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Haemodynamic coherence in haemorrhagic shock
Best Practice & Research Clinical Anaesthesiology 30 (2016) 429e435
Contents lists available at ScienceDirect
Best Practice & Research Clinical Anaesthesiology journal homepage: www.elsevier.com/locate/bean
4
Haemodynamic coherence in haemorrhagic shock Nicolas Libert, M.D., Consultant in Critical Care and Anaesthesia a, b, Anatole Harrois, M.D, PhD, Consultant in Critical Care and Anaesthesia a, c, Jacques Duranteau, M.D, PhD, Senior Consultant in Critical Care and Anaesthesia a, c, * Laboratoire d'Etude de la Microcirculation, UMR 942, Universit e Paris, 7-11-13, Paris, France ^pital d'instruction des arm Service d’Anesth esie-R eanimation, Ho ees Percy, Clamart, France ^pital de Bic^ Service d'Anesth esie-R eanimation Chirurgicale, UMR 942, Ho etre, Universit e Paris-Sud, ^pitaux Universitaires Paris-Sud, Assistance Publique-Ho ^pitaux de Paris, Le Kremlin Bic^ Ho etre, France a
b c
Keywords: haemorrhage microcirculation haemodynamic coherence microcirculatory haemodynamic-driven resuscitation
In case of haemorrhage, a combination of low volume fluid resuscitation and permissive hypotension is used to avoid the adverse effects of early aggressive fluid resuscitation. During this phase, occult microvascular hypoperfusion can possibly develop over time. After controlling the bleeding, it is expected that optimization of macrocirculation will result in an improvement in microcirculation. However, this is the case only without alterations in microcirculation regulation. Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamicdriven resuscitation. However, haemorrhagic shock, reperfusion, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. In these cases, a systemic haemodynamic-driven resuscitation would not be effective in restoring microcirculation and tissue oxygenation. A real-time technique enabling microcirculation monitoring can create an opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future. © 2016 Elsevier Ltd. All rights reserved.
sie-Re animation Chirurgicale, Ho ^ pital de Bice ^tre, Universite Paris-Sud, Ho ^ pitaux * Corresponding author. Service d'Anesthe ^pitaux de Paris, Le Kremlin Bice ^tre, France. Fax: þ33 (0)1 45 21 28 75. Universitaires Paris-Sud, Assistance Publique-Ho E-mail address: [email protected] (J. Duranteau). http://dx.doi.org/10.1016/j.bpa.2016.11.002 1521-6896/© 2016 Elsevier Ltd. All rights reserved.
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Introduction The aim of haemodynamic resuscitation in haemorrhagic shock is to maintain systemic haemodynamics so as to limit microcirculatory hypoperfusion and tissue hypoxia and thus protect organ function. In the acute phase of haemorrhage, the priority is to stop the bleeding as soon as possible. As long as this bleeding is uncontrolled, aggressive fluid resuscitation may increase the risk of bleeding. Indeed, fluid resuscitation may promote coagulopathy by the dilution of coagulation factors and induction of hypothermia. In addition, increasing the arterial pressure may impede clot formation. Thus, a combination of low volume fluid resuscitation and permissive hypotension is used to avoid the adverse effects of early aggressive fluid resuscitation while maintaining a level of tissue perfusion that, although lower than normal, is tolerable over short periods [1]. During this phase, occult microvascular hypoperfusion and tissue hypoxia may develop over time. After bleeding is controlled, the main therapeutic goals are to restore the blood pressure and macrovascular oxygen delivery to limit tissue hypoxia and organ dysfunction. It is expected that the optimization of macrovascular haemodynamic parameters will result in improved microcirculation and restore tissue oxygenation. However, this is the case only if the compensatory haemodynamic response to haemorrhagic shock, including hormonal, neural, biochemical and vascular regulatory control systems, remains intact without alterations in microvascular regulation. Haemodynamic coherence must be maintained [2] to expect restoration of microcirculation and tissue oxygenation through systemic haemodynamic-driven resuscitation. However, haemorrhagic shock, reperfusion, traumatic injury and inflammation can damage the macrocirculatory and microcirculatory compensatory responses to haemorrhage and then lead to a loss of haemodynamic coherence. In these cases, a systemic haemodynamic-driven resuscitation would not be effective in restoring microcirculation and tissue oxygenation. Thus, it is obvious that there is a crucial need for an appropriate technique to monitor microcirculation at the bedside and guide the resuscitation on the basis of macrovascular and microvascular parameters. By doing so, it would be possible to adapt the resuscitation to optimize microcirculation parameters and detect the potential loss of haemodynamic coherence between macrocirculation and microcirculation when the optimization of macrocirculation fails to improve microcirculation. A real-time technique enabling microcirculation monitoring can become a part of haemodynamic algorithms of haemorrhagic shock resuscitation, thus creating the opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future.
