Does monitoring the microcirculation make a difference in sepsis? Outcome?

36 Does Monitoring the Microcirculation Make a Difference in Sepsis? Outcome? Goksel Guven and Can Ince

INTRODUCTION The microcirculation is the final destination of the systemic circulation and is comprised of microvessels with a diameter of less than 20 µm consisting of arterioles, venules, and capillaries. A capillary is a microvessel between 5 and 8 µm in diameter. A red blood cell (RBC) is approximately 8 µm in diameter and deforms to enter a capillary to flow in single file formation. This feature distinguishes the capillaries from arterioles and venules where more than one RBC can exist side by side in the lumen. The capillaries flow into collecting venules where leukocyte adhesion, rolling and migration can occur in states of inflammation. Blood flow enters the capillaries from the arterioles. These vessels control blood flow by modulating tone in smooth muscle cells surrounding the endothelial cells lining the inner lumen.1 Under physiological conditions, the microcirculation contains about 10% of circulating blood and plays a vital role in oxygen transport to and carbon dioxide (CO2) removal from tissues. The microcirculation also plays a key role in inflammation, hemostasis, and substrate and hormonal transport. Finally, capillaries are the primary interface between the circulating blood and the parenchymal cells. For these reasons the microcirculation and its dysfunction plays a central role in critical illness and monitoring its function is essential to a comprehensive evaluation of the cardiovascular system.2

HEMODYNAMIC COHERENCE Conventional hemodynamic monitoring used in routine clinical practice is focused on the macrocirculatory parameters, such as systemic blood pressure, cardiac output and heart rate. It is often assumed that resuscitation of the macrocirculation also corrects microcirculatory abnormalities. Unfortunately, this assumption is often incorrect, and failure to address microcirculatory parameters can result in unrecognized underresuscitation. Indeed, a number of studies in the critically ill have shown that macrocirculatory improvement may occur independently of the microcirculatory blood flow.3 Inconsistency between microcirculation and macrocirculation has recently been defined as “loss of hemodynamic coherence” and has been shown to be an independent predictor of organ dysfunction and adverse outcome.4 The disassociation between the macrocirculation and microcirculation reflects both 256

differences in blood rheology and local metabolic, immunological, myogenic, endothelium-induced and neurovascular factors associated with critical illness.5 Additional mechanisms remain to be determined in order to understand the mechanisms underlying loss of hemodynamic coherence. In clinical practice, a loss of hemodynamic coherence can occur when microcirculatory resuscitation is accompanied by any one of four main types of microcirculatory alterations (Fig. 36.1). Type 1 alterations are associated with microcirculatory flow heterogeneity, where the stagnated flow in capillaries occurs next to fast-flowing RBCs. The result is functional shunting around underresuscitated microcirculatory units. Sepsis is the foremost example of Type 1 alterations. Type 2 alterations are characterized by a decrease in the number of RBCs in a capillary below a critical limit needed to adequately transport oxygen to tissues. An example would be hemodilution secondary to iatrogenic excess fluid therapy. Type 3 alterations are characterized by a state of microcirculatory stasis caused by venoconstriction from vasoactive medications or increased venous pressure, such as that seen in cardiac tamponade. In type 4 alterations, a reduction in the density of functional capillaries results in an increase in diffusion distance between capillaries and oxygen-requiring tissue cells. Type 4 alterations typically result from edema.4 Direct monitoring of alterations in microcirculatory blood flow and vascular density provides unique insight into the underlying pathophysiological mechanisms in patients with loss of hemodynamic coherence. Specifically, monitoring the microcirculation requires specific devices aimed at the bedside measurement of the functional microcirculatory parameters. Since the early 2000s increasing interest in tools for microcirculatory monitoring in both clinical and preclinical practice has led to the development of several imaging techniques that directly or indirectly measure perfusion, oxygenation, and anatomy, separately or in combination.6

OXYGEN TRANSPORT AND THE MICROCIRCULATION Oxygen transport from the capillaries to the mitochondria in cells is determined by RBC movement through the capillaries and diffusion of oxygen from the RBC into cells. RBC movement is complex because RBC supply to capillaries is heterogeneous, dependent on microcirculatory flow rate and local

