890

Hemodynamic Monitoring for the Evaluation

and Treatment of Shock: What Is the Current
State of the Art?
Eric M. Suess, MD1 Michael R. Pinsky, MD1

1 Department of Critical Care Medicine, University of Pittsburgh, Address for correspondence Michael R. Pinsky, MD, Department of
Pittsburgh, Pennsylvania Critical Care Medicine, University of Pittsburgh, 606 Scaife Hall, 3550
Terrace Street, Pittsburgh, PA 15261 (e-mail: pinskymr@upmc.edu).
Semin Respir Crit Care Med 2015;36:890–898.

Abstract Hemodynamic monitoring has become a fundamental and ubiquitous, if not defining,
aspect of critical care medicine practice. Modern monitoring techniques have changed
significantly over the past few years and are now able to rapidly identify shock states
earlier, define the etiology, and monitor the response to therapies. Many of these
techniques are now minimally invasive or noninvasive. Basic hemodynamic monitoring

Downloaded by: Universitätsbibliothek. Copyrighted material.

and evaluation usually includes a focused physical examination and static hemodynamic
vital signs: temperature, heart rate, respiratory rate, mean arterial pressure, and arterial
hemoglobin oxygen saturation, typically measured with pulse photoplethysmography.
When available, measurement of urinary output is often included. Advanced hemody-
namic monitoring incorporates both noninvasive and invasive continuous hemodynam-
ic monitoring. Noninvasive ultrasound has emerged as a fundamental hemodynamic
Keywords evaluation tool and its use is now rapidly increasing. Invasive monitoring from arterial
► functional and central venous catheters, and occasionally pulmonary artery catheters, provides
hemodynamic measurement of arterial pressure, intracardiac filling pressures, arterial and venous
monitoring blood gases, and cardiac index. Minimally invasive and noninvasive measure of arterial
► shock pressure and cardiac output are also possible and often remain as accurate as invasive
► minimally invasive measures. Importantly, such advanced monitoring provides the foundation for goal-
monitoring directed therapies for the treatment of shock. When coupled with functional hemody-
► goal-directed therapy namic monitoring analyses, these measures markedly extend the diagnostic and
► volume therapeutic potential of all monitoring modalities by defining preload reserve, vasomo-
responsiveness tor tone, cardiac performance, and tissue perfusion.

Hemodynamic monitoring is central to the care of most of therapies directed at restoring cardiopulmonary
critically ill patients. It has become a fundamental and sufficiency.
ubiquitous, if not defining, aspect of critical care medicine
practice. Modern monitoring techniques are able to identify
Basic Hemodynamic Monitoring
distinctive physiologic patterns specific for shock states and
monitor the response to therapies aimed at reversing these Basic hemodynamic monitoring in the intensive care unit
abnormalities. A primary goal of hemodynamic monitoring (ICU) for identification and treatment of overall cardiopul-
is to evaluate cardiopulmonary function, cardiovascular monary sufficiency includes a focused history, physical
reserve, and the adequacy of blood flow and oxygen delivery examination, and the noninvasive assessment of primary
to the tissues and, if deemed inadequate, monitor the impact hemodynamic variables, such as vital signs (i.e., heart rate

Issue Theme Controversies and Evolving Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/
Concepts in Critical Care; Guest Editors: Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1564874.
Wassim H. Fares, MD, MSc, and Mark D. New York, NY 10001, USA. ISSN 1069-3424.
Siegel, MD Tel: +1(212) 584-4662.

[HR], mean arterial pressure [MAP], respiratory rate [RR],
temperature, and pulse oximetry O2 saturation) and, if avail-
able, urine output.1 However, these primary variables and the
physical exam have repeatedly proven insufficient and inac-
curate for hemodynamic evaluation, rapid assessment, and
identification of occult or compensated shock, especially in
the previously healthy patient and when cardiopulmonary
status is changing quickly.2–6 Biochemical markers of tissue
hypoperfusion (e.g., lactate, metabolic acidosis, ScvO2) due to
cardiovascular insufficiency may be abnormal indicating
occult tissue hypoperfusion even without hypotension or
other overt clinical signs of shock.7–9 Recently, Casserly
et al9 have again demonstrated markedly increased mortality
in septic patients when lactate was greater than 4 mmol/L,
even in the absence of hypotension. Whether hyperlacticemia
reflects tissue hypoperfusion or overwhelming inflammation
in the setting of sepsis is unknown, but hyperlacticemia is
universally a poor prognostic sign, even if useful in guiding
resuscitation.
Advanced Hemodynamic Monitoring
Consequently, current hemodynamic monitoring has
advanced from the physical exam and these primary he-
modynamic variables. Continuous measures of arterial
pressure, cardiac output (CO), and blood oxygenation are
used to better monitor the critically ill patient.10 Rapid
changes in hemodynamic stability and states of compen-
sated shock are more easily recognized. Importantly, the
continuous monitoring of these advanced variables has
allowed for the development of hemodynamic goal-
directed resuscitation and treatment of shock.
However, the transition from basic to advanced hemody-
namic monitoring is artificial at best. Since many very
important hemodynamic values, like continuous measuring
of arterial waveforms and CO, are now potentially accurately
estimated using completely noninvasive methodologies, sep-
arating basic from advanced monitoring based solely on
invasiveness is misleading. Certain caveats continue to hold
true. First, in the setting of profound circulatory shock,
noninvasive measures of hemodynamics may be less accurate
or may not trend dynamic changes as well as these same
hemodynamic variables when measured invasively. Still, the
ability to rapidly know real-time arterial pressure and its
waveform, and calculate CO and its derived variables greatly
increases the diagnostic and therapeutic options for the
bedside clinician.
