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ACO 340204

REVIEW

CURRENT
OPINION Hemodynamic support in septic shock
Marina Garcı´a-de-Acilu a, Jaume Mesquida b,
Guillem Gruartmoner b, and Ricard Ferrer a

Purpose of review
The current article reviews recent findings on the monitoring and hemodynamic support of septic shock
patients.
Recent findings
The ultimate goal of hemodynamic resuscitation is to restore tissue oxygenation. A multimodal approach
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combining global and regional markers of tissue hypoxia seems appropriate to guide resuscitation. Several
multicenter clinical trials have provided evidence against an aggressive fluid resuscitation strategy. Fluid
administration should be personalized and based on the evidence of fluid responsiveness. Dynamic indices
have proven to be highly predictive of responsiveness. Recent data suggest that balanced crystalloids may
be associated with less renal failure. When fluid therapy is insufficient, a multimode approach with
different types of vasopressors has been suggested as an initial approach. Dobutamine remains the firs
inotropic option in patients with persistent hypotension and decrease ventricular systolic function. Calcium
sensitizer and phosphodiesterase inhibitors may be considered, but evidence is still limited. Veno-arterial
extracorporeal membrane oxygenation may be considered in selected unresponsive patients, particularly
with myocardial depression, and in a highly experienced center.
Summary
Resuscitation should be personalized and based on global and regional markers of tissue hypoxia as well
as the fluid responsiveness indices. The beneficial effect of multimode approach with different types of
vasopressors, remains to be determined.
Keywords
hemodynamic monitoring, resuscitation, septic shock

INTRODUCTION Hemodynamic resuscitation reassures aerobic respi-

The term septic shock refers to a subset of sepsis ration in the tissues and prevents cellular dysfunc-
characterized by profound circulatory and cellular tion and progression to organ failure and death.
metabolism abnormalities and is associated with Accordingly, markers of tissue metabolic status will
higher mortality rates than sepsis alone [1]. be fundamental for guiding the whole process.
Although the classical notion of septic shock was
associated with the need for vasopressor support,
Mean arterial pressure
more recent definitions have highlighted the impor-
tance of cellular abnormalities. It is now accepted Mean arterial pressure (MAP) is considered a reliable
that circulatory failure, or shock, is defined by the surrogate of the driving pressure of tissue perfusion.
evidence of inadequate tissue perfusion with Blood flow to the tissues depends not only on car-
impaired oxygen utilization by the cells [1,2]. The diac output (CO) but also on maintaining a pressure
purpose of hemodynamic support is to detect, mon-
itor, and guide the resuscitation process of the a
Intensive Care Department, Hospital Universitari Vall d’Hebron, Barce-
failing circulation. lona and bCritical Care Department, Parc Taulı́ Hospital Universitari,
Sabadell, Spain
Correspondence to Ricard Ferrer, MD, PhD, Intensive Care Department,
RESUSCITATION ENDPOINTS: RESTORING Vall d’Hebron University Hospital, P. Vall d’Hebron 119-129, 08035
TISSUE HYPOXIA Barcelona, Spain. Tel: +34 93 274 62 09;
The ultimate purpose of the hemodynamic resusci- e-mail: [email protected]
tation process is restoring the availability of oxygen Curr Opin Anesthesiol 2021, 33:000–000
at the cellular level to meet the metabolic demands. DOI:10.1097/ACO.0000000000000959

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Intensive care and resuscitation

