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OPINION New insights into the pathophysiology of
cardiogenic shock: the role of the microcirculation
Jesse F. Ashruf a,b, Hajo A. Bruining c, and Can Ince a

Purpose of review
The ultimate goal of therapy for cardiogenic shock is to restore microcirculatory function and thereby
restore the oxygen supply to sustain cellular function. Therapeutic measures mainly focus on improving
pressure-derived macrocirculatory parameters. However, it is increasingly clear that to achieve significant
progress in treatment, microcirculatory physiopathological mechanisms must be considered.
Recent findings
Microcirculatory function deteriorated during cardiogenic shock and improved after treatment.
Postcardiogenic shock microcirculatory disturbances, both myocardial and peripheral, were a prognostic
factor for the long-term outcome. Hypothermia, whether pharmacologically or physically induced, improved
postresuscitation myocardial and cerebral function, an effect associated with improved postresuscitation
microcirculation. The impact of cardiogenic shock on cerebral and myocardial microcirculation could be
evaluated with MRI. In severe heart failure, pharmacological interventions improved microcirculation. An
assessment of the microcirculation was often performed using handheld video microscopy for direct
observation of the sublingual microcirculation, which proved to be useful for evaluating the effects of
interventions during cardiogenic shock. A large multicenter study on critically ill patients is now being
conducted using this technique.
Cardiogenic shock induces microcirculatory disorders that can be monitored and influenced in various
manners, both pharmacologically and physically. In addition to global hemodynamic optimization,
interventions must also ameliorate the microcirculation.
cardiogenic shock, microcirculation, microvascular flow, SDF imaging

INTRODUCTION resulting in shock) at one end of the spectrum

Cardiogenic shock is characterized by inadequate and cardiogenic shock in patients with chronic
organ perfusion caused by primary cardiac dysfunc- heart failure (i.e. a large myocardial infarction),
tion, mainly caused by damage to the heart muscle who already have significantly abnormal microcir-
(myocardial infarction or cardiomyopathy), culation because of preshock illness at the other end

arrhythmia or cardiac valve disease. Three other [8 ,9]. Cardiogenic shock patients who develop a
types of shock are recognized: hypovolemic, systemic inflammatory response syndrome (SIRS)
obstructive and distributive shock [1]. Specifically have more serious impairment of the microcircula-
in the latter type of shock, a key characteristic tion because of SIRS-related vasodilatation and the
associated with hemodynamic derangement con- resulting hypotension, and are more at risk of the
cerns microcirculatory malfunction with shunting
[2]. All types of shock, however, cause microcircu- a
Department of Translational Physiology, Academic Medical Center,
latory abnormalities beyond obvious global hemo-
University of Amsterdam, Amsterdam, bDepartment of Surgery, OZG
dynamic derangement. It is increasingly clear that Hospital, Groningen and cDepartment of Surgery, Erasmus University of
the microcirculation needs to be addressed, beyond Rotterdam, Rotterdam, the Netherlands
the cardiac disorder, to effectively manage cardio- Correspondence to Jesse F. Ashruf, OZG locatie Delfzicht, Jachtlaan 50,
&& &
genic shock [3 ,4 ,5–7]. Of course, cardiogenic 9934 JD Delfzijl, the Netherlands. Tel: +31 6 42307668; e-mail: j.ashruf
shock patients constitute a heterogeneous group @ozg.eu, jesseashruf@me.com
of pathologies, with cardiogenic shock in relatively Curr Opin Crit Care 2013, 19:381–386
healthy patients (i.e. ventricular fibrillation DOI:10.1097/MCC.0b013e328364d7c8