Over 20 years ago, goal-directed resuscitation protocols
focused on targeting oxygen delivery (DO2) to sustain sys-
temic oxygen uptake (VO2) by achieving threshold levels of
central venous pressure (CVP), pulmonary artery occlusion
pressures (PAOP), intracardiac pressures, and CO. Thus,
advanced hemodynamic monitoring typically required inva-
sive devices that could measure these parameters, specifically
the pulmonary artery catheter (PAC).11 The use of the PAC has
been both championed and vilified ever since its introduc-
tion.12 Trials and observational studies have yielded conflict-
ing results,12–14 but many prominent clinician-researchers
Hemodynamic Monitoring in Shock Suess, Pinsky 891
have proposed limiting PAC use to high-risk, critically ill
patients for whom PAC-derived data will change therapy or
will contribute to protocolized treatment algorithms with
patient-centered outcome benefits.14–19
Shoemaker and colleagues, using PAC-derived data in such
a protocolized manner, performed a landmark randomized
control trial comparing “supranormal” DO2 and cardiac index
(CI > 4.5) to standard care (no PAC) in high-risk surgical
patients.20 Importantly, the supranormal DO2 and CI goals
were met immediately preoperatively using intravenous fluid
infusions, red cell transfusion, and vasopressors/inotropes,
and were then maintained throughout the perioperative
period. This hemodynamic goal-directed intervention was
therefore “early,” as the “pathophysiologic insult” was the
surgical operation itself. Remarkably, patients in the proto-
colized arm had not only decreased rates of mortality, but also
decreased complications, duration of ICU and hospital stay,
and costs.
Although the results of Shoemaker et al20 have been
replicated in high-risk surgical patients who were “preopti-
Downloaded by: Universitätsbibliothek. Copyrighted material.
mized” using early goal-directed protocols to achieve “supra-
normal” DO2,18,19 a series of subsequent trials failed to show
benefit and some identified harms when applied after the
expression of shock-induced end-organ injury.21–23 Place-
ment of PACs declined further as trials consistently showed
no benefit when used in heterogeneous or primarily septic
critically ill patients,24,25 when used without protocols to
achieve hemodynamic goal-directed therapeutic targets,26,27
when used in primarily heart failure,28 and when used as part
of “routine” hemodynamic monitoring.29
Perceived usefulness of the pulmonary catheter has con-
tinued to decrease as CVP and central venous oxygen satura-
tion (ScvO2), values that can be obtained from less invasive
internal jugular or subclavian catheters, are increasingly used
targets of resuscitation.30–32 Furthermore, the introduction of
“minimally invasive” CO monitors has diminished need for
right heart catheterization.33,34 Indeed, the use of the PAC for
advanced hemodynamic monitoring is now relatively rare
outside of teaching hospitals, operating suites, and surgical
care units.35
Clearly, the need for continuous monitoring of pulmo-
nary artery pressure, SvO2, and CO, coupled with measure
of right ventricular volumes, is still indicated under specific
conditions, but the generic use of the PAC for routine
monitoring of the critically ill patient has vanished. With
the decline in use of PACs, goal-directed protocols and
guidelines currently use MAP, CVP, and CO, which are
targets based upon data obtained from “minimally inva-
sive” arterial and central venous catheters, to guide the
initial resuscitation of shock.30
At the most basic level, shock is the inadequate delivery of
oxygen to the tissues, which is dependent upon perfusion
pressure (MAP) and flow. Except for the kidneys and heart,
most organs and tissues autoregulate blood flow and local
DO2 using local adjustment of vasomotor tone. However,
below a critical MAP threshold, autoregulation fails. Although
minimal MAP thresholds for all patients and all organ systems
are unknown and controversial, MAP values < 60 mm Hg are
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
892 Hemodynamic Monitoring in Shock Suess, Pinsky
below most patient’s autoregulation thresholds and result in
insufficient perfusion to the heart and other organs.1,36 The
duration and degree of hypotension below 60 to 65 mm Hg is
well correlated with mortality and organ failure.37,38 Conse-
quently, most studies and guidelines target a minimum MAP
of 65 mm Hg during initial resuscitation of shock.30,39 There
is good evidence that, except in patients with chronic hyper-
tension or severe atherosclerosis, further augmentation of the
MAP provides no further benefit40,41 and artificially in-
creased vasomotor tone may actually decrease blood flow
by constricting arterioles.42 Thus, monitoring and targeting
threshold minimal MAP values during resuscitation using
hemodynamic monitoring is not only indicated but will
improve outcome.
The initial recommended intervention for arterial hypo-
tension is frequently intravenous crystalloid infusion (except
in some cases of hemorrhagic or cardiogenic shock). The
Surviving Sepsis Guidelines recommend an initial fluid
challenge and continued intravenous crystalloid infusion
with a goal CVP of 8 to 12 mm Hg for patients with evidence
of tissue hypoperfusion.30 However, CVP is a very poor
indicator of intravascular fluid status and volume (preload)
responsiveness.43–45 Marik and Cavallazzi performed an
extensive meta-analysis in 2013 of studies comparing CVP
and ventricular stroke volume, CI, and fluid responsive-
ness.46,47 They reported that, “there is no data to support
the widespread practice of using CVP to guide fluid therapy.
This approach should be abandoned.”47
Consequently, intravenous crystalloid infusion, although
the nearly universal initial therapy for hypotension and
hypoperfusion, is particularly difficult to manage when
following current guidelines. This is further complicated by
evidence that around 50% of hemodynamically unstable
patients will not be responsive to crystalloid bolus infusion.48
Additionally, increasing observational and correlational data
have associated positive fluid balance with mortality and
organ failure, particularly acute lung injury/acute respiratory
distress syndrome (ARDS).49–53 Furthermore, it is unclear
from retrospective data whether administration of early
inotropic/vasopressor support in place of or concurrent
with volume expansion improves outcomes or harms
patients.54–56 The CENSAR study group (NCT01945983) is
currently comparing early norepinephrine concurrent with
crystalloid infusion with standard care in a prospective
randomized fashion, but both the control and intervention
groups will still receive volume expansion guided by CVP or
PAOP, indices that are inaccurate assessments of preload or
volume responsiveness.44,57
Therefore, even when using advanced hemodynamic mon-
itoring (e.g., MAP, cardiac filling pressures), clinicians have
the following critical questions left unanswered10: Is the CO,
and therefore DO2, volume (preload) responsive? Is vasomo-
tor tone increased or decreased? And how will changes in
vasomotor tone and CO in response to increased preload or
inotropic support improve DO2 to tissues in the setting of
cardiovascular failure? To answer these questions at the
bedside, functional hemodynamic monitoring (FHM) is
required.10,45,58
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
Functional Hemodynamic Monitoring
FHM is the measurement of the hemodynamic response to a
predetermined intervention and the use of the result to
define the pathophysiologic state of the patient and predict
response to potential therapies.10,58 Recent research has
allowed the use of FHM to predict: (1) volume responsive-
ness; (2) arterial vasomotor tone reactivity (elasticity); and
(3) microvascular tissue hypoxia due to cardiovascular
insufficiency, even in the setting of compensated shock as
measured by advanced hemodynamic monitoring of mac-
rovascular indices.
