Hemodynamic coherence in sepsis

Accepted Manuscript Hemodynamic coherence in sepsis Andrea Morelli, Maurizio Passariello

PII:

S1521-6896(16)30070-2

DOI:

10.1016/j.bpa.2016.10.009

Reference:

YBEAN 919

To appear in:

Best Practice & Research Clinical Anaesthesiology

Received Date: 7 August 2016 Accepted Date: 31 October 2016

Please cite this article as: Morelli A, Passariello M, Hemodynamic coherence in sepsis, Best Practice & Research Clinical Anaesthesiology (2016), doi: 10.1016/j.bpa.2016.10.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Hemodynamic coherence in sepsis Andrea Morelli 1 and Maurizio Passariello 1,2 Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and

Geriatric Sciences, University of Rome, “La Sapienza”, Italy

Adult Intensive Care Unit, Royal Brompton Hospital, Sydney Street, London, UK.

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2

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1

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Andrea Morelli: [email protected], tel.: +390649978024, Fax: +390649978019 Maurizio Passariello: [email protected], tel.: +390649978024, Fax +390649978019

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Corresponding author: Andrea Morelli

ACCEPTED MANUSCRIPT ABSTRACT Microvascular alterations are a typical hallmark of sepsis and play a crucial role in its pathophysiology. Such alterations are the result of overwhelming inflammation which negatively affect all the components of the microcirculation. As the severity of

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microvascular alterations is associated with organ dysfunction and mortality, several strategies have been tested for improving microcirculation. Nevertheless, they are mainly based on the conventional manipulation of systemic hemodynamics in the attempt to

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increase total flow to the organs and tissues. Other therapeutic interventions are still being

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investigated. In this

review, we discuss the pathophysiology of septic microcirculatory dysfunction and its implications for the possible treatments.

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KEY WORDS: microcirculation; septic shock; sepsis; microvascular dysfunction;

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microvascular resuscitation

ACCEPTED MANUSCRIPT INTRODUCTION Microvascular alterations are a typical hallmark of sepsis and play a crucial role in its pathophysiology. They can occur even after achieving conventional hemodynamic targets such as adequate systemic oxygen supply and mean arterial pressure

1,2,3

. These sepsis-

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induced microvascular alterations are the result of the overwhelming inflammation and the consequent massive cytokines release, which negatively affect all the components of the microcirculation. The endothelium, the vascular smooth musculature, as well as the blood

4

. Such microvascular impairment inexorably leads to microcirculatory

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cytokines

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cells are all involved and represent targets of the of the pro inflammatory activity of

dysfunction which becomes manifested within 6–24 hours with a decrease in capillary density together with an increased number of capillaries with intermittent or even stopped flow

5-8

. These alterations have been reported in small and large animal models and

thanks to the development of new imaging tools and techniques, they have been also

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demonstrated in human sepsis and septic shock 5-8. As it is well recognized that the severity of microcirculatory abnormalities and their 9,10

, the

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persistence over time are associated to organ dysfunction and increased mortality

early recognition of microcirculatory dysfunction and therapeutic strategies for its

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improvement are becoming part of the complex treatment of sepsis. This review will summarize current knowledge on microcirculatory failure and the options of treatment in the setting of sepsis.

Alterations in microcirculatory blood flow during sepsis Arterioles, capillaries, venules and microlymphatics with a diameter <100 µm make up the microvascular network. It is a functional system, which can promptly respond to the tissue changes in blood flow and metabolic demand. The microvasculature is therefore able to precisely regulate blood flow to tissues, ensuring adequate oxygen delivery to meet the

ACCEPTED MANUSCRIPT 7,11,12

oxygen demand of the cells

. The key components of this accurate local control of

microvascular blood flow are the endothelium and its luminal cover glycosaminoglycancontaining layer glycocalyx