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Cardiovascular system

which will hopefully establish a basis for future

KEY POINTS studies related to microcirculation in critically ill

 Postresuscitation hypothermia has a beneficial effect on patients [16 ]. A traditional parameter to evaluate
outcome, but in itself has a negative influence on microcirculatory disorder is the measurement of
the microcirculation. serum lactate levels, which have a poor correlation
with the microcirculatory disorders at the organ level
 The inhibition of arginase could be a therapeutic
[5]. Our introduction of handheld video microscopes
strategy to rescue microcirculation in patients with SHF.
to observe microcirculation at the bedside, based on
 Cardiac arrest initiates compensatory sympathetic orthogonal polarization spectral (OPS) imaging, and
nervous system activation, which leads to persistent later sidestream dark-field (SDF) imaging, mainly
microcirculatory abnormalities similar to those applied to observe the sublingual microcirculation,
abnormalities found in septic shock.
has provided great insight into the importance of this
 EECP could be a potential treatment for patients after physiological compartment in perioperative medi-
cardiac arrest and the ROSC; the effects of EECP are && &
cine [3 ,4 ,5,7,17,18]. These previous generations
mediated by improving cerebral microcirculation by of handheld microscopes, however, have been
enhancing the endothelial function. criticized because of poor image quality and the
inability to implement automatic analysis software,
limiting the microscopes’ use as research tools [19].
persistence of shock [10]. In addition, the physio- Recently, however, a new handheld intravital micro-
pathology of the microcirculation differs between scope has been introduced, based on incident dark-
organs, which must be taken into account when field (IDF) imaging [20]. This microscope contains a
evaluating microcirculation in therapy and research computer-controlled high-resolution imaging sensor
&& & &&
[3 ,4 ,11 ,12].
[4 ] with higher image resolution, allowing the direct
Cardiogenic shock results in decreased cardiac analysis of images for the immediate identification of
output with adequate intravascular volume. Fluid microcirculatory alterations and titrating therapy. It
therapy is one of the first interventions in the man- is expected that such technological advances in
agement of shock. Management of cardiogenic microcirculatory monitoring will introduce the diag-
shock requires restoring primary cardiac function; nosis and treatment of this important physiological
however, restoration of systemic hemodynamics compartment to the clinic.
does not necessarily imply restoration of microcir-
culation in the various organ systems [13]. In severe
cardiogenic shock, microvascular perfusion is HYPOTHERMIA IN CARDIOPULMONARY
altered, even when global circulation is restored. RESUSCITATION
A potential hazard, for instance, is that excessive Pharmacologically induced hypothermia with
administration of fluid to restore global circulation WIN55,212-2 was shown to improve postresuscita-
can cause deterioration of microcirculatory function tion neurological and myocardial function and sur-
&& &&
because of edema formation [11 ]. In successful vival in a rat model [21 ]. Outcome was related to
electrical cardioversion in patients with atrial fibril- significant improvements in microcirculatory
lation, sublingual microvascular perfusion improved, parameters, as observed by sublingual SDF imaging.
whereas this improvement was not clearly related to A suggested advantage of WIN55,212-2-induced
global hemodynamic parameters [14 ]. An organ- hypothermia over physical hypothermia is the
ized cardiac rhythm is important for optimal micro- reduction in systemic vascular resistance and
vascular perfusion [15]. increased cardiac output following WIN55,212-2
To develop treatment strategies that target micro- administration, thereby reducing myocardial oxy-
circulation in cardiogenic shock, it is necessary to gen consumption and afterload, and improving
evaluate known therapeutic and diagnostic measures tissue perfusion.
and their relation to the physiopathological mech- Laboratory and clinical studies have demon-
anisms. In this review period, new insights related to strated that actively reducing the blood temperature
hypothermia in cardiopulmonary resuscitation to 32–348C after resuscitation significantly improved
(CPR), the use of vasoactive agents, fluid therapy, the neurologically favorable survival. However,
the prognostic value of microcirculatory alterations therapeutic hypothermia also has adverse effects,
postcardiac arrest, cardiac arrest and (cerebral) micro- so limiting hypothermia’s duration of use could be
circulation, the myocardial microcirculatory effects of benefit to the patient. A shorter duration of early
of myocardial infarction and muscle oxygen metab- hypothermia after resuscitation improved micro-
olism in heart failure are assessed. In addition, an circulation and myocardial and neurological out-
international multicenter study is being performed, comes compared with prolonged hypothermia

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Pathophysiology of cardiogenic shock Ashruf et al.