Volume Responsiveness
Michard et al46 published a classic example of FHM when they
defined what has now become the standard definition of
“volume responsiveness”: an increase in CI 15% in response
to a 500 mL intravenous fluid infusion. Volume responders
and nonresponders were distinguished by respiratory varia-
tion in arterial pulse pressure variation (PPV) of 13%. PPV is
Downloaded by: Universitätsbibliothek. Copyrighted material.
the difference between the maximal pulse pressure and
minimal pulse pressure over 3 to 5 positive-pressure breaths
(Vt 8 mL/kg) divided by the average of these values. The
difference in pulse pressures is due to the increase of
intrathoracic pressure during the mechanical breaths
(►Fig. 1).59
Accurately measuring PPV requires advanced hemody-
namic monitoring and uses mechanical ventilation, but is
based on classical physiology of heart–lung interactions
and Frank–Starling relations.45,59–61 In patients who are on
the “steep” part of the Frank–Starling curve and therefore
preload dependent, mechanical positive pressure inspira-
tion increases intrathoracic pressure and therefore de-
creases venous return. This decreased venous return
decreases right ventricular preload, which in turn, after
a few heartbeats, decreases left ventricular preload.
Frank–Starling curves appropriately predict a correspond-
ing decreased stroke volume. These patients are termed
“responders.” In contrast, patients on the “flat” portion of
the Frank–Starling curve do not experience a proportional
decrease in stroke volume due to an increase in intratho-
racic pressure from mechanical ventilation and are referred
to as “nonresponders.”
To clarify the concept and definition of FHM as introduced
above, the predetermined intervention in Michard et al’s46
study is increased intrathoracic pressure from the mechanical
breath; the measured hemodynamic response is the PPV; the
newly defined pathophysiologic state would be hypovolemia
(inadequate preload); and the predicted response to the
therapy of volume expansion would be increased CO.
Since Michard et al’s46 original publication in 2000,
literature supporting the reliability and reproducibility of
PPV 13 to 15% to predict volume responsiveness has
exploded.62,63 Bedside use of PPV is now both well supported
and easily accessible. Multiple commercial devices are now
available to calculate and continuously display PPV, stroke
volume variation (SVV), and CI based on these FHM
principles.34

Fig. 1 Strip chart recording of airway pressure and arterial pressure for a subject during positive pressure ventilation, illustrating the technique of
calculating both D pulse pressure and pulse pressure variation from the arterial pressure waveform.
In addition to PPV, systolic pressure variation and SVV
calculated from arterial waveform analysis have been shown
to be effective predictors of volume responsiveness.63 Nonin-
vasive measures of stroke volume variability have included
echocardiographic measurement of the velocity-time inte-
gral of aortic blood flow, analysis of the plethysmographic
waveform variability, ultrasonographic assessment of inferior
vena cava,64,65 superior vena cava,66 and internal jugular67
diameter respiratory variations, and noninvasive measure-
ment of carotid arterial blood flow and bioreactance
(NICOM).33,45,68 However, PPV appears to be the most specific
and sensitive predictor of volume responsiveness, even
slightly better than SVV. In a systematic review and analysis
of pooled data, Marik et al63 calculated the correlation
coefficient between PPV and increased CI to be 0.78, while
the same coefficient was 0.72 for SVV. Both were superior to
estimates of volume responsiveness using static measures of
“volume status” (e.g., CVP, left end-diastolic volume index),
which were no better than random chance.
Although robust and useful, the predictive value of PPV
is restricted by confounding disease and therapies. Intra-
abdominal hypertension, cardiac arrhythmia (e.g., atrial
fibrillation), spontaneous breathing, decreased chest wall
compliance, and a rapid RR relative to HR all may result in
inaccurate PPV assessments.10,33 Notably, tidal volume
ventilation with < 8 mL/kg, which is being used more
frequently as part of a lung protective ventilation strategy
in ARDS, 69 decreases the sensitivity but not the specificity
of PPV assessment.70,71 Lower tidal volumes are more likely
to produce insufficient increases in intrathoracic pressure
during mechanical insufflation, thereby minimizing the
potential decreased venous return. Such limitations are
Hemodynamic Monitoring in Shock Suess, Pinsky 893
Downloaded by: Universitätsbibliothek. Copyrighted material.
indeed restrictive and relatively common. When Richard
and colleagues72 recently performed a randomized control
trial using FHM protocols to guide fluid therapy in patients
with septic shock, PPV-guided fluid therapy could only be
applied to 9% of their cases. This was primarily due to the
use of low tidal volume ventilation.
Spontaneous breathing in addition to mechanical ventila-
tion or independent of mechanical support poses perhaps an
even bigger limitation to the use of PPV assessment of volume
responsiveness in the ICU. Alternative techniques for
“dynamic preload assessment” include end-expiratory
occlusion testing73,74 and passive leg raise (PLR) tests.75
PLR-associated changes in CO appear robust under all conditions
including spontaneous breathing76 and cardiac arrhythmia, and
PLR may be more versatile and more applicable to the emergen-
cy department as endotracheal intubation is not required.
PLR testing monitors the change in CO when the patient is
transferred from a traditional, semi-recumbent position with
the head of the bed 30 to 45 degrees to a supine position with the
thoracic spine parallel to the floor and the lower extremities
raised to 45 degrees with the knees extended.77 Conceptually
and theoretically, such a maneuver provides a reversible78
“autotransfusion” of blood from the lower extremities and
splanchnic venous capacitance (hence the preferred “starting
position” with the head of the bed 30–45 degrees)77 to the
cardiac chambers and pulmonary circulation. Volume respon-
siveness by measuring increased CO in the supine position with
the legs raised has been shown to be reliable and reproducible in
multiple studies, as documented in a meta-analysis by Cavallaro
and colleagues.79 Of note, this meta-analysis also showed
increased CO after PLR on continuous monitoring to be more
predictive of volume responsiveness than PPV.