Tissue hypoxia markers: global and regional

KEY POINTS markers
 Recent data point toward the need for a multimodal The ultimate goal of hemodynamic resuscitation is
monitoring approach combining lactate levels, venous to restore tissue oxygenation by ensuring sufficient
oxygen saturation and central venous-to-arterial carbon perfusion pressure. Thus, the whole process should
dioxide difference, as well as regional markers of be conducted according to tissue hypoxia markers.
tissue hypoxia.
These markers are classified as global or regional.
 The recommendation is to use an individualized ‘step-
up’ approach, starting with noninvasive or less invasive
tools and moving to more invasive and continuous Global markers of tissue hypoxia
technologies and patient’s condition deteriorates or is In clinical practice, we dispose of three main physi-
not improving.
ological parameters informing about global tissue
 Evidence has grown against an aggressive fluid perfusion: lactate, venous oxygen saturations
resuscitation and support a more personalized strategy (either central or mixed), and carbon dioxide-
based on signs of tissue hypoxia and derived variables (Fig. 1). Quantitative (or goal-
fluid responsiveness. directed) resuscitation strategies define normaliza-
 Balanced crystalloids may be superior to normal saline. tion of global tissue hypoxia markers as the essential
resuscitation goal, and have proven superior to
 Noradrenaline remains as the first-choice vasopressor, qualitative strategies [8]. However, choosing an ade-
but a beneficial effect of a multimodal approach with
quate endpoint is still a matter of debate. Over the
different vasopressors has been recently suggested.
last 20 years, since the appearance of Rivers’ Early
Goal-Directed Therapy study, central venous oxy-
gen saturation (ScvO2) has been the most widely
gradient between upstream and downstream pres- recommended resuscitation endpoint [9]. However,
sure. This aspect is especially relevant in septic three recent international multicenter randomized-
shock, where the vascular tone is impaired. From controlled trials comparing ScvO2-driven protocols
a pathophysiological point of view, maintaining versus usual care failed to show benefits on survival,
an adequate perfusion pressure of the organs will challenging the recommendation of guiding the
be mandatory before optimizing CO. In clinical resuscitation process according to ScvO2 [10–12].
practice, initial resuscitation usually consists of A detailed analysis of such trials reveals that only
administering fluids, which might increase perfu- 20–30% of the patients studied had values of ScvO2
sion pressure and CO. However, when vascular below the normal range at inclusion. Independently
elastance is low, intravascular volume remains of the debate on the limitations of the trials, the fact
unstressed, and arterial pressure might not increase is that ScvO2 still provides valuable physiological
despite increases in CO [3,4]. Therefore, early information on tissue oxygenation global status,
vasopressor use might be necessary when blood and discarding a prized physiological tool might
pressure (BP) does not improve after initial fluid be erroneous.
administration. Lactate has been consistently associated with
Current international guidelines recommend severity of illness and survival of septic shock
initially targeting a MAP of 65 mmHg [2,5]. This patients. Guiding the resuscitation process accord-
recommendation relies mainly on observational ing to lactate clearance has demonstrated a favor-
studies, and robust data evaluating different pres- able impact on survival, even though the
sure targets are scarce. When higher values of MAP interpretation of hyperlactatemia might be com-
have been pursued, no benefits have been detected plex, and it does not directly preclude tissue hypoxia
&
in terms of survival [6]. Some observations suggest [13 ,14,15]. According to lactate kinetics, plasma
that in patients with chronic hypertension, main- lactate should be measured every 1–2 h in early
taining higher BP values might reduce the risk of septic shock, guiding further hemodynamic inter-
renal failure and the need for renal replacement ventions when lactate clearance is considered to be
therapies [6]. On the other hand, the increased insufficient [2,14].
catecholamine load has been repeatedly associated The combination of lactate kinetics and ScvO2
with adverse effects, such as cardiac arrhythmias, provides a more comprehensive clinical picture of
and even with increased mortality [7]. In general, the perfusion status (Fig. 1). In the context of ele-
there is a broad consensus on the need for an indi- vated lactate and low ScvO2, tissue hypoperfusion
vidualized approach to BP targets. Currently, strong must be assumed. However, the combination of
recommendations cannot be stated. hyperlactatemia and ScvO2 values more than 70%

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Hemodynamic support in septic shock Garcı́a-de-Acilu et al.

FIGURE 1. Representation of the relationship between oxygen delivery, oxygen consumption, and global perfusion markers.
According to lactate and central venous oxygen saturation values, four situations have been classically depicted: (a) adequate
global oxygen delivery and metabolism (normal lactate and normal central venous oxygen saturation); (b) oxygen deficit
(normal lactate and low central venous oxygen saturation); (c) oxygen debt (high lactate and low central venous oxygen
saturation); and (d) impaired oxygen extraction (high lactate and high central venous oxygen saturation). High central venous-
to-arterial carbon dioxide difference values might be helpful in this latter condition, revealing situations where insufficient
blood flow are still responsible for an increased anaerobic production of lactate. DO2, global oxygen delivery; pCO2 gap,
central venous-to-arterial carbon dioxide difference; ScvO2, central venous oxygen saturation; VO2, global oxygen
consumption. Reprinted with permission [22].