Microcirculatory response to haemorrhage In the acute phase of haemorrhage, macrocirculatory and microcirculatory responses rapidly compensate for blood loss and limit tissue hypoxia. The macrocirculatory compensatory response engages the autonomic nervous system. Decrease in venous return and arterial pressure leads to the unloading of cardiopulmonary and arterial baroreceptors. This induces a decrease in the activation of the vasomotor inhibitory centre in the brainstem that in turn leads to the activation of the vasomotor centre (sympathetic centre) and inhibition of vagal activity (sinoatrial node). The increased activity of the sympathetic nerves increases the heart rate, cardiac contractility, and arterial and venous tone and activates the renin-angiotensin-aldosterone system. The magnitude of the compensatory vasoconstriction that follows is the net result of the combined effects of norepinephrine from the peripheral nerves on the peripheral vascular adrenoceptors, epinephrine from the adrenal medulla and nonadrenergic mechanisms (i.e. angiotensin and vasopressin). Arterial vasoconstriction rapidly decreases non-vital organ blood flow (musculocutaneous, splanchnic and renal blood flow) to maintain perfusion pressure and blood flow to vital organs (heart and brain). It is important to keep in mind that the sympathetic stimulation activates both arterial and venous a-adrenergic receptors, which recruit blood from the venous unstressed volume to maintain venous return and cardiac output. Microcirculation regulates the distribution of blood flow within organs to balance oxygen delivery and oxygen demands. To do so, microcirculation limits blood flow in microcirculatory units with low oxygen demands and increases blood flow in microcirculatory units with high oxygen demands. This microvascular heterogeneity of blood flow is an essential property of normal microcirculation and is
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necessary to match oxygen delivery and metabolic needs. Such metabolic-driven heterogeneity of blood flow guarantees optimal oxygen extraction. During haemorrhagic shock simultaneously to the macrovascular redistribution of arterial blood flow at the expense of non-vital organs, blood flow is redistributed within the capillary networks of each organ dictated by the arteriolar tone, rheologic factors and oxygen demand. The local regulation of the arteriolar tone is a crucial factor in the microvascular matching of oxygen supply to oxygen demand. Several mechanisms contribute to the local regulation of the arteriolar tone including response to intra-luminal pressure (myogenic response), shear stress on the glycocalyx and endothelial cells (shear-dependent response), and tissue metabolite concentrations (metabolic response). An increasingly important role is played by the red blood cells (RBCs) and haemoglobin molecule in the regulation of the microvascular tone and in matching the oxygen supply to oxygen demand. Ellsworth et al. suggested that RBCs behave as mobile oxygen sensors and control the vascular tone through the release of ATP [3,4]. ATP is released from RBCs in response to the mechanical deformation of their membranes, the transition of haemoglobin from oxygenated form to the deoxygenated form or receptor-mediated activation of RBC membranebound b-adrenergic receptors or prostacyclin receptors [5,6]. The RBC-derived ATP interacts with endothelial purinergic receptors, thus inducing the release of vasodilator mediators. Vasodilation is conducted in a retrograde fashion, resulting in increased blood flow (oxygen supply) to areas of increased oxygen demand. RBC intra-cellular ATP is decreased in haemorrhage and corrected by transfusion. Other mechanisms involving RBCs in the regulation of the vascular tone have been proposed [7,8]. Although this hypothesis is yet to be confirmed, it remains appealing in explaining the microvascular response to oxygen demand. However, despite the microvascular response, oxygen delivery could be insufficient to cover oxygen demand during haemorrhagic shock, and tissues have to down-regulate their energy needs to limit tissue hypoxia. The compensatory response of microcirculation to acute decrease in oxygen delivery during haemorrhagic shock could be impaired by the damage induced by the severity of the shock, reperfusion and inflammation. Restoring macrocirculation abnormalities can be ineffective in restoring microcirculation and correcting tissue oxygenation. Impact of haemorrhagic shock on microcirculation: pre-clinical research Tissue hypoperfusion and oxygen deficit (i.e. decrease of oxygen delivery below required levels to support aerobic metabolism) have extensively been reported in experimental haemorrhagic shock models as crucial pathophysiological events leading to tissue hypoxia, inflammation, coagulopathy and multiple organ failures [9e11]. A drop in cardiac output and oxygen delivery decreases microvascular blood flow and functional capillary density with an increase in flow heterogeneity in non-vital organs [12e16]. In a progressive model of haemorrhage (three stepwise bleedings of 5 ml/kg at 30-min intervals) in anesthetized pigs, Dubin et al. [14] reported that microvascular flow index (MFI) and capillary density in sublingual and ileal mucosa were progressively reduced with a progressive increase in heterogeneity flow index. These variations in microcirculation are accompanied by progressive decrease in cardiac output, superior mesenteric artery blood flow, lactate concentration and systemic and intestinal oxygen delivery [14]. The fact that microcirculatory variations are closely related to macrocirculatory variables during the initial bleeding phase was confirmed in other haemorrhagic models. Krejci et al. [15] observed that gastric and colon mucosal flow and liver and kidney flows decreased to a similar extent as superior mesenteric artery and systemic flows. In addition, van Iterson et al. [17] reported that changes in microvascular pO2 in the gut and heart follow the changes in macrocirculatory parameters (cardiac index, mean arterial pressure and oxygen delivery) in the acute bleeding phase. Thus, in experimental models of haemorrhagic shock, haemodynamic coherence between macrocirculation and microcirculation is often preserved. However, it is important to notice that these models primarily explore the acute phase of haemorrhagic shock that is induced by blood spoliation without a prolonged analysis of the resuscitation phase. However, some experimental studies suggested that haemorrhagic shock is capable of altering the compensatory microvascular response. For example, Kozar et al. [18] demonstrated in a rodent model that haemorrhagic shock degrades the endothelial glycocalyx. Machiedo et al. [19] reported that