13

, which modulate the vasomotor tone, balance microvascular

fibrinolysis and thrombosis, and promote leucocyte migration and adhesion

7,11-13

. The

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endothelial cells act as metabolic sensors and signal transducers of local wall shear stress and are able to conduct and integrate such metabolic and physical signals along the microvascular endothelium through a “cell to cell” communication. This peculiar

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communication allows the backward transmission of information between the endothelial cells11,13. In response to a hypoxic stimulus, the endothelial cells promote the local release

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of nitric oxide (NO) via the endothelial nitric oxide synthase (eNOS) and prostacyclin (PGI2) via the prostaglandin endoperoxide H2 synthase-1 (PGHS-1), which increase the intracellular concentrations of cGMP and cAMP respectively in the arteriolar smooth muscle cells, inducing smooth muscle relaxation and microvascular dilatation

7,11-15

. With

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this targeted and controlled vasodilatation, the endothelial cells are able to regulate and maintain an adequate microvascular blood flow 7. An additional feedback mechanism for the local regulation of microvascular blood flow is provided by erythrocytes. In the

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presence of hypoxia, through structural changes of hemoglobin, erythrocytes promote the release adenosine triphosphate (ATP) and S-nitrosothiol (NO donor), with the latter that

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can be converted in NO by deoxyhemoglobin

7,11

. Because both ATP and the conversion

of nitrosothiol exert vasodilation, erythrocytes passing through a hypoxic zone are able to induce local vasodilation and an increase in microvascular blood flow 7,11,13-19. During sepsis and septic shock, the overwhelming inflammation induces functional and structural changes in the endothelium, in the glicocalyx, in the vascular smooth muscle cells, as well as in the blood cells leading to microvascular dysfunction. As consequence, the microvasculature loses its ability to regulate oxygen distribution within the capillary network. Several complex mechanisms are involved in the pathogenesis of septic

ACCEPTED MANUSCRIPT microvascular dysfunction. At the level of endothelium, the excessive production of reactive oxygen species (ROS), such as superoxide (O2-) and peroxynitrite (ONOO-) contribute to the inactivation of both eNOS and PGHS-1, and to the heterogeneous expression of inducible NO synthase (iNOS) within microvasculature

15

. In addition, the

cellular amount of NO

15

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reaction of superoxide with NO forming peroxynitrite further decreases the effective . The direct consequence of such alterations is that in localized

areas, due to a relative NO and PGI2 deficiency, blood flow cannot be increased further 2,4,5,7,15,18,19

. Such impaired local vasodilatory response also

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and hypoperfusion occurs

contributes to the opening of pathological artero-venous shunts, which further increase the 2,4,7

. The local

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diversion of blood flow from the hypoperfused to perfused zones

microvascular responsiveness is further compromised by altered endothelial signal transduction pathways and impaired “cell to cell” electrophysiological communication. The sepsis-induced reduction in communication occurs either between the endothelial cells

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themselves, and between the endothelial cells and the smooth muscle cells with a consequent loss of the arteriolar tone control. Therefore, during sepsis the endothelium loses its ability to coupling electrical signals and to transmit information from the capillary

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network to upstream arterioles

20,21

. Nevertheless, all these abnormalities are not

persistent and are reversible after the cessation of the septic insult

8,20,21

. While during

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sepsis erythrocytes may still off-load adequate amounts of O2 within capillaries, their ability to release ATP and convert S-nitrosothiol to NO by deoxyhemoglobin in response to hypoxia is deeply impaired 5. Bateman et al suggest that changes in the biophysical properties of the erythrocyte membrane and decreased deformability may account for the impaired O2-dependent ATP release during sepsis 5. Undoubtedly, inflammatory-induced changes in structure and physical properties of erythrocyte, leukocyte and platelet, which become more rigid and less deformable, facilitate their aggregation on the endothelial surface of capillaries contributing not only to altered cells flowing but also to production of

ACCEPTED MANUSCRIPT ROS and other inflammatory mediators. These alterations in blood rheology contribute to the decrease of functional capillary density

