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EARLY MICROVASCULAR CHANGES IN SEPSIS AND SEVERE SEPSIS

Spanos, Angeliki*; Jhanji, Shaman*; Vivian-Smith, Amanda*; Harris, Tim; Pearse, Rupert M.*

doi: 10.1097/SHK.0b013e3181c6be04
Clinical Aspects
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Efforts to improve survival from sepsis are focusing increasingly on intervention during the earliest stages of this disease. The importance of derangements in microvascular flow in patients with established sepsis is well recognized. However, little data are available to describe microvascular changes in early sepsis. After research ethics committee approval, observational data were collected in healthy volunteers and within 6 h of presentation in patients with sepsis and severe sepsis. Sidestream dark-field imaging was used to obtain video images of the sublingual microcirculation. Cardiac index was measured using the noninvasive suprasternal Doppler method. Forty-eight patients and 16 healthy volunteers were recruited. Twenty-eight patients were diagnosed with sepsis and 19 with severe sepsis. Eight patients (17%) did not survive to leave hospital. For small vessels (<20 μm), microvascular flow index (P < 0.05), heterogeneity index (P < 0.05) and the proportion of perfused vessels (P < 0.05) were lower in patients with sepsis and severe sepsis compared with healthy volunteers. Perfused vessel density (P < 0.05) was lower in the severe sepsis group compared with the sepsis group. The proportion of perfused vessels (P < 0.01) and MAP (P < 0.05) were lower in nonsurvivors compared with survivors. Sepsis results in derangements of microvascular flow, which can be identified in the early stages of this disease. These abnormalities are more marked in the most severely ill patients. Further research is required to fully characterize the effects of sepsis on microvascular function.

*Barts & The London School of Medicine and Dentistry, Queen Mary's University of London; and Department of Emergency Medicine, Barts & The London NHS Trust, London, United Kingdom

Received 29 May 2009; first review completed 18 Jun 2009; accepted in final form 26 Aug 2009

Address reprint requests to Rupert M. Pearse, MD, Intensive Care Unit, Royal London Hospital, London E1 1BB, U.K. E-mail: rupert.pearse@bartsandthelondon.nhs.uk.

This study was supported by a European Union Leonardo Da Vinci Award. RPis a National Institute for Health Research (UK) Clinician Scientist.

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INTRODUCTION

Sepsis is a major cause of death and disability worldwide. It is estimated that 750,000 people develop sepsis each year in North America alone (1). In the UK, approximately 35,000 patients are admitted to the intensive care unit with sepsis each year, of whom 45% do not survive to leave hospital (2). Approximately one third of these patients are admitted directly from the emergency department (3, 4). Sepsis-related deaths result from multiorgan failure that generally develops in the early stages of the disease (5). There is increasing recognition that early therapeutic intervention is key to improving survival after sepsis. This has led to a particular emphasis on the cardiovascular management of the septic patient within the first few hours of hospital admission (6).

Sepsis-related cardiovascular changes are complex and include vasodilatation, hypovolemia, and myocardial depression (7-9). Sepsis also results in important derangements of the microcirculation, which are associated with organ failure and death (10). Such effects include increased endothelial permeability (11, 12), endothelial-leukocyte adhesion (13), and a characteristic heterogeneity of blood flow that is associated with tissue hypoxia (14, 15). Several investigations have identified abnormalities of microvascular flow in patients with established severe sepsis. However, understanding of the natural history of microvascular dysfunction remains incomplete. Recent investigations by Trzeciak et al. (16, 17) have identified abnormalities in sublingual microvascular flow in patients soon after the commencement of early goal-directed hemodynamic therapy. These data illustrate the significance of early impairments in microvascular flow and suggest potentially beneficial effects of hemodynamic resuscitation on such abnormalities. However, these data only describe microvascular changes in severely ill septic patients receiving a specific form of hemodynamic resuscitation. Because of the considerable interest in interventions that may improve microvascular function (18-22), there is a need to further describe patterns of microvascular flow in a wider group of septic patients at the earliest stages after presentation. The aim of this study was to evaluate the sublingual microcirculation of patients with sepsis and severe sepsis within 6 h of hospital admission and compare these data with that of healthy volunteers.