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transfusion of RBCs from trauma haemorrhagic shock rats into naïve rats leads to impaired microcirculatory flow in several important organs, including the lungs, spleen, ileum and cecum. Finally, persistent microvascular alterations have been reported in haemorrhagic shock models despite adequate macrovascular resuscitation [20,21]. Legrand et al. [21] reported that fluid resuscitation with either normal or hypertonic saline targeting a low or high mean arterial pressure did not result in a correction of shock-induced renal microcirculatory hypoxia. Nevertheless, transfusion of fresh blood efficiently improved renal oxygenation, although it led to persistent hypoxic defects. This result reaffirms that microcirculatory oxygen delivery could be altered in haemorrhagic shock despite the restoration of macrocirculatory oxygen delivery, with a systemic haemoglobin level that is deemed adequate. It is important to keep in mind that other factors in addition to the macrovascular haemodynamic factors could induce microvascular alterations in haemorrhagic patients. For example, tissue injury and severe hypoxemia in trauma patients can lead to a pro-inflammatory state through the release of endogenous factors termed damage-associated molecular patterns by activated immune cells or released from necrotic cells, which can contribute to microvascular alterations. Thus, microvascular alterations in haemorrhagic shock may be amplified by associated trauma injury [22], systemic inflammation [22] or hypoxemia [16]. Tissue injury can itself induce intra-vascular leukocyte accumulation and impairment of skeletal muscle microcirculation accompanied by tissue hypoxia [22]. Hypoxemia can also contribute to microvascular dysfunction. This has been well demonstrated by Harrois et al. [16] who found that during haemorrhagic shock, the occurrence of hypoxemia considerably alters villous intestinal perfusion as it decreases the fraction of perfused villi in a synergistic manner with blood loss, thereby increasing the risk of villous ischemia. Therefore, other factors in addition to macrovascular haemodynamic factors could induce microvascular alterations in haemorrhagic patients, and microcirculation can remain hypoperfused despite the restoration of macrocirculation. This has been extensively demonstrated in septic patients in whom the resuscitation response of microcirculation is often dissociated from the macrovascular response [23,24]. Impact of haemorrhagic shock on microcirculation: clinical research Very few studies have been performed to evaluate the patterns of microcirculation during haemorrhagic shock in patients. In severely injured patients experiencing haemorrhagic shock, Tachon et al. [25] reported that sublingual microcirculation was impaired for at least 72 h despite the restoration of macrocirculation. In addition, the initial proportion of perfused vessels appears to be a good predictor of high Sequential Organ Failure Assessment score at day 4, suggesting that microcirculatory parameters could predict outcome. Further studies are required to establish the link between microvascular alterations and organ dysfunction in traumatic haemorrhagic shock patients. A multi-centre prospective longitudinal observational study (MICROSHOCK study) is currently in progress [26]. The macrovascular parameters used to target resuscitation (arterial pressure, cardiac index, systemic haemoglobin and/or oxygen delivery) seem to be inadequate to claim adequate perfusion and oxygen transport to the organ tissues. This may be because compensatory mechanisms needed to sustain haemodynamic coherence between macrocirculation and microcirculation are altered in traumatic haemorrhagic shock because of the damage of microvascular endothelium and glycocalyx, leukocyte adherence, interstitial and endothelial oedema, and coagulation activation. It is also necessary to determine the target value for the macrovascular parameters that are used to guide the resuscitation in shock patients. For example, Tanaka et al. [27] demonstrated that RBC transfusion improves sublingual microcirculation independently of macrocirculation and the haemoglobin level in haemorrhagic shock patients. This positive microcirculatory response to RBC transfusion was not coupled with baseline haemoglobin concentration, the daily parameter in clinical practice for deciding to transfuse RBC. Only baseline microvascular perfusion parameters could predict the microcirculatory response to RBC transfusion. Most of the patients studied notably had haemoglobin concentrations within the recommended target haemoglobin concentrations in haemorrhagic shock (7e9 g/dl). This result suggests that RBC transfusion improves microcirculatory perfusion in ways that cannot be entirely explained by macrocirculatory effects alone. This microcirculatory improvement could involve microvascular local mechanisms in which the RBC could have a central role. In addition, this study
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reinforces the fact that clinicians should not exclusively focus on the haemoglobin concentration as a transfusion trigger and that evaluation of microcirculation perfusion is critical for the optimization of microvascular perfusion and in defining which patients can benefit from RBC transfusion during cardiovascular resuscitation. These results confirm that evaluation of microcirculation perfusion is critical for the optimization of microvascular perfusion and personalize cardiovascular resuscitation. Implications for resuscitation of haemorrhagic shock Haemorrhagic shock can be accompanied by an intact haemodynamic coherence between the macrocirculation and microcirculation or a loss of this haemodynamic coherence. During the initial phase of the haemorrhagic shock, it is reasonable to assume that the coherence is still preserved and to postulate that some degree of improvement in microcirculation will be obtained after an increase in systemic oxygen delivery. Studies performed during the early phase of sepsis are in line with this assumption: in fact, fluid resuscitation within the first 24 h of sepsis was shown to efficiently improve sublingual microcirculation [28e30]. However, an occult microcirculatory oxygen delivery deficit can occur following inadequate resuscitation or a loss of haemodynamic coherence due to alterations in microcirculation. Thus, to explore the haemodynamic coherence and the effect of macrocirculatory haemodynamic-driven resuscitation on microcirculation, physicians need real-time techniques at the bedside that enable microcirculation monitoring. Assessment of microcirculatory perfusion can help in ensuring that the best therapeutic solutions such as fluid resuscitation, transfusion, vasopressors and