CHAPTER 36 Venule

Type 1: Heterogeneity

Capilary

Mitochondria

Erythrocyte

257

Cell

qO2i = K*SRi*SiO2

Type 2: Hemodilution Flux = D*A*(pO2cap – pO2mit)/l

R

P

Type 3: Constriction/tamponade

Type 4: Edema

Fig. 36.1  ​Microcirculatory alterations associated with loss of hemodynamic coherence. States of loss of hemodynamic coherence where macrocirculatory resuscitation does not necessarily cause a parallel improvement in perfusion of the microcirculation. Type 1: Heterogeneous red blood cell (RBC) flow where flowing RBCs carry oxygen (gray RBC) and stagnant RBC (dark gray); correspondingly, tissue cells receive oxygen (gray tissue cells) or not (blue tissue cells). Type 2: A reduction in the oxygen-carrying capacity of the microcirculation due to hemodilution. Type 3: A stagnation in RBC flow in the microcirculation due to arterial vasoconstriction (increased vascular resistance, R) and/or raised venous pressures (P). Type 4: Increased oxygen diffusion distances due to edema. (Modified from Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care. 2015;19 (suppl 3):S8.)

variations in regional oxygen consumption. The variables effecting this process include the RBC supply rate (SRi) and the oxygen saturation in the individual capillary (SiO2). The diffusion of oxygen, in turn, can be estimated by Fick’s laws, and is proportionally associated with variables that include capillary surface area, and the difference in partial pressure of oxygen (pO2) between capillary and mitochondria. Diffusion is also inversely related to the distance from the capillary to the mitochondria (Fig. 36.2). RBC movement and diffusion make similar contributions to O2 transport.7 Deterioration in any of these parameters can be corrected by a change in microvascular hemodynamics. Therefore, monitoring these functional parameters in the microcirculation can be used to measure the main determinants of microcirculatory function.8

MONITORING THE MICROCIRCULATION Features of an ideal microcirculatory monitoring technique are detailed in Box 36.1. Structure and the target depth of the investigated tissue and monitored parameters are also important. Laser-based techniques provide a sense of tissue perfusion of large body surfaces and can penetrate into deeper layers of tissue. However, they are not quantitative and do not

Fig. 36.2  Diffusive and convective mechanism of tissue oxygenation. O2 flow rate in each capillary and diffusion of O2 into cell mitochondria are estimated by the equation [qO2i 5 K*SRi*SiO2] and [Flux 5 D*A*(pO2cap – pO2mit)/l], respectively. A, Capillary surface area; D, diffusion constant; K, single RBCs total O2 carrying capacity at 100% saturation (0.0362 pl O2/RBC); l, length; pO2cap, capillary O2 pressure; pO2mit, mitochondrial O2 pressure; qO2i, O2 flow rate of individual capillary; RBC, red blood cell; SiO2, SO2 in individual capillary; SRi, red blood cell supply rate.

BOX 36.1  Features of an Ideal

Microcirculatory Monitor.

Quantitative and accurate output Real-time functional information Safe, efficacious, affective, easy to use at point-of-care Cost-effective, noninvasive, noncontact Instant analysis of the images Data from Fasterholdt I, Krahn M, Kidholm K, et al. Review of early assessment models of innovative medical technologies. Health Policy 2017;121(8):870-879.

provide important functional parameters such as RBC velocity, vessel density, or capillary distribution. Conversely, handheld video-microscopes (HVMs) have become the gold standard for clinical microcirculatory imaging because they allow quantification of capillary density, flow heterogeneity, RBC velocity, and single RBC/white blood cell (WBC) imaging. The main limitations of HVMs are the small surfaces (max 0.5 mm penetration) that they can examine. Of these, the sublingual area is the most widely used. Microscopic observation of a vital tissue requires magnification and illumination. The latter can be accomplished by either trans- or epi-illumination. Trans-illumination, usually used in intravital microscopes in experimental settings, places the light source on the opposite side of the tissue under observation. Conversely, epi-illumination places the light source as well as the magnification lens on the same side of the tissue surface.