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
894 Hemodynamic Monitoring in Shock Suess, Pinsky
As reviewed by Monnet and Teboul33 in 2013, PPV reliably
predicts increased CO and stroke volume, and actual fluid
bolus–induced increases in CO can be correlated with stroke
volume increases and antecedent PPV80; however, PPV or
fluid responsiveness (i.e., increased CO) cannot reliably be
correlated with MAP changes.80,81 The relationship between
volume responsiveness and MAP response is complex and
multifaceted, but is partially defined and regulated by arterial
elastance.
Dynamic Arterial Vasomotor Tone, Compliance, and
Elastance
Arterial compliance and elastance are reciprocal measures of
the relationship between the change in volume and the
change in pressure. Dynamic arterial compliance is defined
as the ratio of SVV to PPV, and the dynamic elastance, or
“instantaneous stiffness,” is defined by the reciprocal ratio.82
Therefore, one would anticipate that increased CO (i.e., in-
creased SV with unchanged HR) would have a predictable
effect on MAP response based on arterial elastance. Very low
dynamic elastance would be associated with minimal changes
in MAP as CO increased, and vice versa
Indeed, when Monge and colleagues83 studied a popula-
tion of hypotensive patients in acute circulatory shock who
were all determined to be volume responsive (SVV 10%)
before and after infusion of 500 mL hydroxyethyl starch, the
patients who “responded” by increasing their MAP 15%
could only be distinguished from “MAP nonresponders” by
dynamic elastance (PPV/SVV). Remarkably, the area under the
receiver operator curve (ROC) for this prediction based on
dynamic elastance before volume expansion was
0.986  0.02 with the 95% confidence interval 0.84 to 1,
which was statistically higher than areas under the ROC for
the other measured hemodynamic indices including systemic
vascular resistance and the shock index (PP/SV).
These findings are consistent with the two studies dis-
cussed above,80,81 as the dynamic elastance was not explicitly
evaluated. Therefore, although Pierrakos et al81 found an
increased MAP after fluid challenge was given to “respond-
ers” (defined by increased CI) but not in “nonresponders” (no
increased CI after fluid challenge), they were not able to
correlate increased CI or SVV with MAP, as dynamic elastance
was not used as a distinguishing factor. Similarly, when
Monnet et al84 studied patients in septic shock treated with
norepinephrine at baseline, the contribution of dynamic
elastance may explain why the decreased rate of norepineph-
rine infusion alone (i.e., without intravenous fluid bolus) was
shown to decrease static markers of preload (e.g., CVP, left
ventricular end-diastolic volume) and MAP, although CI
(surrogate for volume responsiveness/preload dependency)
did not decrease. The decreased static markers of preload
increased by norepinephrine reduction may also be due to
peripheral vasodilation which would both increase an un-
stressed venous volume in the circulation and the resistance
to venous return.85,86
The peripheral blood volume distends the peripheral
vasculature. Initially, volume is accommodated by conforma-
tional changes in vessel shape rather than distention, such
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
that distending pressure remains zero despite increasing
intravascular volume. The blood volume needed to distend
the vessels enough to cause distending pressure to finally rise
above zero is called the unstressed volume. Also vascular beds
have an unstressed volume, some, like the splanchnic circu-
lation, greater than others, like muscles. Thus, redistribution
of blood to greater numbers of vascular beds or more to the
gut will increase unstressed volume and make the mean
systemic pressure of the body less for the same absolute
blood volume. Fluid resuscitation usually initially increases
stressed blood volume more than unstressed blood volume.
But this may change with volume redistribution, a major
reason why the initial increase in CO seen with fluid resusci-
tation decreases rapidly over minutes. However, this further
supports the concept that FHM must focus not only on volume
responsiveness, but also on macrovascular (i.e., dynamic
elastance and MAP) and microvascular perfusion indices.
Microvascular Tissue Oxygenation
Ultimately, sustaining adequate cellular and tissue oxygen-
Downloaded by: Universitätsbibliothek. Copyrighted material.
ation is the goal of resuscitation therapies in circulatory
shock. Microcirculatory dysfunction and dysoxia have repeat-
edly been shown to play a prominent role in the natural
history of circulatory shock and multiorgan failure, especially
in the pathogenesis of sepsis.87–89 In addition to biochemical
markers of tissue hypoxia and hypoperfusion such as lactate,
SvO2, and pCO2, FHM is now able to assess microcirculatory
flow and tissue oxygenation at the microvascular level,
providing diagnostic, prognostic, and therapeutic
potential.90,91
Local tissue oxygenation saturation (StO2) can be reliably
and noninvasively measured using near-infrared spectrosco-
py (NIRS) probes, but the absolute static value is unrevealing
except in extreme shock states.10 However, by monitoring
dynamic changes in StO2 in response to the vascular occlusion
test (VOT)—that is, by applying functional hemodynamic
principles—tissue oxygen saturation has been shown to be
prognostic and diagnostic in multiple settings including
trauma and sepsis.10,58
Briefly, the VOT is performed by application of a sphyg-
momanometer insufflated to 20 to 30 mm Hg above systolic
blood pressure with the NIRS probe measuring oxygenation
saturation distally at the thenar eminence.10,92 When the
StO2 reaches nadir or insufflation has been maintained for a
predetermined time interval (e.g., 3 minutes or until StO2
< 30%), the occlusive pressure is released while monitoring of
StO2 continues until it returns to baseline. The rate of StO2
deoxygenation is believed to represent local tissue metabolic
rate and oxygen extraction, whereas the rate of StO2 reoxy-
genation reflects microvascular vessel and blood flow recruit-
ment in the setting of worsening oxygen delivery.93
Use of the VOT to augment StO2 has repeatedly shown to be
useful in prognosticating outcomes in sepsis and predictive of
multiorgan failure.94–96 Guyette et al97 were able to show not
only that StO2–VOT was feasible to the out-of-hospital envi-
ronment, but also that deoxygenation and reoxygenation
curves during aeromedical transport of trauma patients
predicted need for ICU admission and life-saving

interventions. Case reviews from this abstract imply that
StO2–VOT may be an earlier and more sensitive indicator of
injury than transient prehospital hypotension or indetermi-
nate lactate levels.