vasodilators are chosen. For example, Pranskunas et al. [31] demonstrated that non-invasive assessment of sublingual microvascular blood flow in ICU patients with clinical signs of impaired organ perfusion may help to identify patients who are eligible for fluid therapy and to evaluate its effect. Recently, Tanaka et al. [27] found that RBC transfusion to haemorrhagic shock patients may be more appropriate than fluid resuscitation in improving sublingual microvascular blood flow and vascular density. In addition, a normal microcirculation must inevitably raise the question of the need to pursue the resuscitation. Xu J. et al. [32] demonstrated that fluid resuscitation guided by sublingual PCO2 in a porcine model of controlled haemorrhagic shock significantly reduced the amount of resuscitation fluid without compromising post-resuscitation tissue microcirculation, myocardial and neurologic functions, and 72-h survival. Surrogates of organ perfusion, such as lactate, peripheral temperature and capillary refill time, are useful in suggesting a persisting microvascular hypoperfusion. Direct visualization of flowing RBCs in sublingual microcirculation using sidestream dark field or incident dark field illumination imaging technologies allows to diagnose the nature of microcirculatory alterations and directly visualize the microvascular response to resuscitation procedures such as fluid therapy, blood transfusion and vasopressor administration. Although the visualization of sublingual circulation has improved in terms of image quality, speed of acquisition and analysis, the use of this technique is still limited in routine at the bedside by its perceived complexity and offline analysis. Evolution of these technologies requires the demonstration of the feasibility of data acquisition and analysis at the bedside by medical or paramedical staff and their ability to guide the management of shock patients. Recently, a real-time qualitative bedside evaluation of MFI by nurses showed good agreement with the conventional delayed analysis by physicians (MICRONURSE study) [33]. The bedside evaluations of MFI and total vascular density were highly sensitive and specific for detecting impaired microvascular flow and low capillary density. These results suggest that this technique can become part of ICU nurse routine surveillance and be implemented in algorithms for haemodynamic resuscitation in future clinical trials and regular practice. Tissue CO2 accumulation and venous-to-arterial carbon dioxide difference (PvaCO2) can also be used to detect changes in microvascular perfusion. Ospina-Tasco et al. [34] observed that Pv-aCO2 was closely related to microcirculatory blood flow parameters during the early phases of resuscitation of septic shock. In the future, new technologies will allow us to analyze microcirculation in several organs. For example, contrast-enhanced ultrasound (CEUS) has been validated to assess and quantify microcirculation up to capillary perfusion in several organs. The injection of microbubble contrast agents allows the quantification of the renal microcirculatory perfusion with low mechanical index ultrasonography. Renal CEUS was reported to detect changes in renal cortical perfusion after an increase in mean arterial pressure level in vasoplegic shock [35]. Further studies are needed to
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demonstrate whether renal CEUS can become a useful monitoring tool to guide renal resuscitation in ICU patients. In conclusion, a real-time technique enabling microcirculation monitoring can become part of haemodynamic algorithms of haemorrhagic shock resuscitation, and a microcirculatory haemodynamic-driven resuscitation can become the gold standard in the future. Conclusion Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamic-driven resuscitation. During the initial phase of the haemorrhagic shock, it is reasonable to assume that the coherence is still preserved and to postulate that improvement in microcirculation will be obtained after an increase in systemic oxygen delivery. However, haemorrhagic shock, reperfusion injury, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. To explore the haemodynamic coherence and the effect of macrocirculatory haemodynamic-driven resuscitation on microcirculation, physicians need real-time techniques at the bedside that enable microcirculation monitoring.
Practice points Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamic-driven resuscitation. During the initial phase of haemorrhagic shock, it is reasonable to assume that the coherence is still preserved and to postulate that improvement in microcirculation will be obtained after an increase in systemic oxygen delivery. However, haemorrhagic shock, reperfusion injury, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. To explore haemodynamic coherence and the effect of macrocirculatory haemodynamicdriven resuscitation on microcirculation, physicians need real-time techniques at the bedside that enable microcirculation monitoring. A real-time technique enabling microcirculation monitoring can create an opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future.
Research agenda Further research is warranted to establish the link between microvascular alterations and organ dysfunction in traumatic haemorrhagic shock patients. Further studies are required to explore the incidence of loss of haemodynamic coherence in haemorrhagic shock. Further research is warranted to demonstrate whether a real-time technique of microcirculation monitoring at the bedside has a clinical impact on the management of haemorrhagic shock patients.
Conflict of interest None. References [1] Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care 2016;20:100. *[2] Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 2015;19(Suppl. 3):S8.
