker and Ince

FIGURE 1. Microcirculatory changes in lost hemodynamic coherence. Different microcirculatory changes characterize the
mechanisms associated with the loss of hemodynamic coherence resulting in a decreased delivery of oxygen to the cells. Type
1: Heterogenous perfusion of the microcirculation as seen in sepsis. Some capillaries have no flow where others have normal
or increased flow resulting in scanted oxygen delivery to some cells. Type 2: Loss of hematocrit in the microcirculation as seen
in hemodilution. The result in not only reduced delivery of oxygen but also increased diffusion distance between the red blood
cells and the tissue cells. Type 3: Stasis in the microcirculation induced by altered systemic variables. Increased arterial
resistance (R), increased venous pressure (P) resulting in a tamponade of the microcirculation. Type 4: Development of tissue
edema (e.g. due to capillary leak) resulting in increased diffusion distance between the normally perfusion capillaries and the
tissue cells. Red: well oxygenated red blood cells and tissue cells. Dark red/black: red blood cells with decreased oxygen
saturation. Blue: tissue cells with reduced oxygenation. From [10].

healthy volunteers, hemodynamic coherence is also volunteers resulted in a decrease in mean arterial
present during the progression of circulatory abnor- pressure and an increase in heart rate (HR) charac-
malities. In a model of simulated hypovolemia Bar- teristic of clinical sepsis. The bolus of endotoxin was
tels et al. [35] showed that lower body negative also associated with a decrease in vascular reactivity
pressure resulted in decreased CO (while BP was and a decrease in microcirculatory perfusion, both
maintained) coinciding with abnormal sublingual being restored 4 h after the bolus [38].
microcirculatory perfusion. In human models of With the exception of the brain microcircula-
sepsis, the (macrohemodynamic) characteristics tion, we can thus assume that in the early phase
mimic the ones seen in patients presenting with of severe macrocirculatory dysfunction the micro-
sepsis [36–39]. In a volunteer study, Draisma et al. circulation is compromised. It is conceivable that
[38] showed that a bolus of endotoxin in healthy microcirculatory perfusion abnormalities may

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Cardiopulmonary monitoring

develop before macrocirculatory hemodynamic there were no control animals in their study, the
changes are prominent. This could especially be the effect of time could not be ruled out [20]. Although
case during a tamponade of the microcirculation by some (experimental) treatments have shown to be
increased central venous pressure (CVP). A clue to this more effective in restoring microcirculatory perfu-
was the finding by Vellinga et al. [40] that patients with sion and oxygen exchange than the use of fluids only
increased CVP showed an impaired sublingual micro- [46,49,50] the type of fluids may not be an unimpor-
circulation. In patients with sepsis [41] and cardiac tant aspect of restoring microcirculatory perfusion as
failure [42], CVP has been shown to be an independent well [51,52]. However, a detailed discussion about
risk factor for acute kidney injury despite adequate this is beyond the scope of this publication.
macrocirculatory parameters. However, all of these
findings were postresuscitation and thus, other than
keeping CVP as low as possible during resuscitation of CLINICAL DATA
shock, general recommendations cannot be made Several studies in patients with sepsis and septic
from this [43]. It is clinically not feasible to monitor shock have shown a lack of coherence between the
sublingual microcirculatory perfusion in all patients at macrocirculation and microcirculation when treat-
risk while having normal macrocirculatory parameters ing the patient or following optimization of macro-
although monitoring by ICU nurses of the sublingual hemodynamics [53–59]. Similar findings have been
microcirculation using a simplified scoring system has shown in patients with cardiac failure, cardiogenic
been shown to be feasible [44]. In addition, the benefit shock and hemorrhagic shock [56,60–62]. When
of intervening to restore microcirculatory abnormali- there is a lack of coherence following initial resusci-
ties in patients with adequate macrocirculatory tation, some of these studies have shown that recov-
parameters has not been shown, this clearly has a ery of the microcirculation may take a much longer
sound rationale and represents a research challenge. time. In many of these studies, the lack of coherence
Overall, the assumption that the microcirculation is and prolonged recovery time of the microcirculation
compromised in patients with developing abnormal has been associated with mortality. Persistent macro-
macrocirculatory parameters in a relevant context hemodynamic abnormalities in combination with
seems valid. microcirculatory abnormalities may impose an even
more increased risk of mortality [63].
The relevance of different microcirculations,
COHERENCE IN THE TREATMENT PHASE: limited by the scarce availability of these in patients,
EXPERIMENTAL DATA is unknown. In a study in patient with sepsis two
The main clinically relevant phase of the presence or studies reported on the coherence of the intestinal
absence of hemodynamic coherence is the resusci- microcirculation [64,65]. Both studies showed the
tation phase. As argued earlier, the absence of coher- absence of coherence between intestinal microcir-
ence in this phase may have significant effects on culation the sublingual microcirculation and the
the adequacy of resuscitation as it may result in both macrohemodynamics. In the study by Boerma
over-resuscitation and under-resuscitation. It is et al. [64], it was shown that recovery of coherence
clear from experimental models in many different between the sublingual and intestinal sites was
pathophysiologic conditions, including sepsis, that restored after several days.
resuscitation on global hemodynamic parameters The use of vasoactive agents to resuscitate the
frequently fails to restore microcirculatory perfusion microcirculation has been reviewed earlier [66] and is
and oxygenation [25,28,45–47]. The effects in dif- outside of the scope of this article. The use of beta
ferent microcirculatory systems or even within one blocker therapy has gained new interest as both
microcirculatory system may however not be similar experimental and clinical studies have shown posi-
[30,48]. There may be few exceptions possibly tive effects on microcirculatory perfusion [50,67,68].
related to the specific hemodynamic compromise As in these studies beta blockers were titrated to HR,
or that may reflect differences in individual the recent finding of the additional effect on mortality
responses. In a model of tamponade, van Genderen of increased HR in patients with abnormal microcir-
et al. [20] showed that removing the pericardial fluid culatory perfusion [63] should encourage additional
resulted in a rapid restoration of both macrocircu- research in this context.
latory and microcirculatory perfusion parameters.
This was very different in the model of septic shock
these researchers studied, where restoration of base- CONCLUSION
line macrohemodynamics did not restore the micro- From the previous the following clinical consequences
circulation, only resuscitation to a hyperdynamic could be drawn. In patients with abnormal macro-
state restored the microcirculation. However, as hemodynamics it is very likely that microcirculatory

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 Monitoring coherence between the macro and microcirculation Bakker and Ince

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