Similar results have been found using alternative measures
of microvascular circulation and perfusion. Assessment of the
microcirculation using sidestream dark field (SDF) imaging, a
technique that records images of sublingual capillaries and
microcirculatory flow, has shown similar diagnostic and
prognostic value in sepsis patients.98,99 Although the practi-
cal and time commitment required for SDF image collection,
processing, and interpretation has so far limited widespread
use by clinicians at the bedside, both SDF imaging of the
sublingual microcirculation and tissue oxygenation using
StO2–VOT are already being used in randomized control trials
as guides to resuscitation of the microcirculation.100,101 For
example, Hernandez et al101 performed a randomized, place-
bo-controlled, double-blind crossover study comparing the
effect of dobutamine infusion on markers of microcirculatory
perfusion in vasopressor-dependent septic shock patients
whose macrocirculatory hemodynamics were optimized at
the time of enrollment. Although they were not able to show
improvement in microcirculatory flow by augmenting the CI
with dobutamine, they provided an excellent example of the
future direction of FHM: goal-directed macrocirculatory
optimization followed by therapeutic intervention focused
on microcirculatory dysfunction and oxygen delivery at the
tissue and cellular level.
Future Directions
Modern hemodynamic monitoring has advanced rapidly
from simple observation of the physical exam, vital signs,
and static measures of vascular and intracardiac pressures
to FHM of both the macro- and microcirculation. Functional
hemodynamic variables, particularly measures of volume
responsiveness, are now widely used not just for diagnosis
or prognostication, but also as guides and targets in goal-
directed therapy protocols. These targets and techniques
are beginning to show that continued focus on the adequate
delivery of oxygen to the cellular level will improve
outcomes.
Perioperative goal-directed protocols have shown im-
proved outcome in high-risk surgical patients by focusing
on early and adequate, if not supernormal, DO 2 to the
tissues.102 Similar trials in septic and nonsurgical patients
have not been as successful,27,101,103,104 but FHM has
started to reveal potential goals and targets at which future
protocols may direct therapies. Macrocirculatory targets
are becoming clear and research is now focused on local-
ized tissue perfusion, the balance between perfusion pres-
sures at the levels of arterioles and venules within organs
and tissues, microcirculatory dysfunction, endothelial dis-
turbance, mitochondrial dysoxia, and capillary flow. The
most exciting question regarding hemodynamic monitor-
ing may not be “What is the current state of the art?” but
rather “What is the future?”
Hemodynamic Monitoring in Shock Suess, Pinsky 895
References
1 Pinsky MR. Hemodynamic evaluation and monitoring in the ICU.
Chest 2007;132(6):2020–2029
2 Grissom CK, Morris AH, Lanken PN, et al; National Institutes of
Health/National Heart, Lung and Blood Institute Acute Respira-
tory Distress. Association of physical examination with pulmo-
nary artery catheter parameters in acute lung injury. Crit Care
Med 2009;37(10):2720–2726
3 Eisenberg PR, Jaffe AS, Schuster DP. Clinical evaluation com-
pared to pulmonary artery catheterization in the hemodynam-
ic assessment of critically ill patients. Crit Care Med 1984;
12(7):549–553
4 Connors AF Jr, McCaffree DR, Gray BA. Evaluation of right-heart
catheterization in the critically ill patient without acute myocar-
dial infarction. N Engl J Med 1983;308(5):263–267
5 Thomas JT, Kelly RF, Thomas SJ, et al. Utility of history, physical
examination, electrocardiogram, and chest radiograph for differ-
entiating normal from decreased systolic function in patients
with heart failure. Am J Med 2002;112(6):437–445
6 Schriger DL, Baraff LJ. Capillary refill—is it a useful predictor of
hypovolemic states? Ann Emerg Med 1991;20(6):601–605
7 Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in
the ED: responses of blood pressure, heart rate, shock index,
Downloaded by: Universitätsbibliothek. Copyrighted material.
central venous oxygen saturation, and lactate. Am J Emerg Med
1996;14(2):218–225
8 Fuller BM, Dellinger RP. Lactate as a hemodynamic marker in the
critically ill. Curr Opin Crit Care 2012;18(3):267–272
9 Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in
sepsis-induced tissue hypoperfusion: results from the Surviving
Sepsis Campaign database. Crit Care Med 2015;43(3):567–573
10 Pinsky MR. Functional hemodynamic monitoring. Crit Care Clin
2015;31(1):89–111
11 Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D.
Catheterization of the heart in man with use of a flow-directed
balloon-tipped catheter. N Engl J Med 1970;283(9):447–451
12 Whitener S, Konoske R, Mark JB. Pulmonary artery catheter. Best
Pract Res Clin Anaesthesiol 2014;28(4):323–335
13 Connors AF Jr, Speroff T, Dawson NV, et al; SUPPORT Investiga-
tors. The effectiveness of right heart catheterization in the initial
care of critically ill patients. JAMA 1996;276(11):889–897
14 Mimoz O, Rauss A, Rekik N, Brun-Buisson C, Lemaire F, Brochard L.
Pulmonary artery catheterization in critically ill patients: a
prospective analysis of outcome changes associated with cathe-
ter-prompted changes in therapy. Crit Care Med 1994;22(4):
573–579
15 Pinsky MR, Vincent J-L. Let us use the pulmonary artery catheter
correctly and only when we need it. Crit Care Med 2005;33(5):
1119–1122
16 Vincent JL. A reappraisal for the use of pulmonary artery cath-
eters. Crit Care 2006;10(Suppl 3):S1–S2
17 Hadian M, Pinsky MR. Evidence-based review of the use of the
pulmonary artery catheter: impact data and complications. Crit
Care 2006;10(Suppl 3):S8
18 Wilson J, Woods I, Fawcett J, et al. Reducing the risk of major
elective surgery: randomised controlled trial of preoperative
optimisation of oxygen delivery. BMJ 1999;318(7191):
1099–1103
19 Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of
the effect of deliberate perioperative increase of oxygen delivery
on mortality in high-risk surgical patients. JAMA 1993;270(22):
2699–2707
20 Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospec-
tive trial of supranormal values of survivors as therapeutic goals
in high-risk surgical patients. Chest 1988;94(6):1176–1186
21 Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented
hemodynamic therapy in critically ill patients. SvO2 Collabora-
tive Group. N Engl J Med 1995;333(16):1025–1032
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
896 Hemodynamic Monitoring in Shock Suess, Pinsky
22 Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D.