5,7,22,23,24

. Even the glicocalyx, the thin layer of

endothelial cell-derived proteoglycans and glycosaminoglycans which covers the luminal surface of endothelium and ensures anti-adhesive and anti-thrombotic activities, is 7,8,25-27

. Due to

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affected by oxidative stress and high levels of proinflammatory mediators

glycocalyx degradation and shedding, the endothelium becomes procoagulant and promotes the luminal adhesion of red blood cells, leukocytes and platelets, which lead to a Such

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vicious cycle of further production of inflammatory mediators and ROS.

prothrombotic state favors vascular microthrombosis leading to capillary perfusion 7,8,25-27

. Cabrales et al. reported that the degradation of glycocalyx following

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impairments

the administration of hyaluronidase, was associated with a 35% decrease in functional capillary density (the capillaries perfused with red blood cells) 27. In addition, the loss of the protective barrier properties of the glicocalyx and disruption of endothelial cell tight

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junctions, alter the endothelial permeability with consequent increased capillary fluid leakage and formation of tissue water. The consequent increase in oxygen diffusion distance and the poor oxygen solubility in tissue water further impair local oxygen delivery 7,8,2,25-27

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. Finally, Secor et al. demonstrated that ROS promote expression of P-selectin at

the surface of platelets and endothelial cells, leading to augmented platelet adhesion to

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the endothelium and activation of coagulation which contribute to stoppage of capillary blood flow

23

. The evidence of elevated serum concentrations of intercellular adhesion

molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin during sepsis confirms the activation of endothelium and coagulation

28

. Although activation of

coagulation clearly contributes to septic microvascular derangement, thrombotic events probably play a secondary role

29

. This assumption is supported by the results of the study

of De Backer et al. who showed that topical administration of acetylcholine, which acts through NO-dependent and independent vasodilatory pathways completely restored

ACCEPTED MANUSCRIPT sublingual capillary perfusion and density in patient with septic shock

1,30

. This important

finding suggests that the septic microcirculatory dysfunction is functional rather than morphological and the microcirculation is still able to respond to a supra physiological stimulation with vasodilators. The fact that it can be fully reversed also confirms that the

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formation of microthrombi in the microcirculatory network is probably less important 1,8,29,30.

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Consequences of septic microcirculatory dysfunction on tissue perfusion

The direct consequence of septic microcirculatory dysfunction is the decrease of capillary

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density and the presence of capillaries with altered blood flow, which respectively lead to diffusive and convective oxygen transport alterations. Due to the simultaneous presence of stopped, normal, intermittent and high-flow perfused capillaries, the microvascular blood flow becomes highly heterogeneous and promotes the presence of tissue oxygenated

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zones in contiguity with hypoxic zones, with the latter characterized by increased oxygen extraction despite adequate organ blood flow

1,2,4-8

. The reduction of perfused vessel

density seems to play a major role, as it increases the intercapillary distances and thus the

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effective tissue volume supplied by the remaining perfused vessels. Consequently, the oxygen diffusion distance increases and may exceed the critical threshold (the maximum

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distance from oxygen source that allow the maintenance of mitochondrial efficiency) (Fig 1). Furthermore, the reduction of perfused vessel density leads to an increase of red blood cells flow in the remainder of the capillaries, as the same number of red blood cells has to pass through a reduced number of capillaries. Several studies confirmed that the heterogeneity of microvascular blood flow is associated both with heterogeneity in oxygenation but also with impaired local oxygen extraction

5,6,31-35

. Ellis et al showed that

an increase in the percentage of capillaries with stopped flow was associated with a linear reduction of oxygen saturation and increased capillary oxygen extraction in the remaining

ACCEPTED MANUSCRIPT normally perfused capillaries in an experimental model of sepsis 6. Taken together, all these findings suggest that sepsis causes an increase in the number of tissue zones in which the microvascular oxygen regulatory systems are impaired and cannot adequately and rapidly redistribute oxygen supply, leading to uncoupled local oxygen demand and