cannot rule out the persistence of local tissue hypo- or elevated ScvO2 values [2]. No prospective data on
perfusion. Abnormally elevated ScvO2 may result the impact of including the pCO2 gap in a resusci-
from microcirculatory shunting phenomena. In tation protocol is currently available.
these latter situations, carbon dioxide parameters To date, a multimodal approach combining
might be of utility. Central venous-to-arterial car- these three parameters seems appropriate. Adequate
bon dioxide difference (pCO2 gap) is highly linked physiological reasoning is mandatory to increase
to tissue perfusion due to inadequate oxygen deliv- oxygen delivery to the tissues when tissue hypoper-
ery (DO2). Increased PCO2 gap (>5 mmHg), reflects fusion is presumed. Clinicians should avoid unnec-
low blood flow situations, as it is a surrogate of the essary and potentially harmful interventions when
adequacy of CO for a particular clinical situation tissue dysoxia does not depend on decreased
[16]. In sepsis, normal ScvO2 values and persistent oxygen availability.
hyperlactatemia, pCO2 gap more than 6 mmHg val-
ues discriminate patients with worse outcomes
[17,18]. These observations have led to the recom- Regional markers of tissue hypoxia
mendation of further increasing CO when high By definition, regional markers provide information
lactate and pCO2 gap values coexist, despite normal about the perfusion or metabolic status of a given

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Intensive care and resuscitation

tissue. One of the main limitations of regional fluid-responsiveness accounts for approximately
parameters has been their inability to mirror the 50% of cases with shock [26]. The use of bedside
status of the whole body, namely the representative tools to predict the hemodynamic effect of a fluid
value. On the other hand, regional parameters bolus prior to its administration seems reasonable
might provide valuable evidence of tissue hypoxia (Fig. 2).
persistence despite the normalization of global
parameters. Indeed, many regional perfusion and
oxygenation variables have demonstrated their Fluid-responsiveness predictors
prognostic value independently of global hemody- Static parameters for fluid-responsiveness predic-
namic variables [19]. On the contrary, data on the tion consist of steady-state measurements of cardio-
impact of including the regional parameters in the vascular pressures, volumes, or areas in an attempt
&&
decision-tree is limited [20,21 ]. Recently, the to estimate the absolute value of ventricular preload.
ANDROMEDA-Shock trial compared a resuscitation In this group of parameters, we can include the
protocol driven by capillary refill time (CRT) with a measurement of inferior vena cava diameter by
lactate-driven protocol, showing a tendency to low echocardiography, global end-diastolic volume by
mortality rates in the CRT-driven group, with sig- transpulmonary thermodilution (TTD), or central
&&
nificant reductions in fluid administration [21 ]. venous pressure (CVP). By far, CVP is the most
Again, these results point toward the need for a commonly used parameter at the bedside [26]. Still,
multimodal approach, combining perfusion and the evidence has repeatedly shown that CVP (like
metabolic parameters [22]. other static parameters) fails to predict fluid respon-
siveness, even in its extreme values [27]. Therefore,
guiding fluid administration using static parameters
HEMODYNAMIC MONITORING TOOLS is strongly discouraged [2].
To achieve the chosen endpoints, DO2 might be Dynamic parameters are based on evaluating the
optimized to match the metabolic demands. Despite cardiovascular response to a temporary and revers-
DO2 depends on arterial oxygenation, hemoglobin ible change in preload. In that regard, pulse pressure
concentration, and CO, the whole process will rely variation (PPV) and stroke volume variation (SVV)
on CO manipulation in most cases. Accordingly, are excellent fluid-responsiveness predictors in
hemodynamic monitoring tools can estimate CO mechanically ventilated patients [28]. On the con-
and its changes in response to a given intervention. trary, these parameters have certain limitations that
Hemodynamic monitoring tools are useful to pre- have precluded their widespread use. For instance,
dict whether CO will increase as a result of fluid the patient has to be in regular cardiac rhythm, fully
administration (fluid-responsiveness), indepen- adapted to mechanical ventilation, with no sponta-
dently of the value of CO. neous efforts, and receiving tidal volumes more
than 8 ml/kg of ideal body weight. This last limita-
tion might be overcome by the incorporation of a
Fluid-responsiveness ‘tidal volume challenge’ maneuver, which allows
Fluid administration is considered the first step in keeping the good predictive value of PPV/SVV dur-
the resuscitation process of patients with septic ing protective ventilation (<6 ml/kg) [29], and over-
shock. The main goal of fluid administration is to come the ‘grey zone’ of a continuous parameter [30].
increase venous return and cardiac preload. Ulti- Furthermore, the end-expiratory occlusion test has
mately, if the patient’s condition is in the Frank– also been proposed as a reliable fluid responsiveness
Starling curve’s preload-dependent area, fluid resus- predictor in critically ill patients. Significantly, it is
citation may increase CO and DO2. This is of utmost also useful in patients with cardiac arrhythmias,
importance since hemodynamic benefits would spontaneously breathing, and low pulmonary com-
only be expected when the patient is still in the pliance [31]. Finally, the passive leg raising (PLR)
fluid-responsive area; otherwise, fluid will only be maneuver is a standardized test that predicts fluid
detrimental [23]. A robust body of evidence shows responsiveness when inducing an increase of CO
that fluid overload is associated with increased more than 10% [32]. Significantly, PLR may be used
morbidity and mortality, particularly in septic in patients with cardiac arrhythmias, spontaneous
patients [24]. In the assessment of preload-depen- breathing efforts, or low pulmonary compliance. Its
dence, the so-called fluid challenge is a simple main limitation is that some specific subgroups of
method based on infusing a 500 cm3 fluid bolus critically ill patients may not tolerate the maneuver.
and evaluating its effect on CO. This approach is Of note, except for PPV, all dynamic parameters
still considered the gold standard for assessing fluid need a continuous CO monitoring technology in
responsiveness at bedside [25]. On the contrary, place for its calculation.