Elevation of systemic oxygen delivery in the treatment of criti-
cally ill patients. N Engl J Med 1994;330(24):1717–1722
23 Pearse RM, Harrison DA, MacDonald N, et al; OPTIMISE Study
Group. Effect of a perioperative, cardiac output-guided hemody-
namic therapy algorithm on outcomes following major gastroin-
testinal surgery: a randomized clinical trial and systematic
review. JAMA 2014;311(21):2181–2190
24 Yu M, Levy MM, Smith P, Takiguchi SA, Miyasaki A, Myers SA.
Effect of maximizing oxygen delivery on morbidity and mortality
rates in critically ill patients: a prospective, randomized, con-
trolled study. Crit Care Med 1993;21(6):830–838
25 Tuchschmidt J, Fried J, Astiz M, Rackow E. Elevation of cardiac
output and oxygen delivery improves outcome in septic shock.
Chest 1992;102(1):216–220
26 Sandham JD, Hull RD, Brant RF, et al; Canadian Critical Care
Clinical Trials Group. A randomized, controlled trial of the use of
pulmonary-artery catheters in high-risk surgical patients. N Engl
J Med 2003;348(1):5–14
27 Richard C, Warszawski J, Anguel N, et al; French Pulmonary
Artery Catheter Study Group. Early use of the pulmonary artery
catheter and outcomes in patients with shock and acute respira-
tory distress syndrome: a randomized controlled trial. JAMA
2003;290(20):2713–2720
28 Binanay C, Califf RM, Hasselblad V, et al; ESCAPE Investigators and
ESCAPE Study Coordinators. Evaluation study of congestive heart
failure and pulmonary artery catheterization effectiveness: the
ESCAPE trial. JAMA 2005;294(13):1625–1633
29 Harvey S, Harrison DA, Singer M, et al; PAC-Man study collabora-
tion. Assessment of the clinical effectiveness of pulmonary artery
catheters in management of patients in intensive care (PAC-Man):
a randomised controlled trial. Lancet 2005;366(9484):472–477
30 Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Cam-
paign Guidelines Committee including the Pediatric Subgroup.
Surviving sepsis campaign: international guidelines for manage-
ment of severe sepsis and septic shock: 2012. Crit Care Med 2013;
41(2):580–637
31 Reinhart K, Kuhn HJ, Hartog C, Bredle DL. Continuous central
venous and pulmonary artery oxygen saturation monitoring in
the critically ill. Intensive Care Med 2004;30(8):1572–1578
32 Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy
Collaborative Group. Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med 2001;345(19):
1368–1377
33 Monnet X, Teboul J-L. Assessment of volume responsiveness
during mechanical ventilation: recent advances. Crit Care
2013;17(2):217
34 Monnet X, Teboul J-L. Minimally invasive monitoring. Crit Care
Clin 2015;31(1):25–42
35 Gershengorn HB, Wunsch H. Understanding changes in estab-
lished practice: pulmonary artery catheter use in critically ill
patients. Crit Care Med 2013;41(12):2667–2676
36 Bose EL, Hravnak M, Pinsky MR. The interface between monitor-
ing and physiology at the bedside. Crit Care Clin 2015;31(1):1–24
37 Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettilä V.
Hemodynamic variables related to outcome in septic shock.
Intensive Care Med 2005;31(8):1066–1071
38 Lehman LW, Saeed M, Talmor D, Mark R, Malhotra A. Methods of
blood pressure measurement in the ICU. Crit Care Med 2013;
41(1):34–40
39 Ochagavía A, Baigorri F, Mesquida J, et al; Grupo de Trabajo de
Cuidados Intensivos Cardiológicos y RCP de la SEMICYUC. Mon-
itorización hemodinámica en el paciente crítico. Recomenda-
ciones del Grupo de Trabajo de Cuidados Intensivos Cardiológicos
y RCP de la Sociedad Española de Medicina Intensiva, Crítica y
Unidades Coronarias [in Spanish]. Med Intensiva 2014;38(3):
154–169
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
40 LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion
pressure on tissue perfusion in septic shock. Crit Care Med 2000;
28(8):2729–2732
41 Asfar P, Meziani F, Hamel J-F, et al; SEPSISPAM Investigators. High
versus low blood-pressure target in patients with septic shock. N
Engl J Med 2014;370(17):1583–1593
42 Kellum JA, Pinsky MR. Use of vasopressor agents in critically ill
patients. Curr Opin Crit Care 2002;8(3):236–241
43 Marik PE, Baram M, Vahid B. Does central venous pressure predict
fluid responsiveness? A systematic review of the literature and
the tale of seven mares. Chest 2008;134(1):172–178
44 Kumar A, Anel R, Bunnell E, et al. Pulmonary artery occlusion
pressure and central venous pressure fail to predict ventricular
filling volume, cardiac performance, or the response to volume
infusion in normal subjects. Crit Care Med 2004;32(3):691–699
45 Marik PE, Monnet X, Teboul J-L. Hemodynamic parameters to
guide fluid therapy. Ann Intensive Care 2011;1(1):1–9
46 Michard F, Boussat S, Chemla D, et al. Relation between respira-
tory changes in arterial pulse pressure and fluid responsiveness
in septic patients with acute circulatory failure. Am J Respir Crit
Care Med 2000;162(1):134–138
47 Marik PE, Cavallazzi R. Does the central venous pressure predict
fluid responsiveness? An updated meta-analysis and a plea for
Downloaded by: Universitätsbibliothek. Copyrighted material.
some common sense. Crit Care Med 2013;41(7):1774–1781
48 Michard F, Teboul JL. Predicting fluid responsiveness in ICU
patients: a critical analysis of the evidence. Chest 2002;121(6):
2000–2008
49 Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid
resuscitation in septic shock: a positive fluid balance and elevated
central venous pressure are associated with increased mortality.
