Citation for published version (APA): Boerma, E. C. (2009). Distributive failure in the microcirculation of septic patients

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1 UvA-DARE (Digital Academic Repository) Distributive failure in the microcirculation of septic patients Boerma, E.C. Link to publication Citation for published version (APA): Boerma, E. C. (2009). Distributive failure in the microcirculation of septic patients General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 16 Apr 2018

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3 10 Introduction

4 The context Sepsis is a life-threatening complication of infection with a reported crude mortality between 20% and 60% [1,2]. The infection itself and a complex reaction of the body eventually leads to multiple organ failure, often despite adequate antibiotic treatment and (surgical) control of the infection site. By definition, sepsis in combination with organ dysfunction is called severe sepsis, arising the need for intensive treatment to prevent death. Mortality progressively increases with the number of organs that fail [3]. It is estimated that over 9000 patients with severe sepsis are annually admitted to an Intensive Care Unit in the Netherlands, which accounts for 11% of all ICU-admittances in the Netherlands [4]. Apart from high mortality rates, severe sepsis and its intensive treatment also lead to substantial morbidity: physical and psychological effects for patients are considerable and may be longlasting [5]. With an average cost of per treatment the overall annual direct medical costs of 168 million represent 0.5% of all health-care costs and 1,7% of the annual hospital budget in the Netherlands [6]. In summary, (severe) sepsis represents a large healthcare burden, both in costs and human suffering. In order to reduce morbidity and mortality, for many decades extensive efforts have been exerted to correct the circulatory shock that accompanies organ failure in severe sepsis [7]. This condition occurs when oxygen supply cannot meet the needs of the tissue cells [8], and, if not corrected in time, may result in organ dysfunction. As opposed to other forms of shock, septic shock results from distributive alterations in tissue perfusion, caused by abnormal control of microvasculature with an abnormal distribution of a normal or increased cardiac output [9]. Many years ago, Weil and Shubin proposed a classification of shock with special reference to its distributive form [10]. The distributive defect in septic shock has been classically defined as a redistribution of volumes and reflects a defect in vascular regulation in the presence of normal or even supranormal oxygen supply. The complex nature of the pathophysiology of this syndrome has led to considerable controversy regarding patient management. Despite an increase in cardiac output and oxygen delivery to tissue, seemingly paradoxical regional dysoxia is evident, as indicated by high lactate levels, disturbed acid base balance, and enhanced levels of gastric CO 2 [11,12]. This situation is described as a deficit in oxygen extraction by peripheral tissues. Under conditions of distributive shock, the concept of heterogeneity of blood flow within the microcirculation could explain dysoxia, despite adequate upstream and downstream parameters of oxygen delivery [13,14]. Microcirculatory weak units are shunted at the regional level causing patchy hypoxic areas, whereas at the same time both arterial and venular p0 2 may appear normal. However, until 1999 sepsis-specific animal models, such as direct in-vivo microscopy of the microcirculation after specific tissue preparation, could not be translated into human sepsis studies for practical reasons. In that year, orthogonal polarization spectral (OPS) imaging was introduced [15]. The OPS technique consists of a handheld device that illuminates an 11

5 area of interest with polarized light, while imaging the remitted light through a second polarizer (analyzer), oriented in a plane precisely orthogonal to the plane of illumination. If a wavelength within the haemoglobin absorption spectrum (e.g., 548 nm) is chosen, erythrocytes will appear dark and leukocytes may be visible as refringent bodies. The vessel walls itself are not visualized directly, although faint contours can be identified depending on the presence of intravascular erythrocytes. Visualization of the microcirculation by the technical successor of OPS imaging, sidestream darkfield (SDF) imaging, is essentially based on the same physical principles [16]. As a result of direct in-vivo observation of the microcirculation in septic patients, microcirculatory abnormalities, and in particular heterogeneity of flow, are now being recognized as key characteristics in the pathogenesis of organ dysfunction during sepsis [17-19]. Presence and persistence of such abnormalities were found to be associated with prognosis of morbidity and mortality, in contrast to all the available systemic hemodynamic variables [17-19]. Combining OPS/SDF imaging with other techniques such as sublingual and buccal capnometry, has added to the understanding of the relation between microcirculatory abnormalities and metabolic tissue variables [20,21]. Thesis If heterogeneity of microcirculatory blood flow is a prominent characteristic in septic shock, not sensed by conventional systemic hemodynamic parameters, what are the consequences for the way doctors monitor the state and progression of the disease itself, as well as their therapeutic interventions? In chapter 1 a general introduction to this question is applied to the gut in sepsis. Before scientific comparison between observations of the microcirculation under specific experimental conditions can be performed, quantification of observed microcirculatory alterations is needed. Apart from the technical complexity to transform visual images into concrete numbers, the proposed system of quantification should specifically be sensitive to detect microcirculatory alterations under these heterogeneous flow conditions. In chapter 2 we describe a study that aims to validate both intra- and interobserver variability of a semiquantitative way for assessment of microcirculatory alterations in sepsis, in organs with different microvascular architecture. In chapter 3 the discordance between systemic hemodynamic parameters and (sublingual) microcirculatory alterations is illustrated with a case report, in which the blood pressure of a patient with a septic shock is successfully restored with the potent vasopressive agent terlipressin, at the expense of a complete shutdown of the microcirculation. 12

6 Given the fact that heterogeneity of blood flow can be observed within the microcirculation during sepsis, what does this imply for heterogeneity of flow between different organs and between different vascular compartments? In other words, is it conceivable that microcirculatory alterations in one particular organ may be different in a second organ at the same time? And will this relation be constant over time? In chapter 4 an observational study is described, in which microcirculatory alterations in human sepsis are observed in two organs, the tongue and the intestinal tract, at 2 different time points. In chapter 5 the results of a comparable study are reported; under human septic conditions the relation between parameters of the peripheral vascular compartment and the microcirculatory compartment is elaborated. An important issue up-to-date remains the specific meaning of the numerous observations that microcirculatory alterations occur under conditions of distributive- and other forms of shock. The absence of such alterations in several healthy control groups, its prognostic value in terms of morbidity and mortality in sepsis, as well as the relation with the occurrence of intracellular hypoxia and acidosis are strongly indicative for its relevance. However, this does not necessarily implicate that interventions to improve microvascular blood flow are beneficial to outcome of patients. The proof of the pudding is in the eating. In chapter 6 we describe the design and the results of a large single-centre double-blind randomised placebo controlled clinical trial, that aimed to improve microcirculatory flow in severe human sepsis with the organic nitrate nitroglycerin, in the setting of an initial strictly protocolised resuscitation. Distributive shock is not restricted to sepsis, but may also occur under other conditions such as ischemia-reperfusion, systemic inflammatory response syndrome and CABG-procedures [13, 22]. During on-pump cardiac surgery patients are subject to a number of hemodynamic changes, associated with intestinal hypoperfusion [23]. In an observational study (chapter 7) we combined postoperative direct observation of the rectal microcirculation by means of SDF-imaging with rectal tonometry, to test the hypothesis that splanchnic ischemia is associated with (persistant) splanchnic microcirculatory alterations. Chapter 8 aims to provide a state of the union with regard to development of the microcirculation as a clinical concept and gives an overview over recent literature. The thesis ends with a summary in English and Dutch. 13

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