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Hemodynamic support in septic shock Garcı́a-de-Acilu et al.

FIGURE 2. Current recommended approach to fluid administration. Dynamic parameters are recommended over static
parameters. Pulse pressure variation and vena cava respiratory-induced changes do not require a continuous cardiac output
monitoring system, while other dynamic indices can only be evaluated when cardiac output is measured. Performing a fluid
challenge also requires the measurement of cardiac output. CO, cardiac output; EEO, end-expiratory occlusion test; IVC,
inferior vena cava; PLR, passive leg raising; PPV, pulse pressure variation; SVC, superior vena cava; SVV, stroke volume
variation; VT, tidal volume. Reprinted with permission [32]; Copyrightß 2017 Wolters Kluwer Health, Inc. All rights reserved.

Hemodynamic monitoring in septic shock: a proposed as a bedside tool to assess cardiac function
‘step-up’ approach and structure, and rules out other possible shock
The recommendation is to use an individualized causes. Echocardiography has also been proposed as
‘step-up’ approach: starting with noninvasive or less a reliable tool to monitor CO, but it is crucial to
invasive tools, and if patient’s condition deterio- understand that this capability is at hand only for
rates or is not improving, move to more invasive experts in the field. In that regard, recent scientific
and continuous hemodynamic monitoring technol- evidence has shown unacceptable degrees of inac-
&
ogies [2,33,34]. curacy in CO estimations [35,36 ]. Overall, caution
The first step for hemodynamic monitoring is should be taken in the widespread use of this tool for
the placement of a central venous catheter, often bedside CO monitoring in critically ill patients. It
necessary to administer vasoactive drugs and fluids seems reasonable to remark that echocardiography
infusion. A central venous catheter facilitates ScvO2 should be considered a cardiac evaluation tool and
monitoring and CVP when necessary. The insertion not a continuous hemodynamic monitoring tech-
of an arterial catheter is also recommended for nique in septic shock.
patients with shock and vasopressors, allowing the A further step of hemodynamic monitoring will
continuous measurement of BP and monitoring be the continuous measurement of CO. This level of
PPV. In addition, echocardiography has been monitoring is recommended for patients that are