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delivery 5,6,7,8,31-35. These assumptions are also confirmed by the evidence that reversal of microcirculatory alterations is followed by improved tissue bioenergetics, as suggested by the decrease in lactate concentration and NADPH levels

7,8,30,36

. Sepsis induced

are therefore tightly related

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microvascular dysfunction, cellular bioenergetics alterations and mitochondrial impairment 37,39

. From a pathophysiological point of view, microvascular

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derangement precedes and contributes to cellular metabolic alterations, mitochondrial dysfunction, and finally cell apoptosis

7,8,38-40

. Nevertheless, the overwhelming NO

production that typically occurs during septic shock may inhibit mitochondrial activity and thus negatively affecting cellular function even in presence of maintained microcirculatory

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blood flow. Both factors are therefore strictly related and act in a synergistic manner in determining cellular damage 41,42.

Although microcirculatory abnormalities can be found in different settings of hemodynamic

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instability such as heart failure, cardiogenic shock and even in patients undergoing to non-

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cardiac surgery 43,44,45, their clinical relevance during sepsis and septic shock is particularly high. In this regard several groups of research have shown a clear association between the severity of microvascular alterations and the development of organ failure leading to poor outcome 1,9,10,46-49. In line with their previous findings, De Backer et al in a large series of septic shock patients elegantly confirmed that mortality increased with the alterations in microcirculation outcome

9,10

, with the proportion of perfused capillaries that best correlated with

10

. Notably, they also noticed timeframe differences in the evolution of such

microvascular alterations with microvascular blood flow that rapidly improved in survivors

ACCEPTED MANUSCRIPT compared to non-survivors

10

. A similar association between microvascular abnormalities

and outcome was also found in children with septic shock 50. Finally, even the severity of glicocalyx degradation correlates with mortality. Indeed, Nelson et al. showed a correlation between elevated plasma circulating levels of heparan

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sulphate and hyaluronic acid (glycosaminoglycan derived species) and increased mortality in patients with septic shock 51,52.

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Hemodynamic coherence between macro- and microcirculation in sepsis

The concept of hemodynamic coherence implies that manipulation of systemic

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hemodynamics through the administration of volume, vasoactive agents and red blood cells, to achieve targeted hemodynamic endpoints 3, results in improved microvascular blood flow, and thus in the correction of oxygen delivery and consumption mismatch within different organs and their cells

53

. To be effective, hemodynamic coherence therefore

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requires: 1) the integrity of the mechanisms that allow the microcirculation to sense and regulate oxygen delivery to tissues; 2) that the mechanisms by which fluids and vasoactive agents affect systemic hemodynamics

3

are similar to those that act at the level of

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microcirculation. Because microcirculation and its ability to control local oxygen delivery are profoundly impaired and conventional therapeutic interventions on systemic 3

act through different pathophysiological pathways, loss of hemodynamic

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hemodynamics

coherence may frequently occur during sepsis. Therefore, the restoration and the maintenance of adequate systemic hemodynamics do not always correspond to parallel improvement or prevention of microcirculatory perfusion and local oxygen delivery abnormalities

9,31,49,53-57

. Furthermore, macro and microcirculatory decoupling may occur

between different organs and even in different compartments of a single organ 53,57. Dubin et al. showed that fluid resuscitation corrected both serosal intestinal and sublingual microcirculation; however, it was unable to restore intestinal mucosal perfusion

58

.

ACCEPTED MANUSCRIPT Siegemund et al. reported that although fluids were effective in restoring mucosal microcirculatory oxygenation, their administration failed in restoring the intestinal serosa oxygenation

59

. Even the timeframe of the septic insult affects hemodynamic coherences.