[22 ]. A possible explanation could be that pro- FLUID RESUSCITATION
longed hypothermia induced vasoconstriction and Restoration of global hemodynamic parameters by
decreased capillary density. Another explanation fluid loading is one of the most important therapies
might be that postresuscitation oxygen debt should in managing shock. Amelioration of the micro-
be repaid as quickly as possible, which is impeded by circulatory blood flow is the primary goal of this
prolonged hypothermia and concomitant micro- treatment. However, fluid loading may also alter
circulatory dysfunction. microcirculatory oxygen delivery by hemodilution
He et al. [23 ] attempted to clarify whether the or tissue edema [13]. In this context, blood trans-
positive effects of hypothermia in resuscitation fusion during cardiac surgery has been shown to
were related to a physiological adjustment to the improve red blood cell availability and oxygenation
balance between oxygen supply and demand, which in the microcirculation [29]. The long-term impact
are both reduced during hypothermia, or whether of fluid loading on the microcirculation is minimal
hypothermia per se has deleterious effects on tissue compared with the impact during the early phase of
perfusion. Sublingual microvascular flow was shock. Therefore, it is important to monitor the
decreased compared with the normothermic state. effect of fluid loading on the microcirculation to
better balance the amount of administered fluid
with amelioration of microcirculation. In SHF, the
VASOACTIVE AGENTS microcirculation is impaired even when global
Factors contributing to microcirculatory dysfunc- hemodynamic or laboratory signs of hypoperfusion
tion in severe heart failure (SHF) are a persistent are absent. Effective fluid loading and pharmaco-
inflammatory response, leading to increased micro- logical treatment aimed at decreasing neurohu-
vascular permeability and reduced capillary density moral activation improve microcirculation, as
(SIRS) [10]; neurohumoral mechanisms, with the evaluated by sublingual SDF imaging [30]. A similar
secretion of potent vasoconstrictive agents; finding was reported by Hogan et al. [31 ], who
increased blood viscosity; altered erythrocyte rheo- evaluated the microcirculation by measuring per-
logical properties; and hypercoagulability secondary ipheral microvascular oxygen-extraction ratios on
to platelet activation. Angiotensin II, the main effec- the hypothenar eminence during the emergency
tor of the renin–angiotensin–aldosterone system department treatment of SHF.
(RAAS), is an important mediator of these effects. In hemorrhagic shock in pigs, fluid resuscitation
Indeed, Salgado et al. [24 ] showed that angiotensin guided by sublingual pCO2 and sublingual SDF
II inhibitors improved microcirculation in patients imaging significantly reduced the amount of resus-
with SHF and that this finding was not related to citation fluid, without compromising the outcomes
global hemodynamic improvement. The beneficial of hemorrhagic shock [32 ]. The authors believe
effects of angiotensin II inhibition in SHF may be that this would also be the case in SHF or cardiogenic
caused by microcirculatory improvement. shock. Used in this way, microcirculatory monitor-
In SHF, there is endothelial dysfunction result- ing could help to reduce the adverse effects of fluid
ing in a reduced bioavailability of nitric oxide. Sev- overloading in shock.
eral studies showed that intravenous nitroglycerin, a
nitric oxide donor, improved tissue perfusion in
SHF, as observed by SDF imaging [17,25,26 ].
The reduced bioavailability of nitric oxide in MICROCIRCULATORY ALTERATIONS
SHF is further aggravated by the upregulation of AFTER CARDIAC ARREST
arginase, a competitive enzyme for endothelial Sublingual microvascular blood flow alterations
nitric oxide synthase. Topical inhibition of arginase measured by OPS imaging are frequently observed
improved sublingual microcirculation in SHF [26 ]. in patients with SHF and are more severe in patients
Inhibition of arginase could therefore be a thera- who do not survive [33]. This finding sustains the
peutic target to rescue microcirculation in SHF. hypothesis that in cardiogenic shock, microvascular
Microcirculatory blood flow was highly corre- abnormalities result in impaired tissue oxygenation
lated with macrocirculatory hemodynamics, includ- and thereby the development of multiple organ
ing coronary perfusion pressure in distinction failure.
with septic shock. Administration of epinephrine After cardiac arrest, in the early postresuscita-
dramatically decreased the microcirculatory blood tion phase, there are significant microcirculatory
flow. This earlier study [27] showed that simply abnormalities that return to normal within 48 h
increasing the blood pressure by inotropic agents, [34]. These abnormalities in the early phase closely
without taking notice of the microcirculation, could resemble those abnormalities found in septic shock.
leave the vital organs ischemic [28 ]. However, in septic shock, they persist. This suggests