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[3] Ellsworth ML, Ellis CG, Goldman D, et al. Erythrocytes: oxygen sensors and modulators of vascular tone. Physiology 2009; 24:107e16. [4] Sprague RS, Bowles EA, Achilleus D, et al. Erythrocytes as controllers of perfusion distribution in the microvasculature of skeletal muscle. Acta Physiol 2011;202:285e92. [5] Akatsu T, Tsukada K, Hishiki T, et al. T-state stabilization of hemoglobin by nitric oxide to form alpha-nitrosyl heme causes constitutive release of ATP from human erythrocytes. Adv Exp Med Biol 2010;662:109e14. [6] Locovei S, Bao L, Dahl G. Pannexin 1 in erythrocytes: function without a gap. Proc Natl Acad Sci U. S. A 2006;103:7655e9. [7] Jia L, Bonaventura C, Bonaventura J, et al. S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 1996;380:221e6. [8] Stamler JS, Jia L, Eu JP, et al. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997;276:2034e7. [9] Shoemaker WC, Appel PL, Kram HB. Tissue oxygen debt as a determinant of lethal and nonlethal postoperative organ failure. Crit Care Med 1988;16:1117e20. [10] Rixen D, Raum M, Holzgraefe B, et al. A pig hemorrhagic shock model: oxygen debt and metabolic acidemia as indicators of severity. Shock 2001;16:239e44. [11] Dunham CM, Siegel JH, Weireter L, et al. Oxygen debt and metabolic acidemia as quantitative predictors of mortality and the severity of the ischemic insult in hemorrhagic shock. Crit Care Med 1991;19:231e43. [12] Vajda K, Szabo A, Boros M. Heterogeneous microcirculation in the rat small intestine during hemorrhagic shock: quantification of the effects of hypertonic-hyperoncotic resuscitation. Eur Surg Res 2004;36:338e44. €lzl C, Pajk W, et al. Microcirculatory parameters after isotonic and hypertonic colloidal fluid resuscitation [13] Maier S, Holz-Ho in acute hemorrhagic shock. J Trauma 2009;66:337e45. *[14] Dubin A, Pozo MO, Ferrara G, et al. Systemic and microcirculatory responses to progressive hemorrhage. Intensive Care Med 2009;35:556e64. [15] Krejci V, Hiltebrand L, Banic A, et al. Continuous measurements of microcirculatory blood flow in gastrointestinal organs during acute haemorrhage. Br J Anaesth 2000;84:468e75. *[16] Harrois A, Baudry N, Huet O, et al. Synergistic deleterious effect of hypoxemia and hypovolemia on microcirculation in intestinal villi. Crit Care Med 2013;41:e376e84. [17] van Iterson M, Bezemer R, Heger M, et al. Microcirculation follows macrocirculation in heart and gut in the acute phase of hemorrhagic shock and isovolemic autologous whole blood resuscitation in pigs. Transfusion 2011;52:1552e9. *[18] Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg 2011;112:1289e95. [19] Machiedo GW, Zaets SB, Berezina TL, et al. Trauma-hemorrhagic shock-induced red blood cell damage leads to decreased microcirculatory blood flow. Crit Care Med 2009;37:1000e10. [20] Sinaasappel M, van Iterson M, Ince C. Microvascular oxygen pressure in the pig intestine during haemorrhagic shock and resuscitation. J Physiol (Lond) 1999;514:245e53. *[21] Legrand M, Mik EG, Balestra GM, et al. Fluid resuscitation does not improve renal oxygenation during hemorrhagic shock in rats. Anesthesiology 2010;112:119e27. [22] Gierer P, Hoffmann JN, Mahr F, et al. Sublethal trauma model with systemic endotoxemia for the study of microcirculatory disorders after the second hit. J Surg Res 2008;147:68e74. *[23] De Backer D, Donadello K, Sakr Y, et al. Microcirculatory alterations in patients with severe sepsis. Crit Care Med 2013;41: 791e9. [24] Sakr Y, Dubois M-J, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004;32:1825e31. *[25] Tachon G, Harrois A, Tanaka S, et al. Microcirculatory alterations in traumatic hemorrhagic shock. Crit Care Med 2014;42: 1433e41. [26] Hutchings S, Naumann DN, Harris T, et al. Observational study of the effects of traumatic injury, haemorrhagic shock and resuscitation on the microcirculation: a protocol for the MICROSHOCK study. BMJ Open 2016:e010893e7. *[27] Tanaka S, Escudier E, Hamada S, et al. Effect of RBC transfusion on sublingual microcirculation in hemorrhagic shock patients. Crit Care Med 2016 Sep 15 [Epub ahead of print]. [28] Trzeciak S, McCoy JV, Phillip Dellinger R, et al. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 2008;34:2210e7. *[29] Ospina-Tascon G, Neves AP, Occhipinti G, et al. Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med 2010;36:949e55. *[30] Pottecher J, Deruddre S, Teboul J-L, et al. Both passive leg raising and intravascular volume expansion improve sublingual microcirculatory perfusion in severe sepsis and septic shock patients. Intensive Care Med 2010;36:1867e74. [31] Pranskunas A, Koopmans M, Koetsier PM, et al. Microcirculatory blood flow as a tool to select ICU patients eligible for fluid therapy. Intensive Care Med 2012;39:612e9. [32] Xu J, Ma L, Sun S, et al. Fluid resuscitation guided by sublingual partial pressure of carbon dioxide during hemorrhagic shock in a porcine model. Shock 2013;39:361e5. [33] Tanaka S, Harrois A, Nicolaï C, et al. Qualitative real-time analysis by nurses of sublingual microcirculation in intensive care unit: the MICRONURSE study. Crit Care 2015;19:388. n GA, Uman ~ a M, Bermúdez WF, et al. Can venous-to-arterial carbon dioxide differences reflect microcir[34] Ospina-Tasco culatory alterations in patients with septic shock? Intensive Care Med 2015;42:211e21. [35] Schneider AG, Goodwin MD, Schelleman A, et al. 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Contents lists available at ScienceDirect
Best Practice & Research Clinical Anaesthesiology journal homepage: www.elsevier.com/locate/bean
4
Haemodynamic coherence in haemorrhagic shock Nicolas Libert, M.D., Consultant in Critical Care and Anaesthesia a, b, Anatole Harrois, M.D, PhD, Consultant in Critical Care and Anaesthesia a, c, Jacques Duranteau, M.D, PhD, Senior Consultant in Critical Care and Anaesthesia a, c, * Laboratoire d'Etude de la Microcirculation, UMR 942, Universit e Paris, 7-11-13, Paris, France ^pital d'instruction des arm Service d’Anesth esie-R eanimation, Ho ees Percy, Clamart, France ^pital de Bic^ Service d'Anesth esie-R eanimation Chirurgicale, UMR 942, Ho etre, Universit e Paris-Sud, ^pitaux Universitaires Paris-Sud, Assistance Publique-Ho ^pitaux de Paris, Le Kremlin Bic^ Ho etre, France a
b c
Keywords: haemorrhage microcirculation haemodynamic coherence microcirculatory haemodynamic-driven resuscitation
In case of haemorrhage, a combination of low volume fluid resuscitation and permissive hypotension is used to avoid the adverse effects of early aggressive fluid resuscitation. During this phase, occult microvascular hypoperfusion can possibly develop over time. After controlling the bleeding, it is expected that optimization of macrocirculation will result in an improvement in microcirculation. However, this is the case only without alterations in microcirculation regulation. Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamicdriven resuscitation. However, haemorrhagic shock, reperfusion, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. In these cases, a systemic haemodynamic-driven resuscitation would not be effective in restoring microcirculation and tissue oxygenation. A real-time technique enabling microcirculation monitoring can create an opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future. © 2016 Elsevier Ltd. All rights reserved.
sie-Re animation Chirurgicale, Ho ^ pital de Bice ^tre, Universite Paris-Sud, Ho ^ pitaux * Corresponding author. Service d'Anesthe ^pitaux de Paris, Le Kremlin Bice ^tre, France. Fax: þ33 (0)1 45 21 28 75. Universitaires Paris-Sud, Assistance Publique-Ho E-mail address: [email protected] (J. Duranteau). http://dx.doi.org/10.1016/j.bpa.2016.11.002 1521-6896/© 2016 Elsevier Ltd. All rights reserved.