NAILFOLD CAPILLAROSCOPY Nailfold capillaroscopy is a noninvasive imaging technique used to visualize the superficial capillaries within a few millimeters depth of the nail fold. The microscope and magnification lens

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are combined with a digital video camera. Light backscattered from the tissue passes through a magnification lens to form an image that is projected onto the capturing camera system. Most often this technique visualizes capillary loops characteristic of the nailfold microcirculation. Nailfold capillaroscopy, when combined with other techniques and with micropipettes connected to micropressure devices, provides structural and functional information regarding RBC velocity and capillary pressure. Moreover, the use of fluorescein dye permits assessment of transcapillary diffusion. Nailfold capillaroscopy is often used in assessing patients with scleroderma, Reynaud’s phenomenon, and mixed connective tissue disease.9

as the difference between the highest and lowest MFI divided by mean MFI. It is particularly valuable in sepsis. RBC velocity is quantitatively calculated with HVMs via space time diagram (STD) analysis (Fig. 36.3). Unfortunately, very fast RBCs, where flow is defined as hyperdynamic, cannot be measured with STD. Moreover, RBCs should be tracked clearly inside the capillary in order to use STD analysis. STD cannot be created for all capillaries and therefore leads to bias.1 In addition to RBC-based calculations, recently, a new method has been validated using HVMs in monitoring leukocyte kinetics and function.17 The density of the vessels is estimated by the proportion of total vessels present in the field of view. The total vessel density (TVD) is calculated as the total length of vessels divided by the total surface area of the field of view as units mm/mm2. Perfused vessel density (PVD) is estimated as the proportion of perfused vessels divided by the TVD.1 Direct visualization of these parameters providing quantitative values is the main advantage of HVMs over other microcirculatory monitoring techniques. First generation HVM is based on orthogonal polarization spectral imaging (OPS, see later),18 second generation, side-stream dark field (SDF)19 and the third, incident dark field (IDF).20 HVMs have outperformed OPS imaging,21 and provided great insight into the microcirculatory basis of the pathophysiology of many disease states in medicine.22–24

HAND-HELD VIDEO-MICROSCOPES HVM techniques can be used to directly visualize the microcirculation of all organ surfaces. Because of its accessibility, the sublingual area is the most commonly used target of HVMs, although intraoperative examination of other organ surfaces is feasible.10–12 HVM analysis of the microcirculation with moving RBCs and WBCs provides unique and direct information regarding the functional activity of the microcirculation.13 Measurements include capillary RBC flow (mean flow index and proportion of perfused vessel) and the density of perfused capillaries (also referred to as functional capillary density). Blood flow in the microvessels indicates the quality of perfusion and is described as microvascular flow index (MFI).14 MFI, in turn, is determined by scoring the flow in each microvessel (3 5 continuous, 2 5 sluggish, 1 5 intermittent, 0 5 no flow) in each of four quadrants. Predominant flow type defines the MFI score per quadrant and the average of the four quadrants gives the total MFI score. An alternative MFI calculation option is to score all individual vessels and average their scores.15 The heterogeneity index16 is calculated

Orthogonal Polarization Spectral Technique In OPS imaging, the incident light is polarized and projected through a beam splitter to illuminate the tissue of interest. The penetrated light becomes depolarized after scattering several times within the tissue. The orthogonally polarized analyzer filters the reflected polarized light (surface reflection) allowing only the depolarized light to pass through to

X0 – X1

X0

X1

X1

A

B

X0 t0 – t1

C

Fig. 36.3  ​Space time diagram analysis. Incident dark field image of a sublingual microcirculation. (A) and (B) indicate the same microcirculation image from different time points (1/6 seconds). X0 defines the first localization of the red blood cell, and X1 defines the localization of the same red blood cell (RBC) in 1/6 seconds. (C) indicates how the red blood cell velocity is calculated by the space time diagram. t0 defines the first time point, t1 defines the last time point. The red blood cell velocity is calculated as the proportion of the distance in a defined time interval.