Accordingly, Boerma et al. reported the lack of correlation not only between

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microcirculatory alterations and variables of systemic circulation, but also between the intestinal and sublingual microcirculation in the earlier phases of sepsis. Nevertheless, the latter correlation was restored after three days 60. The key alterations implicated in the loss

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of coherences are the opening of pathological shunts, the reduction of perfused vessel density and the presence of more profound flow alterations in the smaller vessels than in

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the larger vessels. Due to the opening of arteriovenous shunts, an increase in systemic blood flow results in increased amount of blood passing from arterioles to venules by shunting blood vessels without passing through the microcirculation. As consequence microcirculatory PO2 becomes lower than venous PO2

61

. Likewise, the reduction of

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perfused vessel density leads to an increase in blood flow only in that portion of capillaries still able to be perfused. Because microvascular blood flow is more altered in smaller vessels, increased systemic blood flow diverges from smaller to larger vessels in which

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normal flow can be still present. These microvascular alterations explain why during sepsis the development of tissue hypoxia may occur despite the achievement of adequate

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systemic hemodynamic parameters. In this regard Jhanji et al. demonstrated that in patients with septic shock increases in mean arterial pressure (MAP) from 60 to 70, 80, and 90 mm Hg with norepinephrine were associated with an increase in global oxygen delivery but there were no changes in preexisting abnormalities of microvascular blood flow

62

. Similarly, Dubin et al. noticed that microvascular perfusion was not affected by

changes in mean arterial pressure from 65 to 75 and 85 mmHg. Nevertheless, they also reported differences in the individual response among the investigated patients, highlighting the individual variability in the microvascular response to changes in systemic

ACCEPTED MANUSCRIPT hemodynamic

63

. More recently, Edul et al. showed that volume administration was

followed by increased cardiac index (2.6 ± 0.5 vs. 3.3 ± 1.0 L/min/m2) and MAP (68 ± 11 vs. 82 ± 12 mm Hg). However, only the sublingual and not the intestinal red blood cell velocity increased. Of note, both the sublingual and intestinal perfused vascular density remained

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unchanged 57.

Ince recently classified four types of microcirculatory alterations underlying the loss of hemodynamic coherence

53

(Table 1). Nevertheless, such alterations cannot be detected

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by conventional hemodynamic monitoring tools. New devices through the bedside observation of microcirculatory alterations may help in choosing the best therapeutic

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approach to correct the type of alteration observed.

Potential therapeutic strategies for improving septic microcirculatory dysfunction Finding an effective therapeutic strategy for improving septic microcirculatory dysfunction

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is still difficult as multiple mechanisms are involved in its pathogenesis and some of them are not fully understood. Furthermore, microvascular alterations may be theoretically considered instrumental rather than completely pathological, as they contribute to the

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compartmentalization of infection through the activation of inflammation and coagulation 8. If this assumption is true it is reasonable to think that therapeutic strategies should be

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aimed at modulating the underlying mechanisms rather than totally inhibiting them 8. Current treatments are mainly based on the manipulation of systemic hemodynamics and such approaches essentially increase total flow to the organs and influence the microcirculation to a lesser extent. However, pharmacological agents and treatments that are used for correcting hemodynamic parameters 3 may have pleiotropic properties which can be effective in improving microcirculation. Fluid Resuscitation

ACCEPTED MANUSCRIPT It has been demonstrated that the administration of fluids by decreasing blood viscosity, leukocyte and platelet aggregation as well as endothelial interactions, may improve microvascular blood flow. Furthermore, fluids promote NO-induced vasodilation at level of microcirculation. Accordingly, an increased proportion of perfused capillaries and reduced

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perfusion heterogeneity have been demonstrated following the administration of fluids 64,65. Nevertheless, such beneficial effects were observed only when fluids were administered in the very early but not late phase of sepsis (after 48 hours from onset), despite the fact that 65

cardiac output increased

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. It is therefore conceivable that the effects of fluids are

transient rather than persistent and “saturable” 8, as the first bolus of fluids improved 8,65

. The intravascular volume

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microvascular perfusion but the second had no effect

expansion with colloids (6% hydroxyethyl starch 130/04) seems to better improve microcirculation when compared with the use of crystalloids 66. However, this finding needs to be confirmed in larger trials. Finally, albumin by reducing endothelial activation and

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oxidative and nitrosative stresses in concentration-dependent manner, may improve microcirculatory dysfunction 67,68.