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N. Libert et al. / Best Practice & Research Clinical Anaesthesiology 30 (2016) 429e435
Introduction The aim of haemodynamic resuscitation in haemorrhagic shock is to maintain systemic haemodynamics so as to limit microcirculatory hypoperfusion and tissue hypoxia and thus protect organ function. In the acute phase of haemorrhage, the priority is to stop the bleeding as soon as possible. As long as this bleeding is uncontrolled, aggressive fluid resuscitation may increase the risk of bleeding. Indeed, fluid resuscitation may promote coagulopathy by the dilution of coagulation factors and induction of hypothermia. In addition, increasing the arterial pressure may impede clot formation. Thus, a combination of low volume fluid resuscitation and permissive hypotension is used to avoid the adverse effects of early aggressive fluid resuscitation while maintaining a level of tissue perfusion that, although lower than normal, is tolerable over short periods [1]. During this phase, occult microvascular hypoperfusion and tissue hypoxia may develop over time. After bleeding is controlled, the main therapeutic goals are to restore the blood pressure and macrovascular oxygen delivery to limit tissue hypoxia and organ dysfunction. It is expected that the optimization of macrovascular haemodynamic parameters will result in improved microcirculation and restore tissue oxygenation. However, this is the case only if the compensatory haemodynamic response to haemorrhagic shock, including hormonal, neural, biochemical and vascular regulatory control systems, remains intact without alterations in microvascular regulation. Haemodynamic coherence must be maintained [2] to expect restoration of microcirculation and tissue oxygenation through systemic haemodynamic-driven resuscitation. However, haemorrhagic shock, reperfusion, traumatic injury and inflammation can damage the macrocirculatory and microcirculatory compensatory responses to haemorrhage and then lead to a loss of haemodynamic coherence. In these cases, a systemic haemodynamic-driven resuscitation would not be effective in restoring microcirculation and tissue oxygenation. Thus, it is obvious that there is a crucial need for an appropriate technique to monitor microcirculation at the bedside and guide the resuscitation on the basis of macrovascular and microvascular parameters. By doing so, it would be possible to adapt the resuscitation to optimize microcirculation parameters and detect the potential loss of haemodynamic coherence between macrocirculation and microcirculation when the optimization of macrocirculation fails to improve microcirculation. A real-time technique enabling microcirculation monitoring can become a part of haemodynamic algorithms of haemorrhagic shock resuscitation, thus creating the opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future.
Microcirculatory response to haemorrhage In the acute phase of haemorrhage, macrocirculatory and microcirculatory responses rapidly compensate for blood loss and limit tissue hypoxia. The macrocirculatory compensatory response engages the autonomic nervous system. Decrease in venous return and arterial pressure leads to the unloading of cardiopulmonary and arterial baroreceptors. This induces a decrease in the activation of the vasomotor inhibitory centre in the brainstem that in turn leads to the activation of the vasomotor centre (sympathetic centre) and inhibition of vagal activity (sinoatrial node). The increased activity of the sympathetic nerves increases the heart rate, cardiac contractility, and arterial and venous tone and activates the renin-angiotensin-aldosterone system. The magnitude of the compensatory vasoconstriction that follows is the net result of the combined effects of norepinephrine from the peripheral nerves on the peripheral vascular adrenoceptors, epinephrine from the adrenal medulla and nonadrenergic mechanisms (i.e. angiotensin and vasopressin). Arterial vasoconstriction rapidly decreases non-vital organ blood flow (musculocutaneous, splanchnic and renal blood flow) to maintain perfusion pressure and blood flow to vital organs (heart and brain). It is important to keep in mind that the sympathetic stimulation activates both arterial and venous a-adrenergic receptors, which recruit blood from the venous unstressed volume to maintain venous return and cardiac output. Microcirculation regulates the distribution of blood flow within organs to balance oxygen delivery and oxygen demands. To do so, microcirculation limits blood flow in microcirculatory units with low oxygen demands and increases blood flow in microcirculatory units with high oxygen demands. This microvascular heterogeneity of blood flow is an essential property of normal microcirculation and is
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necessary to match oxygen delivery and metabolic needs. Such metabolic-driven heterogeneity of blood flow guarantees optimal oxygen extraction. During haemorrhagic shock simultaneously to the macrovascular redistribution of arterial blood flow at the expense of non-vital organs, blood flow is redistributed within the capillary networks of each organ dictated by the arteriolar tone, rheologic factors and oxygen demand. The local regulation of the arteriolar tone is a crucial factor in the microvascular matching of oxygen supply to oxygen demand. Several mechanisms contribute to the local regulation of the arteriolar tone including response to intra-luminal pressure (myogenic response), shear stress on the glycocalyx and endothelial cells (shear-dependent response), and tissue metabolite concentrations (metabolic response). An increasingly important role is played by the red blood cells (RBCs) and haemoglobin molecule in the regulation of the microvascular tone and in matching the oxygen supply to oxygen demand. Ellsworth et al. suggested that RBCs behave as mobile oxygen sensors and control the vascular tone through the release of ATP [3,4]. ATP is released from RBCs in response to the mechanical deformation of their membranes, the transition of haemoglobin from oxygenated form to the deoxygenated form or receptor-mediated activation of RBC membranebound b-adrenergic receptors or prostacyclin receptors [5,6]. The RBC-derived ATP interacts with endothelial purinergic receptors, thus inducing the release of vasodilator mediators. Vasodilation is conducted in a retrograde fashion, resulting in increased blood flow (oxygen supply) to areas of increased oxygen demand. RBC intra-cellular ATP is decreased in haemorrhage and corrected by transfusion. Other mechanisms involving RBCs in the regulation of the vascular tone have been proposed [7,8]. Although this hypothesis is yet to be confirmed, it remains appealing in explaining the microvascular response to oxygen demand. However, despite the microvascular response, oxygen delivery could be insufficient to cover oxygen demand during haemorrhagic shock, and tissues have to down-regulate their energy needs to limit tissue hypoxia. The compensatory response of microcirculation to acute decrease in oxygen delivery during haemorrhagic shock could be impaired by the damage induced by the severity of the shock, reperfusion and inflammation. Restoring macrocirculation abnormalities can be ineffective in restoring microcirculation and correcting tissue oxygenation. Impact of haemorrhagic shock on microcirculation: pre-clinical research Tissue