Crit Care Med 2011;39(2):259–265
50 Micek ST, McEvoy C, McKenzie M, Hampton N, Doherty JA, Kollef
MH. Fluid balance and cardiac function in septic shock as
predictors of hospital mortality. Crit Care 2013;17(5):R246
51 Murphy CV, Schramm GE, Doherty JA, et al. The importance of
fluid management in acute lung injury secondary to septic shock.
Chest 2009;136(1):102–109
52 Wiedemann HP, Wheeler AP, Bernard GR, et al; National Heart,
Lung, and Blood Institute Acute Respiratory Distress Syndrome
(ARDS) Clinical Trials Network. Comparison of two fluid-man-
agement strategies in acute lung injury. N Engl J Med 2006;
354(24):2564–2575
53 Vincent J-L, Sakr Y, Sprung CL, et al; Sepsis Occurrence in Acutely
Ill Patients Investigators. Sepsis in European intensive care units:
results of the SOAP study. Crit Care Med 2006;34(2):344–353
54 Waechter J, Kumar A, Lapinsky SE, et al; Cooperative Antimicro-
bial Therapy of Septic Shock Database Research Group. Interac-
tion between fluids and vasoactive agents on mortality in septic
shock : a multi-center, observational study. Crit Care Med 2014;
42(10):2158–2168
55 Morimatsu H, Singh K, Uchino S, Bellomo R, Hart G. Early and
exclusive use of norepinephrine in septic shock. Resuscitation
2004;62(2):249–254
56 Beck V, Chateau D, Bryson GL, et al; Cooperative Antimicrobial
Therapy of Septic Shock (CATSS) Database Research Group.
Timing of vasopressor initiation and mortality in septic shock:
a cohort study. Crit Care 2014;18(3):R97
57 Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not
appropriate to predict hemodynamic response to volume chal-
lenge. Crit Care Med 2007;35(1):64–68
58 Pinsky MR. Functional haemodynamic monitoring. Curr Opin Crit
Care 2014;20(3):288–293
59 Michard F, Teboul JL. Using heart-lung interactions to assess fluid
responsiveness during mechanical ventilation. Crit Care 2000;
4(5):282–289
60 Hadian M, Pinsky MR. Functional hemodynamic monitoring. Curr
Opin Crit Care 2007;13(3):318–323

61 Pinsky MR, Kellum JA, Brochard L. Ten recent advances that could
not have come about without applying physiology. Intensive
Care Med (in press). doi: 10.1007/s00134-015-3746-9
62 Cannesson M, Aboy M, Hofer CK, Rehman M. Pulse pressure
variation: where are we today? J Clin Monit Comput 2011;
25(1):45–56
63 Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in
arterial waveform derived variables and fluid responsiveness in
mechanically ventilated patients: a systematic review of the
literature. Crit Care Med 2009;37(9):2642–2647
64 Feissel M, Michard F, Faller JP, Teboul JL. The respiratory variation
in inferior vena cava diameter as a guide to fluid therapy.
Intensive Care Med 2004;30(9):1834–1837
65 Bodson L, Vieillard-Baron A. Respiratory variation in inferior vena
cava diameter: surrogate of central venous pressure or parameter
of fluid responsiveness? Let the physiology reply. Crit Care 2012;
16(6):181
66 Vieillard-Baron A, Chergui K, Rabiller A, et al. Superior vena caval
collapsibility as a gauge of volume status in ventilated septic
patients. Intensive Care Med 2004;30(9):1734–1739
67 Guarracino F, Ferro B, Forfori F, Bertini P, Magliacano L, Pinsky MR.
Jugular vein distensibility predicts fluid responsiveness in septic
patients. Crit Care 2014;18(6):647
68 Marik PE, Levitov A, Young A, Andrews L. The use of bioreactance
and carotid Doppler to determine volume responsiveness and
blood flow redistribution following passive leg raising in hemo-
dynamically unstable patients. Chest 2013;143(2):364–370
69 The Acute Respiratory Distress Syndrome Network. Ventilation
with lower tidal volumes as compared with traditional tidal
volumes for acute lung injury and the acute respiratory distress
syndrome. N Engl J Med 2000;342(18):1301–1308
70 De Backer D, Heenen S, Piagnerelli M, Koch M, Vincent JL. Pulse
pressure variations to predict fluid responsiveness: influence of
tidal volume. Intensive Care Med 2005;31(4):517–523
71 Mesquida J, Kim HK, Pinsky MR. Effect of tidal volume, intratho-
racic pressure, and cardiac contractility on variations in pulse
pressure, stroke volume, and intrathoracic blood volume. Inten-
sive Care Med 2011;37(10):1672–1679
72 Richard J-C, Bayle F, Bourdin G, et al. Preload dependence indices
to titrate volume expansion during septic shock: a randomized
controlled trial. Crit Care 2015;19(1):5
73 Monnet X, Osman D, Ridel C, Lamia B, Richard C, Teboul J-L.
Predicting volume responsiveness by using the end-expiratory
occlusion in mechanically ventilated intensive care unit patients.
Crit Care Med 2009;37(3):951–956
74 Monnet X, Bleibtreu A, Ferré A, et al. Passive leg-raising and end-
expiratory occlusion tests perform better than pulse pressure
variation in patients with low respiratory system compliance. Crit
Care Med 2012;40(1):152–157
75 Monnet X, Teboul JL. Passive leg raising. Intensive Care Med 2008;
34(4):659–663
76 Biais M, Vidil L, Sarrabay P, Cottenceau V, Revel P, Sztark F.
Changes in stroke volume induced by passive leg raising in
spontaneously breathing patients: comparison between echo-
cardiography and Vigileo/FloTrac device. Crit Care 2009;13(6):
R195
77 Jabot J, Teboul JL, Richard C, Monnet X. Passive leg raising for
predicting fluid responsiveness: importance of the postural
change. Intensive Care Med 2009;35(1):85–90
78 Boulain T, Achard JM, Teboul JL, Richard C, Perrotin D, Ginies G.
Changes in BP induced by passive leg raising predict response to
fluid loading in critically ill patients. Chest 2002;121(4):
1245–1252
79 Cavallaro F, Sandroni C, Marano C, et al. Diagnostic accuracy of
passive leg raising for prediction of fluid responsiveness in
adults: systematic review and meta-analysis of clinical studies.