CHAPTER 36

259

Light source

Polarized light

Polarizer

Camera

Depolarized light

Beam splitter

Analyser

Skin

Fig. 36.4  ​Orthogonal polarized spectral technique.

the camera to generate an image of the microcirculation (Fig. 36.4). By using green light, which is absorbed by hemoglobin (Hb), the technique allows visualization of RBC movement. Thus the technique only visualizes functional blood vessels containing RBCs. A wavelength with 548 nm green light, which is equally absorbed by oxyhemoglobin and deoxyhemoglobin, generates images (black/gray dots) that are independent of Hb oxygenation. This technique can be combined with a hand-held device for bedside imaging in critically ill patients. The OPS technique has been validated with intravital fluorescence and conventional capillary microscopy.21,25 It has largely been replaced by SDF and IDF, which provide better image quality without requiring high power light sources. Thus, OPS is no longer commercially available.10,14,26

Camera

Lens Disposable cap Green LED Skin

Sidestream Dark-Field Technique The main difference between SDF and OPS lies in the use of dark field imaging via light-emitting diodes (LED) concentrically arranged around a 53 magnification lens located at the tip of the light guide (Fig. 36.5). This approach avoids reflections from the tissue surface, allowing examination of the microcirculation below the organ surface.20 RBCs can be visualized using green light with a 530 nm wavelength.19 The use of a rapid, synchronized LED pulse of green light partially eliminates image blurring caused by rapid RBC movement. Thus the SDF technique provides higher quality images and capillary contrast.19

Incident Dark Field Technique The IDF technique uses incident dark field illumination. High power illuminating LEDs with rapid pulse time (2 ms) provide appropriate tissue penetration and allow even more accurate cell tracking by further minimizing motion-induced blurring (Fig. 36.6). An advantage of IDF over OPS and SDF lies in the ability to capture fully digitalized images, eliminating the need to convert images from analog to digital.27 Secondly, IDF uses a novel stepping motor-assisted quantitative

Fig. 36.5  ​Sidestream dark field technique. LED, Light-emitting diode.

focusing mechanism to provide measurement of focal depth,28 also allowing multiple observations in the same subject without the need to refocus. Thirdly, reducing the weight of the camera from 320 g (SDF) – 500 g (OPS) to 120 g minimizes pressure artifact. Fourthly, the IDF device is integrated and controlled by a computer screen making data acquisition more reliable and controlled. Finally, the new IDF devices have incorporated microscope lenses instead of simple magnification lenses. In summary, improvement of the lens, the use of a high-resolution sensor, and an automatic, and a quantitative focusing mechanism resulted in an increase in contrast and sharpness compared with the

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Camera

Lens

regarding the use of HVM has led an expert panel to generate a comprehensive consensus article on the assessment of sublingual microcirculation in critically ill patients.2 In the future, the use of HVMs can be expected to provide clinicians caring for the critically ill with both an important technique for early diagnosis of circulatory inadequacies and a more physiologically-based approach to therapy.

Disposable cap Green LED Skin

Fig. 36.6  ​Incident dark field technique. LED, Light-emitting diode.

AUTHORS’ RECOMMENDATIONS • Direct visualization of microcirculatory alterations at the bedside is the ideal way of microcirculatory imaging. • Hand-held video-microscopes are appropriate for direct visualization of microcirculation. • Further developments of the equipment and techniques are required to overcome the main limitation of videomicroscopy. Pressure and movement artifact-free image and new fully automatic analysis software are promising approaches. • If combined with other monitoring techniques that permit estimation of capillary hematocrit and RBC hemoglobin saturation, evaluation of microcirculatory heterogeneity promises to provide valuable and comprehensive information about shock and resuscitation.

BOX 36.2  Limitations of Hand-Held

Video-Microscopes.

Movement artifact requiring subject to remain motionless Pressure artifact constricting microcirculation despite decreasing weight of device29 Off-line analysis required for quantitative output (being addressed by novel software)30 Training required to optimize scoring metrics15 1. illumination (optimal brightness and contrast) 2. duration (minimum 4 seconds per video) 3. focus (optimal image sharpness) 4. content (free of occlusion and vessel loops) 5. stability (adequate stabilization of the video without motion blur) 6. pressure.