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Intensive care and resuscitation

not responding to initial therapy or patients with high-quality evidence is scarce regarding a more sig-
complex conditions, such as myocardial dysfunc- nificant benefit of one vasopressor over another [48],
tion or acute respiratory distress syndrome [34]. noradrenaline has been associated with decreased
These circumstances usually involve the use of mortality [49]. Less adverse events have been observed
advanced monitoring techniques, such as TTD sys- from noradrenaline than other agents such as dopa-
tems or pulmonary artery catheter (PAC). Current mine [50], epinephrine, and phenylephrine [51,52].
recommendations assume both TTD and PAC as Recently, some studies suggest that the early
equivalent techniques. Both can accurately estimate administration of noradrenaline may be associated
CO and are useful in different clinical scenarios. with improved shock control, with no differences in
&&
However, experts advocate for the use of PAC in the occurrence of organ failure [53 ,54].
cases of right ventricular dysfunction [2,34]. Of Adding a noncatecholamine vasopressor, such
note, minimal or noninvasive CO monitoring tech- as vasopressin, may be considered for refractory
niques, such as noncalibrated pulse contour analy- hypotension, decreasing noradrenaline dose, and
sis, are not recommended for septic shock because preventing the toxicity associated with high doses
their reliability has been questioned in severe vas- of a single agent [5].
cular tone dysfunction states [37]. The individual response to different vasopressor
agents may vary from one patient to another [55].
This response is difficult to assess at the bedside,
THERAPIES FOR HEMODYNAMIC albeit it might impact clinical outcomes [56]. A
SUPPORT multimodal approach with different vasopressors
has been suggested as an initial approach to septic
Fluids &
shock [57 ], mimicking the antimicrobial therapy
Current international guidelines recommend infus- paradigm of broad-spectrum antibiotics.
ing at least 30 ml/kg of crystalloids within the first
3 h [5]. Nevertheless, an individualized, hemody-
namic-guided fluid resuscitation strategy is strongly Inotropes
supported [2]. Fluid administration should ideally Patients with persistent hypoperfusion despite ade-
be personalized and based on the presence of signs quate fluid resuscitation might benefit from inotro-
of tissue hypoxia and the evidence that CO will pic support. The administration should be
increase, as well as a continuous reassessment of individualized and intended to improve tissue per-
&&
hemodynamic status [38,39 ]. Challenge remains fusion associated with an increase in CO, taking into
in the individual assessment of the benefits/risks account potential adverse events.
ratio of fluid administration at bedside. Dobutamine remains the first option [5], though
Crystalloids are recommended as the resuscita- it may be associated with an increased incidence of
tion fluid of choice [5]. Recent data suggest that arrhythmias and worse outcomes [58]. Alternative
balanced crystalloids may be preferred over normal inotropic agents such as the calcium-sensitizer, lev-
saline. They may be associated with a lower risk of osimendan, and a phosphodiesterase-inhibitor, mil-
&&
renal failure and death [40,41,42 ], although fur- rinone, may be considered. Evidence is still limited
ther research is needed. and indicates no clear advantage of these agents
Among colloids, albumin is the only one that over dobutamine [59].
has been reported to be safe [43–45]. Its administra-
tion is suggested ‘when patients require substantial
amounts of crystalloids’ [5]. However, the right Veno-arterial extracorporeal membrane
timing for switching from crystalloids to colloids oxygenation
remains uncertain, and the benefit of albumin is still The use of extracorporeal life support in adult
controversial. Data continue to report potential patients with refractory septic shock remains con-
harm of hydroxyethyl starch solutions [46,47]. troversial. Few case reports describe the use of this
technique, with highly variable clinical outcomes
&
[60 ]. The best results are reported in patients with
Vasopressors severe cardiac dysfunction [61], in which extracor-
Vasopressors are recommended when fluid therapy is poreal membrane oxygenation (ECMO) may help
insufficient for restoring BP levels. Uncertainties restore adequate tissue perfusion. This strategy may
remain for the type of vasopressor, timing, optimal reverse multiple organ failures and buy time to
dose, response monitoring, and weaning strategy. achieve infection control.
Current consensus guidelines recommend noradren- Large high-quality studies are needed before
aline as the first-choice vasopressor [5]. Although veno-arterial ECMO becomes the standard of care

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Hemodynamic support in septic shock Garcı́a-de-Acilu et al.

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