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MATERIALS AND METHODS

This single-center, observational study was approved by the local research ethics committee. Adult patients within 6 h of admission to the Emergency Department at The Royal London Hospital with confirmed or strongly suspected sepsis were eligible for recruitment (23). In addition, adult hospital in-patients within 6 h of identification of the onset of sepsis were also eligible for inclusion. Written informed consent was sought from patients with capacity. Where a patient did not have capacity to give or withhold consent, a relative or healthcare practitioner was approached to provide assent. Retrospective consent for data use was sought once capacity was regained. There were no exclusion criteria except refusal of patient consent or relatives' assent. Treatment in the emergency department was guided by local policies. Patients subsequently admitted to the intensive care unit received treatment in accordance with the Surviving Sepsis guidelines current at that time (24). All treatment decisions were made by the attending physician.

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Measurements

In addition to routine hemodynamic data, sublingual microvascular flow and cardiac output were measured using noninvasive technology. Sublingual microvascular flow was evaluated using sidestream dark-field (SDF) imaging with a 5× objective lens (Microscan, Microvision Medical, Amsterdam, Netherlands) (25). Image acquisition and subsequent analysis were performed according to published consensus criteria as described in detail elsewhere (26, 27). In brief, SDF images were obtained from at least three sublingual areas. Microvascular flow index (MFI) was calculated after dividing each image into four equal quadrants. Quantification of flow for small (<20 μm) and large (>20 μm) vessels was performed using an ordinal scale (0, no flow; 1, intermittent flow; 2, sluggish flow; 3, normal flow). Microvascular flow index is the average score of all quadrants for a given category of vessel size at a given time point. Images were recorded at three sites at each time point, giving a total of 12 quadrants for analysis. To determine heterogeneity of flow across sublingual sites, we calculated the heterogeneity index as the highest MFI minus the lowest MFI divided by the mean MFI across all sublingual sites at that time point. Vessel density was calculated by inserting a grid of three equidistant horizontal and three equidistant vertical lines over the image. Vessel density is equal to the number of vessels crossing these lines divided by their total length. Flow was then categorized as present, intermittent, or absent, allowing calculation of the proportion of perfused vessels and perfused vessel density. Analysis of the videos was performed by two blinded observers (A.S. and A.V.S.). Cardiac output was measured using the suprasternal Doppler technique (USCOM Ltd., Sydney, New South Wales, Australia) (28). Patients were followed up for 28-day in-hospital mortality.

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Statistical analysis

There was no formal sample size calculation. Instead, we planned to recruit 20 patients with sepsis, severe sepsis, and septic shock, as well as 20 healthy volunteers. Normally distributed data were tested with unpaired t tests or one-way ANOVA with post hoc Bonferroni multiple comparison tests as appropriate. The Mann-Whitney U test or Kruskal-Wallis test with post hoc Dunn tests were used when data were not normally distributed. Data are presented as mean (SD) where normally distributed or median (interquartile range [IQR]) where not normally distributed. Normality was tested with the D'Agostino-Pearson test. Significance was set at P < 0.05. Analysis was performed using GraphPad Prism version 5.0 (GraphPad Software, San Diego, Calif).

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RESULTS

A total of 48 patients and 16 healthy volunteers were recruited between September 2007 and April 2008. The healthy volunteers had a median age of 39 (36-43) years, and eight (50%) were men. Septic patients had a median age of 50 (30-70) years, and 24 (50%) were men. Baseline patient data are presented in Table 1. Four hospital in-patients who had developed severe sepsis during hospital admission were recruited. The remaining 44 patients were recruited in the emergency department. The median time from arrival at the emergency department to recruitment was 159 (104-218) min. Nineteen patients were classified as having severe sepsis on the following basis: fluid resuscitation required to treat hypotension (n = 9), persistent hypotension despite fluid resuscitation (n = 7), and serum lactate greater than 4 mM (n = 3). The remaining 29 patients were classified as having uncomplicated sepsis. Eight patients were admitted to critical care within 24 h of enrolment. At the time of admission to critical care, four of these patients required invasive ventilation, and five required vasopressor or inotropic therapy. None of these patients required renal replacement therapy. Sublingual microvascular flow and hemodynamic data were collected in all patients. Two patients were receiving vasopressor therapy at the time measurements were taken. There were no significant differences in microvascular flow between these patients and the rest of the cohort. Thirty patients had received intravenous fluid before measurements (volume infused, 1,000 mL [500-1,750 mL]). The intravenous fluids used were 0.9% sodium chloride, compound sodium lactate solution, or a gelatin colloid solution (Gelofusine; B Braun, Melsungen, Germany). For large vessels (>20 μm), MFI was 3.0 (2.9-3.0), and the proportion of perfused vessels was 100% (100-100) in all patients. The κ coefficient with linear weighting for interobserver variability for calculation of MFI was 0.76 (0.68-0.84). The interobserver coefficient of variability for vessel density was 5.9%.