SDF technique, which in turn, led to visualization of 30% more microvessels than SDF imaging.21

CLINICAL APPLICATION OF HAND-HELD VIDEO-MICROSCOPES HVM-based microcirculatory assessment represents a promising approach to facilitate the evolution of personalized medicine from randomized trials.31–33 The technique has proven to be helpful in the management of a number of different types of critically ill patients. Examples include guiding therapy of heart failure patients, timing of withdrawal of cardiac support devices and quantifying the impact of the therapeutic maneuvers on hemodynamics.24,34–36 In addition, monitoring of microcirculation has shown to be helpful in detection of hemodynamic coherence in patients with sepsis and septic shock.33,37,38 The accumulated clinical evidence

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26. Biberthaler P, Langer S, Luchting B, Khandoga A, Messmer K. In vivo assessment of colon microcirculation: comparison of the new OPS imaging technique with intravital microscopy. Eur J Med Res. 2001;6:525-534. 27. Aykut G, Veenstra G, Scorcella C, Ince C, Boerma C. CytocamIDF (incident dark field illumination) imaging for bedside monitoring of the microcirculation. Intensive Care Med Exp. 2015;3:40. 28. Weber MA, Diedrich CM, Ince C, Roovers JP. Focal depth measurements of the vaginal wall: a new method to noninvasively quantify vaginal wall thickness in the diagnosis and treatment of vaginal atrophy. Menopause. 2016;23:833-838. 29. Balestra GM, Bezemer R, Boerma EC, et al. Improvement of sidestream dark field imaging with an image acquisition stabilizer. BMC Med Imaging. 2010;10:15. 30. Arend S, Ince C, Assen M, et al. A software tool to quantify capillary hematocrit and microvascular hemodilution in sublingual incident dark field microscopy video clips. Critical Care. 2018;22(suppl 1):115. 31. Ince C. Personalized physiological medicine. Crit Care. 2017;21:308. 32. Legrand M, Ait-Oufella H, Ince C. Could resuscitation be based on microcirculation data? Yes. Intensive Care Med. 2018;44:944-946. 33. Lima A, Jansen TC, van Bommel J, Ince C, Bakker J. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med. 2009;37:934-938. 34. Erol-Yilmaz A, Atasever B, Mathura K, et al. Cardiac resynchronization improves microcirculation. J Card Fail. 2007;13:95-99. 35. Lauten A, Ferrari M, Goebel B, et al. Microvascular tissue perfusion is impaired in acutely decompensated heart failure and improves following standard treatment. Eur J Heart Fail. 2011;13:711-717. 36. Munsterman LD, Elbers PW, Ozdemir A, van Dongen EP, van Iterson M, Ince C. Withdrawing intra-aortic balloon pump support paradoxically improves microvascular flow. Crit Care. 2010;14:R161. 37. De Backer D, Donadello K, Sakr Y, et al. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med. 2013;41:791-799. 38. Edul VS, Enrico C, Laviolle B, Vazquez AR, Ince C, Dubin A. Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock. Crit Care Med. 2012;40:1443-1448.

e1 Abstract: The main function of the microcirculation is to supply the tissues with oxygen-rich blood and nutrients in physiological and pathophysiological states. The expectation during resuscitation procedures is that correction of systemic hemodynamic variables (e.g., blood pressure, cardiac output) results in a parallel improvement of microcirculatory parameters (tissue perfusion and oxygenation). This expectation which occurs under normal physiology is known as hemodynamic coherence. This hemodynamic coherence however can be lost in certain disease states associated with critical illness. There is increasing evidence that loss of the hemodynamic coherence between macro- and microcirculation

is associated with poor outcome, which raises the importance of microcirculatory imaging. Currently, several techniques exist for monitoring the microcirculation at the bedside. Hand-held microscopes applied to observe the sublingual microcirculation have provided important insights into its importance by enabling direct visualization of blood cells flowing within it. This chapter provides a general overview of direct microcirculatory monitoring techniques, highlighting their main working principles, advantages and limitations. Keywords: hemodynamic coherence; IDF imaging; microcirculation; OPS imaging; SDF imaging; shock