Intensive Care Med 2010;36(9):1475–1483
Hemodynamic Monitoring in Shock Suess, Pinsky 897
80 Monnet X, Letierce A, Hamzaoui O, et al. Arterial pressure allows
monitoring the changes in cardiac output induced by volume
expansion but not by norepinephrine. Crit Care Med 2011;39(6):
1394–1399
81 Pierrakos C, Velissaris D, Scolletta S, Heenen S, De Backer D,
Vincent JL. Can changes in arterial pressure be used to detect
changes in cardiac index during fluid challenge in patients with
septic shock? Intensive Care Med 2012;38(3):422–428
82 Chemla D, Hébert JL, Coirault C, et al. Total arterial compliance
estimated by stroke volume-to-aortic pulse pressure ratio in
humans. Am J Physiol 1998;274(2, Pt 2):H500–H505
83 Monge García MI, Gil Cano A, Gracia Romero M. Dynamic arterial
elastance to predict arterial pressure response to volume loading
in preload-dependent patients. Crit Care 2011;15(1):R15
84 Monnet X, Jabot J, Maizel J, Richard C, Teboul J-L. Norepinephrine
increases cardiac preload and reduces preload dependency as-
sessed by passive leg raising in septic shock patients. Crit Care
Med 2011;39(4):689–694
85 Funk DJ, Jacobsohn E, Kumar A. The role of venous return in
critical illness and shock-part I: physiology. Crit Care Med 2013;
41(1):255–262
86 Funk DJ, Jacobsohn E, Kumar A. Role of the venous return in
critical illness and shock: part II-shock and mechanical ventila-
Downloaded by: Universitätsbibliothek. Copyrighted material.
tion. Crit Care Med 2013;41(2):573–579
87 De Backer D, Creteur J, Dubois M-J, Sakr Y, Vincent J-L. Microvas-
cular alterations in patients with acute severe heart failure and
cardiogenic shock. Am Heart J 2004;147(1):91–99
88 Vincent JL, De Backer D. Circulatory shock. N Engl J Med 2013;
369(18):1726–1734
89 Vincent JL, De Backer D. Microvascular dysfunction as a cause of
organ dysfunction in severe sepsis. Crit Care 2005;9(4, Suppl 4):
S9–S12
90 van Beest PA, Lont MC, Holman ND, Loef B, Kuiper MA, Boerma EC.
Central venous-arterial pCO2 difference as a tool in resuscitation
of septic patients. Intensive Care Med 2013;39(6):1034–1039
91 Vincent JL, Rhodes A, Perel A, et al. Clinical review: update on
hemodynamic monitoring—a consensus of 16. Crit Care 2011;
15(4):229
92 Gómez H, Torres A, Polanco P, et al. Use of non-invasive NIRS
during a vascular occlusion test to assess dynamic tissue O(2)
saturation response. Intensive Care Med 2008;34(9):1600–1607
93 Mesquida J, Gruartmoner G, Espinal C. Skeletal muscle oxygen
saturation (StO2) measured by near-infrared spectroscopy in the
critically ill patients. Biomed Res Int 2013;2013:502194
94 Creteur J, Carollo T, Soldati G, Buchele G, De Backer D, Vincent JL.
The prognostic value of muscle StO2 in septic patients. Intensive
Care Med 2007;33(9):1549–1556
95 Mesquida J, Espinal C, Gruartmoner G, et al. Prognostic implica-
tions of tissue oxygen saturation in human septic shock. Intensive
Care Med 2012;38(4):592–597
96 Neto AS, Pereira VGM, Manetta JA, Espósito DC, Schultz MJ.
Association between static and dynamic thenar near-infrared
spectroscopy and mortality in patients with sepsis: a systematic
review and meta-analysis. J Trauma Acute Care Surg 2014;76(1):
226–233
97 Guyette FX, Gomez H, Suffoletto B, et al. Prehospital dynamic
tissue oxygen saturation response predicts in-hospital lifesaving
interventions in trauma patients. J Trauma Acute Care Surg 2012;
72(4):930–935
98 Bezemer R, Bartels SA, Bakker J, Ince C. Clinical review: Clinical
imaging of the sublingual microcirculation in the critically ill—
where do we stand? Crit Care 2012;16(3):224
99 Vellinga NAR, Boerma EC, Koopmans M, et al; microSOAP Study
Group. International study on microcirculatory shock occurrence
in acutely ill patients. Crit Care Med 2015;43(1):48–56
100 Trzeciak S, Glaspey LJ, Dellinger RP, et al. Randomized controlled
trial of inhaled nitric oxide for the treatment of microcirculatory
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
898 Hemodynamic Monitoring in Shock Suess, Pinsky
dysfunction in patients with sepsis. Crit Care Med 2014;42(12):
2482–2492
101 Hernandez G, Bruhn A, Luengo C, et al. Effects of dobutamine on
systemic, regional and microcirculatory perfusion parameters in
septic shock: a randomized, placebo-controlled, double-blind,
crossover study. Intensive Care Med 2013;39(8):1435–1443
102 Hamilton MA, Cecconi M, Rhodes A. A systematic review and
meta-analysis on the use of preemptive hemodynamic interven-
Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 6/2015
tion to improve postoperative outcomes in moderate and high-
risk surgical patients. Anesth Analg 2011;112(6):1392–1402
103 Peake SL, Delaney A, Bailey M, et al; ARISE Investigators; ANZICS
Clinical Trials Group. Goal-directed resuscitation for patients
with early septic shock. N Engl J Med 2014;371(16):1496–1506
104 Yealy DM, Kellum JA, Huang DT, et al; ProCESS Investigators. A
randomized trial of protocol-based care for early septic shock. N
Engl J Med 2014;370(18):1683–1693
Downloaded by: Universitätsbibliothek. Copyrighted material.