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Red Blood Cell administration

The beneficial microvascular response to red blood cell transfusion can be attributed to an

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increase in functional capillary density, through the filling of red blood cells-depleted capillaries 69. In addition, red blood cell transfusions may improve microvascular blood flow by replacing erythrocytes, which have become more rigid and less deformable, with more functional exogenous red blood cells with intact ability to release ATP and NO 70. However, such responses are characterized by a considerable individual variability and are strictly related to the severity of microvascular abnormalities

7,8,69

Sakr et al. demonstrated a

dichotomous response after red blood cell transfusion, with improved microvascular perfusion in patients with impaired perfusion at baseline and a deterioration of

ACCEPTED MANUSCRIPT microvascular perfusion in patients with preserved baseline perfusion

69

. All these findings

suggest that red blood cell transfusions may be effective only patients with severe microvascular alterations at baseline 7,8,69,70.

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Vasopressors The rationale for vasopressor administration in shock states is based on the knowledge that an intact microcirculation is able to regulate its blood flow in all organs within a

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pressure threshold. When MAP falls below a 60-65 mmHg (autoregulatory threshold), such autoregulation is lost and organ blood flow also decreases in an almost linear fashion.

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Increasing MAP above such threshold with vasopressors may therefore restore microvascular autoregulation. By contrast, in the presence of an impaired microcirculation as in septic shock vasopressor agents may have variable effects on microvascular blood flow depending on the severity of the microvascular impairment. Furthermore, the local

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microvascular responses to catecholaminergic agents including norepinephrine may be unpredictable due to heterogeneity in adrenergic receptor distribution and desensitation. It has been reported that increases in MAP with norepinephrine do not improve preexisting

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abnormalities of microvascular flow

62,63

. However, they may impair microcirculation in

septic shock patients with close to normal microcirculation at baseline

62,63

. It has to be

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kept in mind that in the presence of microcirculatory dysfunction, pressure-guided resuscitation leads to an increase of flow in the larger vessels but not in the capillaries, where flow may remain stagnant. As for the type of vasoconstrictor agents we demonstrated that in septic shock patients the administration of norepinephrine, continuous terlipressin or vasopressin (vasopressinergic receptor agonists) to achieve the same level of MAP was not associated with differences in microvascular blood flow. These findings suggest that microcirculatory flow abnormalities are mainly related to other factors

ACCEPTED MANUSCRIPT (volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se 71,72. Inotropes and Inodilators

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β-adrenergic agents may theoretically improve microcirculatory blood flow during sepsis through increased cardiac output. De Backer et al. demonstrated that the administration of 5 µg/kg·min dobutamine improved but failed to normalize capillary blood flow in septic shock patients

30

cardiac output

30

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. However, such improvement was not the consequence of changes in . By contrast, Hernandez et al. recently reported that similar dose of

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dobutamine failed to improve microvascular perfusion parameters despite inducing a significant increase in systemic hemodynamic variables

73

. These contradictory results are

not surprising as β-adrenergic receptors are not present at the level of capillaries and thus dobutamine may affect microcirculation only by acting on larger arterioles where β-

patients

with

septic

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receptors are expressed. Owing to adrenergic receptor and signaling abnormalities in shock,

dobutamine

administration

may

therefore

lead

to

heterogeneous responses in systemic hemodynamics and microcirculation. Furthermore,

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microvessels may reach a near maximal vasodilation in the early phase of dobutamine administration lasting for a brief period

74

. Dobutamine may also have “saturable” effects

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as it has been shown that microcirculatory blood flow remains unchanged while increasing doses 75. We demonstrated that a stronger vasodilatory compound, such as levosimendan, is more effective than dobutamine in improving microcirculation

74

. A likely explanation is

that (besides the effects on myocardial contractility) levosimendan - by exerting vasodilatory and pleiotropic effects such as antioxidative/nitrosative and anti-inflammatory activities - enhances both convection and diffusion, thereby improving oxygen delivery at the level of the microcirculation. As shown for dobutamine, the improvement in microvascular perfusion was independent from changes in cardiac output 74.