hypoperfusion and oxygen deficit (i.e. decrease of oxygen delivery below required levels to support aerobic metabolism) have extensively been reported in experimental haemorrhagic shock models as crucial pathophysiological events leading to tissue hypoxia, inflammation, coagulopathy and multiple organ failures [9e11]. A drop in cardiac output and oxygen delivery decreases microvascular blood flow and functional capillary density with an increase in flow heterogeneity in non-vital organs [12e16]. In a progressive model of haemorrhage (three stepwise bleedings of 5 ml/kg at 30-min intervals) in anesthetized pigs, Dubin et al. [14] reported that microvascular flow index (MFI) and capillary density in sublingual and ileal mucosa were progressively reduced with a progressive increase in heterogeneity flow index. These variations in microcirculation are accompanied by progressive decrease in cardiac output, superior mesenteric artery blood flow, lactate concentration and systemic and intestinal oxygen delivery [14]. The fact that microcirculatory variations are closely related to macrocirculatory variables during the initial bleeding phase was confirmed in other haemorrhagic models. Krejci et al. [15] observed that gastric and colon mucosal flow and liver and kidney flows decreased to a similar extent as superior mesenteric artery and systemic flows. In addition, van Iterson et al. [17] reported that changes in microvascular pO2 in the gut and heart follow the changes in macrocirculatory parameters (cardiac index, mean arterial pressure and oxygen delivery) in the acute bleeding phase. Thus, in experimental models of haemorrhagic shock, haemodynamic coherence between macrocirculation and microcirculation is often preserved. However, it is important to notice that these models primarily explore the acute phase of haemorrhagic shock that is induced by blood spoliation without a prolonged analysis of the resuscitation phase. However, some experimental studies suggested that haemorrhagic shock is capable of altering the compensatory microvascular response. For example, Kozar et al. [18] demonstrated in a rodent model that haemorrhagic shock degrades the endothelial glycocalyx. Machiedo et al. [19] reported that
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transfusion of RBCs from trauma haemorrhagic shock rats into naïve rats leads to impaired microcirculatory flow in several important organs, including the lungs, spleen, ileum and cecum. Finally, persistent microvascular alterations have been reported in haemorrhagic shock models despite adequate macrovascular resuscitation [20,21]. Legrand et al. [21] reported that fluid resuscitation with either normal or hypertonic saline targeting a low or high mean arterial pressure did not result in a correction of shock-induced renal microcirculatory hypoxia. Nevertheless, transfusion of fresh blood efficiently improved renal oxygenation, although it led to persistent hypoxic defects. This result reaffirms that microcirculatory oxygen delivery could be altered in haemorrhagic shock despite the restoration of macrocirculatory oxygen delivery, with a systemic haemoglobin level that is deemed adequate. It is important to keep in mind that other factors in addition to the macrovascular haemodynamic factors could induce microvascular alterations in haemorrhagic patients. For example, tissue injury and severe hypoxemia in trauma patients can lead to a pro-inflammatory state through the release of endogenous factors termed damage-associated molecular patterns by activated immune cells or released from necrotic cells, which can contribute to microvascular alterations. Thus, microvascular alterations in haemorrhagic shock may be amplified by associated trauma injury [22], systemic inflammation [22] or hypoxemia [16]. Tissue injury can itself induce intra-vascular leukocyte accumulation and impairment of skeletal muscle microcirculation accompanied by tissue hypoxia [22]. Hypoxemia can also contribute to microvascular dysfunction. This has been well demonstrated by Harrois et al. [16] who found that during haemorrhagic shock, the occurrence of hypoxemia considerably alters villous intestinal perfusion as it decreases the fraction of perfused villi in a synergistic manner with blood loss, thereby increasing the risk of villous ischemia. Therefore, other factors in addition to macrovascular haemodynamic factors could induce microvascular alterations in haemorrhagic patients, and microcirculation can remain hypoperfused despite the restoration of macrocirculation. This has been extensively demonstrated in septic patients in whom the resuscitation response of microcirculation is often dissociated from the macrovascular response [23,24]. Impact of haemorrhagic shock on microcirculation: clinical research Very few studies have been performed to evaluate the patterns of microcirculation during haemorrhagic shock in patients. In severely injured patients experiencing haemorrhagic shock, Tachon et al. [25] reported that sublingual microcirculation was impaired for at least 72 h despite the restoration of macrocirculation. In addition, the initial proportion of perfused vessels appears to be a good predictor of high Sequential Organ Failure Assessment score at day 4, suggesting that microcirculatory parameters could predict outcome. Further studies are required to establish the link between microvascular alterations and organ dysfunction in traumatic haemorrhagic shock patients. A multi-centre prospective longitudinal observational study (MICROSHOCK study) is currently in progress [26]. The macrovascular parameters used to target resuscitation (arterial pressure, cardiac index, systemic haemoglobin and/or oxygen delivery) seem to be inadequate to claim adequate perfusion and oxygen transport to the organ tissues. This may be because compensatory mechanisms needed to sustain haemodynamic coherence between macrocirculation and microcirculation are altered in traumatic haemorrhagic shock because of the damage of microvascular endothelium and glycocalyx, leukocyte adherence, interstitial and endothelial oedema, and coagulation activation. It is also necessary to determine the target value for the macrovascular parameters that are used to guide the resuscitation in shock patients. For example, Tanaka et al. [27] demonstrated that RBC transfusion improves sublingual microcirculation independently of macrocirculation and the haemoglobin level in haemorrhagic shock patients. This positive microcirculatory response to RBC transfusion was not coupled with baseline haemoglobin concentration, the daily parameter in clinical practice for deciding to transfuse RBC. Only baseline microvascular perfusion parameters could predict the microcirculatory response to RBC transfusion. Most of the patients studied notably had haemoglobin concentrations within the recommended target haemoglobin concentrations in haemorrhagic shock (7e9 g/dl). This result suggests that RBC transfusion improves microcirculatory perfusion in ways that cannot be entirely explained by macrocirculatory effects alone. This microcirculatory improvement could involve microvascular local mechanisms in which the RBC could have a central role. In addition, this study