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that in this study, cardiogenic shock was insuffi- cardiac arrest is partially caused by the complex
ciently severe to trigger the same mechanisms of mechanisms of brain injury. Liu et al. [37 ] devel-
microvascular dysfunction as in sepsis. Whereas oped an animal model that mimics cardiac arrest
postresuscitation microvascular flow normalized, and used early MRI to observe the disorders in brain
this was not the case for microvascular reactivity, microcirculation. They found that even though
as postresuscitation reactive hyperemia in the the- blood pressure returned to normal after ROSC,
nar muscle remained disturbed. cerebral microcirculation did not return to physio-
Patients with acute myocardial infarction (AMI) logical baseline levels. These abnormalities in the
complicated by cardiogenic shock and who have brain microcirculation were found using perfusion-
impaired sublingual microcirculation at baseline weighted MRI (PWI), which conveys information
or following treatment have a poor outcome [9]. about microvessels less than 100 mm, which is not
Interestingly, there was a weak correlation of micro- obtainable by conventional angiography. Using this
circulatory alterations with global hemodynamic technique, clinicians could determine specific brain
parameters, as was reported earlier. Assessment of damage in cardiac arrest patients and even predict
the sublingual microcirculation with SDF imaging outcome.
could therefore be used as a noninvasive tool to Hu et al. [28 ] showed that early enhanced
assess the outcomes of SHF patients. Indeed, an external counterpulsation (EECP) after the ROSC
international multicenter trial is now being per- protected the brain by improving brain microcircu-
formed, among others, to address this issue [16 ]. lation. EECP could be a potential treatment for
A later study [35 ] showed that early postresus- patients after cardiac arrest and the ROSC. EECP
citation microcirculatory abnormalities (sublingual resulted in opening of the highly resistant areas of
and peripheral) were caused by vasoconstriction the cerebral microcirculation, thereby overcoming
because of induced systemic hypothermia, and regional and global perfusion disturbances caused
the persistence of these alterations was associated by edema and blood clots. EECP increased the left
with organ failure and death. Also, there was again ventricular ejection fraction, carotid blood flow and
no relationship between systemic hemodynamics endothelial shear stress, and thereby promoted
and microcirculatory status. It was theorized that nitric oxide and tissue plasminogen-activator pro-
nonsurvivors of cardiac arrest suffered from ongoing duction and decreased endothelin-1 release after the
sympathetic activity and the development of SIRS. A ROSC. Earlier work on the effect of mechanical
similar relationship was observed in patients with circulatory support devices on the microcirculation
septic shock. (the Impella LP2.5 percutaneous left ventricular
Another study [8 ] reported that impaired myo- assist, the intra-aortic balloon pump, the HeartMate
cardial microcirculation (evaluated by assessing the II, Centrimag and TandemHeart) [38–40] showed
coronary flow reserve with transthoracic Doppler that the mechanical support of the failing ventricle
echocardiography) is associated with the develop- results in improved tissue perfusion, as evaluated by
ment of heart failure and acute coronary syndrome. SDF imaging of the sublingual microcirculation. It
This phenomenon is likely because of a reduction in was also shown that improved microvascular per-
the functional capacity of the myocardium caused fusion is not necessarily correlated with an increased
by microcirculatory dysfunction. mean arterial pressure [40]. In contrast to EECP,
A recent study [36 ] found that dying patients treatment with norepinephrine increased carotid
treated with extracorporeal membrane oxygenation blood flow but had no effect on nitric oxide, tissue
(ECMO) for cardiogenic shock showed major func- plasminogen activator or endothelin-1 levels [28 ].
tional and structural pathology in the skin micro- The neurologic deficit in norepinephrine-treated
vasculature, whereas surviving patients had normal animals was larger compared with EECP-treated
skin microcirculation. Therefore, the authors stated animals. Treatment with vasopressors alone
that finding intact skin microcirculation early after increased blood flow to important organs, but after
establishing ECMO is a clinically useful finding ROSC the left ventricle could not tolerate the
implying a good prognosis. increased vascular resistance. Furthermore, a1-adre-
nergic and b-adrenergic drugs also lead to greater
oxygen consumption via fibrillating ventricles,
CARDIAC ARREST AND (CEREBRAL) which has detrimental effects on cardiac function
MICROCIRCULATION postresuscitation. This finding explains the poor
Because the frequency of CPR is growing, the num- outcome of cardiac arrest with only hypertensive
ber of patients with severe neurological deficit after reperfusion.
the restoration of spontaneous circulation (ROSC) Interestingly, whereas EECP improved cerebral
has steadily increased. The high mortality rate of microcirculation by means of a hypertensive effect,

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Pathophysiology of cardiogenic shock Ashruf et al.

Elbers et al. [41] concluded that pulsatile perfusion to predict the postresuscitation outcomes: heart
did not alter human microvascular perfusion in failure, neurological and survival. Future trials
routine cardiac surgery. However, several studies should be directed toward developing and integrat-
did show an improvement in microvascular flow ing methods to evaluate microcirculation in cardio-
with pulsatile perfusion, for example [42]. One genic shock and titrating therapy based on the
explanation for this discrepancy is that these normalization of microcirculatory flow, as it is
patients [41] may have been too healthy to show becoming clear that further progress in the treat-
pulsatile perfusion-related improvement in micro- ment of cardiogenic shock must have a focus on
circulation. In addition, measurements were per- the microcirculation.
formed for the sublingual microcirculation, which
may not be representative of the cerebral micro- Acknowledgements
circulation. None.
Compensatory neurohumoral mechanisms pre-
serve the perfusion pressure and viability of vital Conflicts of interest
organs, and induce early splanchnic ischemia in C.I. is the inventor of sidestream dark-field technology
terminal circulatory shock. Microcirculatory per- and holds shares in MicroVision Medical. He has served
fusion pressure might be a more significant deter- as a consultant for this company in the past, but has
minant of central nervous system viability than ended all contact for more than 4 years. C.I. has no other
commonly recognized in clinical practice [43 ]. competing interests in this field beyond his commitment
to promoting the importance of the microcirculation with
regard to patient care.
Microvascular obstruction (MVO) following AMI REFERENCES AND RECOMMENDED
with reperfusion (‘no-reflow’ phenomenon) is READING
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associated with a poor clinical outcome. Future been highlighted as:
& of special interest
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