ACCEPTED MANUSCRIPT Vasodilators According to the capillary flow physiology, vasodilators may improve microcirculatory blood flow by increasing the driving pressure of blood flow at the entrance of the microcirculation 76

. Vasodilators may therefore increase perfused capillary density by recruiting non-

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perfused microvessels. Furthermore, the simultaneous administration with vasoconstrictor agents such as norepinephrine may counteract the reduced vascular density and stoppedflow capillaries in the microvascular zones in which norepinephrine causes excessive

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vasoconstriction. This assumption is supported by the finding of De backer at al. who noticed restored sublingual micro vascular blood flow after the local application of a large 30

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dose of acetylcholine in patients with septic shock

. As for inodilators, vasodilators

improve convective and diffusive oxygen transport. However, for being effective at the level of microcirculation, both compounds require carefully maintenance of adequate intravascular volume during their administration in order to avoid relative hypovolemia, as

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the latter may further impair microvascular blood flow. As the majority of common available vasodilators act through non-selective NO pathways and NO responsiveness may be differently impaired within microcirculation, their administration carries the risk of flow

Studies aimed at investigate the ability of nitroglycerin in improving

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heterogeneity.

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diversion from non-perfused to perfused micro vessels thereby increasing microvascular

microcirculation have led to conflicting findings

77,78

. Differences in doses and timing of

administration, adequacy of volume status and most importantly, the severity of basal microvascular impairment account for these contradictory results

77,78

. Magnesium sulfate

has also been tested in septic shock patients but it failed to improve microvascular alterations 79. Anticoagulants

ACCEPTED MANUSCRIPT Activated protein C, antithrombin, and low molecular weight heparin have been shown to improve microcirculation

80,81,82

. Interestingly, improvements of microcirculation following

anticoagulant agents seem to be not related to anticoagulation, but rather to pleiotropic effects, including antinflammatory activity, modulation of the endothelial activation and 7,8

. Improved blood cells flow in the capillary network

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decreased glicocalyx degradation

due to reduced leukocyte and platelet adhesion and rolling may contribute to such improvements. Nevertheless, the increased risk of bleeding has to be taken into account

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and limits their use for this purpose.

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Modulation of endothelial NO synthase

As overwhelming NO production is a typical feature of sepsis, it was assumed that NOS inhibition may improve macro and microcirculation

2,7,8

. Although it has been shown that

blocking NO production is effective in increasing MAP during sepsis, at the level of

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microcirculation causes the worsening of leukocyte adhesion, platelet aggregation and microthrombosis thereby increasing mortality

2,7,8

. Different effects at the level of macro

and microcirculation can be attributed to the fact that eNOS activity is fundamental for

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regulating microvascular blood flow during sepsis. Modulation rather than total inhibition of eNOS activity may therefore favor the improvement of local NO release leading to

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improved microcirculation. In the light of this, the efficacy of tetrahydrobiopterin (BH4) in improving microcirculation has been recently tested in experimental setting. BH4 is cofactor of eNOS and has the ability to produce and release NO with the advantage of not increasing ROS production. In experimental sepsis BH4 administered 4 and 12 h after the onset of sepsis blunted the decrease in proportion of perfused capillaries and in functional capillary density and improved organ function and survival duration 83.