Table 1

Table 1

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Comparison with healthy volunteers

For small vessels (<20 μm), MFI, heterogeneity index, and the proportion of perfused vessels were significantly reduced in both groups compared with healthy volunteers (Table 2; Fig. 1). Significant reductions in perfused vessel density were identified in the severe sepsis group but not in the sepsis group when compared with healthy volunteers. Heart rate was significantly greater in all patients, and MAP was reduced in the severe sepsis group.

Table 2

Table 2

Fig. 1

Fig. 1

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Comparison between patients with sepsis and severe sepsis

Abnormalities of MFI and perfused vessel density for small vessels (<20 μm) were more marked in the severe sepsis group compared with the sepsis group (Table 2). There was no difference in cardiac index between the sepsis and severe sepsis groups. MAP was lower, and serum lactate was greater in the severe sepsis group.

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Comparison between survivors and nonsurvivors

The proportion of perfused vessels was significantly reduced in those patients who did not survive to leave hospital (Fig. 2). In nonsurvivors, MAP was lower and heart rate was greater. There was also a trend toward higher serum lactate concentration (P = 0.05) in nonsurvivors (Table 3).

Table 3

Table 3

Fig. 2

Fig. 2

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DISCUSSION

The principal finding of this study was that there were significant derangements in sublingual microvascular flow in patients early after the diagnosis of sepsis, which were more marked in the most severely ill patients. However, these abnormalities were less severe than those previously described in patients with established severe sepsis (9, 20). These findings confirm that the characteristic abnormalities of microvascular flow in established sepsis are already present in the earliest stages of the disease. Clinical interventions to improve microvascular flow should be considered at hospital presentation.

Previous investigations have characterized changes in sublingual microvascular flow in patients with established severe sepsis and demonstrated that persistent microvascular derangements are associated with poor outcome (9, 10). This work has led to interest in the effects of various therapeutic interventions on microvascular flow (18-22, 29). However, only one group has investigated microvascular derangements in patients with early sepsis (16, 17). In keeping with our findings, the investigators described derangements of sublingual microvascular flow that were more severe in nonsurvivors (16) and improved after goal-directed hemodynamic therapy guided by central venous oxygen saturation (17). It is important to note that most patients recruited in these studies were hospital in-patients (62% and 48%, respectively) representing a different population to those presenting with sepsis in the emergency department. In the current study, 92% of patients were recruited in the emergency department. This difference may explain the differences in the severity of abnormalities of microvascular flow. It remains uncertain to what extent sublingual microvascular flow correlates with that in other vascular beds (30, 31).

Sublingual SDF imaging is a valuable technique, which allows visualization of the intact microcirculation in the clinical environment. Whereas several studies have demonstrated improvements in sublingual microvascular flow associated with specific clinical interventions (19-21), at present, there are no published data describing the use of this technique to guide clinical interventions. In a small number of individual cases, R.P. has found it helpful to use sublingual SDF imaging as part of the clinical assessment of complex critically ill patients. However, at present, this technique remains primarily a research tool, and until further research establishes a clear role for routine clinical use, the authors would urge caution in this approach. Existing scoring systems for SDF image analysis remain semiquantitative (27), and data reliability may be affected by technical expertise and interobserver bias. We specifically evaluated these factors, and our data indicate that they did not result in a significant degree of bias. All patients were recruited by A.S., who recorded detailed clinical notes as well as collecting hemodynamic and microvascular data. At the end of the study, S.J. and R.P. reviewed these notes in a blinded fashion to confirm the diagnostic category. This review, which resulted in reclassification of 13 patients, may have introduced bias and reduced the number of significant findings. Although we identified a pattern of global hemodynamic and microvascular changes that was consistent with our expectations, some comparisons between groups did not achieve statistical significance because of the small number of patients recruited. A much larger investigation would be required to confirm the frequency and severity of early sepsis-related abnormalities of microvascular flow. Patients in the severe sepsis group were significantly older than those in the sepsis group. Age may be associated with depletion of microvessels and may therefore represent a confounding factor (32).

In conclusion, our findings confirm that the abnormalities of sublingual microvascular flow characteristic of established sepsis are already present in the earliest stages of the disease. These abnormalities are greatest in more severely ill patients. Further research is needed to confirm these findings in a larger population and to investigate the efficacy of therapeutic strategies that maintain and improve microvascular flow.

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Keywords:

Sepsis; microcirculation

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