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reinforces the fact that clinicians should not exclusively focus on the haemoglobin concentration as a transfusion trigger and that evaluation of microcirculation perfusion is critical for the optimization of microvascular perfusion and in defining which patients can benefit from RBC transfusion during cardiovascular resuscitation. These results confirm that evaluation of microcirculation perfusion is critical for the optimization of microvascular perfusion and personalize cardiovascular resuscitation. Implications for resuscitation of haemorrhagic shock Haemorrhagic shock can be accompanied by an intact haemodynamic coherence between the macrocirculation and microcirculation or a loss of this haemodynamic coherence. During the initial phase of the haemorrhagic shock, it is reasonable to assume that the coherence is still preserved and to postulate that some degree of improvement in microcirculation will be obtained after an increase in systemic oxygen delivery. Studies performed during the early phase of sepsis are in line with this assumption: in fact, fluid resuscitation within the first 24 h of sepsis was shown to efficiently improve sublingual microcirculation [28e30]. However, an occult microcirculatory oxygen delivery deficit can occur following inadequate resuscitation or a loss of haemodynamic coherence due to alterations in microcirculation. Thus, to explore the haemodynamic coherence and the effect of macrocirculatory haemodynamic-driven resuscitation on microcirculation, physicians need real-time techniques at the bedside that enable microcirculation monitoring. Assessment of microcirculatory perfusion can help in ensuring that the best therapeutic solutions such as fluid resuscitation, transfusion, vasopressors and vasodilators are chosen. For example, Pranskunas et al. [31] demonstrated that non-invasive assessment of sublingual microvascular blood flow in ICU patients with clinical signs of impaired organ perfusion may help to identify patients who are eligible for fluid therapy and to evaluate its effect. Recently, Tanaka et al. [27] found that RBC transfusion to haemorrhagic shock patients may be more appropriate than fluid resuscitation in improving sublingual microvascular blood flow and vascular density. In addition, a normal microcirculation must inevitably raise the question of the need to pursue the resuscitation. Xu J. et al. [32] demonstrated that fluid resuscitation guided by sublingual PCO2 in a porcine model of controlled haemorrhagic shock significantly reduced the amount of resuscitation fluid without compromising post-resuscitation tissue microcirculation, myocardial and neurologic functions, and 72-h survival. Surrogates of organ perfusion, such as lactate, peripheral temperature and capillary refill time, are useful in suggesting a persisting microvascular hypoperfusion. Direct visualization of flowing RBCs in sublingual microcirculation using sidestream dark field or incident dark field illumination imaging technologies allows to diagnose the nature of microcirculatory alterations and directly visualize the microvascular response to resuscitation procedures such as fluid therapy, blood transfusion and vasopressor administration. Although the visualization of sublingual circulation has improved in terms of image quality, speed of acquisition and analysis, the use of this technique is still limited in routine at the bedside by its perceived complexity and offline analysis. Evolution of these technologies requires the demonstration of the feasibility of data acquisition and analysis at the bedside by medical or paramedical staff and their ability to guide the management of shock patients. Recently, a real-time qualitative bedside evaluation of MFI by nurses showed good agreement with the conventional delayed analysis by physicians (MICRONURSE study) [33]. The bedside evaluations of MFI and total vascular density were highly sensitive and specific for detecting impaired microvascular flow and low capillary density. These results suggest that this technique can become part of ICU nurse routine surveillance and be implemented in algorithms for haemodynamic resuscitation in future clinical trials and regular practice. Tissue CO2 accumulation and venous-to-arterial carbon dioxide difference (PvaCO2) can also be used to detect changes in microvascular perfusion. Ospina-Tasco et al. [34] observed that Pv-aCO2 was closely related to microcirculatory blood flow parameters during the early phases of resuscitation of septic shock. In the future, new technologies will allow us to analyze microcirculation in several organs. For example, contrast-enhanced ultrasound (CEUS) has been validated to assess and quantify microcirculation up to capillary perfusion in several organs. The injection of microbubble contrast agents allows the quantification of the renal microcirculatory perfusion with low mechanical index ultrasonography. Renal CEUS was reported to detect changes in renal cortical perfusion after an increase in mean arterial pressure level in vasoplegic shock [35]. Further studies are needed to
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demonstrate whether renal CEUS can become a useful monitoring tool to guide renal resuscitation in ICU patients. In conclusion, a real-time technique enabling microcirculation monitoring can become part of haemodynamic algorithms of haemorrhagic shock resuscitation, and a microcirculatory haemodynamic-driven resuscitation can become the gold standard in the future. Conclusion Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamic-driven resuscitation. During the initial phase of the haemorrhagic shock, it is reasonable to assume that the coherence is still preserved and to postulate that improvement in microcirculation will be obtained after an increase in systemic oxygen delivery. However, haemorrhagic shock, reperfusion injury, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. To explore the haemodynamic coherence and the effect of macrocirculatory haemodynamic-driven resuscitation on microcirculation, physicians need real-time techniques at the bedside that enable microcirculation monitoring.
Practice points Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamic-driven resuscitation. During the initial phase of haemorrhagic shock, it is reasonable to assume that the coherence is still preserved and to postulate that improvement in microcirculation will be obtained after an increase in systemic oxygen delivery. However, haemorrhagic shock, reperfusion injury, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. To explore haemodynamic coherence and the effect of macrocirculatory haemodynamicdriven resuscitation on microcirculation, physicians need real-time techniques at the bedside that enable microcirculation monitoring. A real-time technique enabling microcirculation monitoring can create an opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future.
Research agenda Further research is warranted to establish the link between microvascular alterations and organ dysfunction in traumatic haemorrhagic shock patients. Further studies are required to explore the incidence of loss of haemodynamic coherence in haemorrhagic shock. Further research is warranted to demonstrate whether a real-time technique of microcirculation monitoring at the bedside has a clinical impact on the management of haemorrhagic shock patients.
Conflict of interest None. References [1] Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care 2016;20:100. *[2] Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 2015;19(Suppl. 3):S8.
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