ACCEPTED MANUSCRIPT Summary Microvascular dysfunction is a typical hallmark of sepsis and it plays a pivotal role in the development of organ dysfunction and mortality. Underlying mechanisms include endothelial dysfunction and cell to cell comunication, glycocalyx degradation, and altered

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interactions between the endothelium and blood cells. They also contribute to the loss of hemodynamic coherence. New diagnostic tools such as new hand-held microscopes through the bedside observation of microcirculatory alterations may help in choosing the

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best therapeutic approach to correct the type of alteration observed. However, the lack of

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validated microcirculatory end points for resuscitation still limits their use in clinical practice. Strategies for improving microcirculation are mainly based on the conventional manipulation of systemic hemodynamics in the attempt to increase total flow to the organs and tissues. Other compounds including eNOS modulation, α-2 agonists and β-blockers are under investigation. Nevertheless, the bedside observation of microcirculatory

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alterations confirms the high variability in the microvascular response to these interventions. On this basis, although they may potentially improve microcirculation, a careful evaluation of the impact of these interventions on microcirculatory blood flow has to

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be performed to assess their efficacy in each single septic patient.

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ACCEPTED MANUSCRIPT

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Practice points

Microvascular dysfunction is a typical hallmark of sepsis and contributes to the loss of hemodynamic coherence

•

Current treatments for improving microcirculation are mainly based on the manipulation of systemic hemodynamics, in the attempt to increase total flow to the organs and tissues.

•

Pharmacological agents and treatments for correcting hemodynamic parameters may have pleiotropic properties, which can be effective in improving microcirculation.

•

Fluids, red blood cell transfusions, inotropes, inodilators, vasopressors and anticoagulant agents may potentially improve microcirculatory dysfunction. However, such interventions are characterized by high variability in the individual response at the level of microcirculation.

•

When adopting these interventions, a carefully evaluation of their impact on microcirculation has to be performed to assess their efficacy in each single septic patient.

•

New diagnostic tools such as new hand-held microscopes through the bedside observation of microcirculatory alterations may help in choosing the best therapeutic approach to correct the type of alteration observed

•

eNOS modulation with tetrahydrobiopterin seems to be a promising strategy for improving microcirculation

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•

Research agenda

•

Further research is warranted to validated microcirculatory end points for resuscitation

ACCEPTED MANUSCRIPT Pleiotropic effects of levosimendan, β-blockers and α-2 agonists, which may affect microcirculation, need to be better elucidated.

•

Studies aimed at investigating the efficacy of eNOS modulation in improving microcirculation in human septic shock are urgently needed.

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•

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Conflict of Interest Statement: None

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microcirculation and outcome in an ovine model of septic shock. Crit Care Med

Fig 1.

Photograph of the sublingual microcirculation obtained with a sidestream dark field (SDF) imaging device in septic shock patient with a MAP of 70 mmHg. The red arrow identifies a

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stopped flow capillary. Cylinders represents the area of tissue that is supplied with oxygen by an individual capillary. If perfused vessel density is reduced, the effective tissue volume supplied by the remaining vessels is increased, thereby increasing the diffusion distance

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arterial pressure.

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for oxygen. Dotted arrows represent the diffusion distances for oxygen (d, d1). MAP, mean

ACCEPTED MANUSCRIPT Tab 1. Classification of microcirculatory alterations associated with loss of hemodynamic coherence.

Mechanisms involved

Type 1

heterogeneous perfusion of the microcirculation with obstructed capillaries next to perfused capillaries, resulting in a heterogeneous oxygenation of the tissue cells.

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Type of alterations

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hemodilution with the dilution of microcirculatory blood resulting in the loss of RBC-filled capillaries and increasing diffusion distance between RBCs in the capillaries and the tissue cells

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Type 2

stasis of microcirculatory RBC flow induced by altered systemic variables (e.g. increased arterial vascular resistance and or increased venous pressures causing tamponade)

Type 3

alterations involve edema caused by capillary leak syndrome and which results in increased diffusive distance and reduced ability of the oxygen to reach the tissue cells

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Type 4

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Types of microcirculatory alterations associated with loss of hemodynamic coherence proposed by Ince 53. RBC, red blood cells.

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ACCEPTED MANUSCRIPT