The Microcirculation in Sepsis

Introduction

Sepsis and its progression to severe sepsis, sep­tic shock and multiple organ dysfunction syndrome is a major cause of ICU admissions and mortality [1] . Severe sepsis and septic shock may be characterized by a derangement in global cardiac indices typically leading to low peripheral resistance, which the body tries to
compensate for by increasing the cardiac output. How­ever, despite this increase in cardiac output, the tissues are unable to utilize oxygen as evidenced by the high lactate levels, deranged acid-base balance, and in­creased gastric carbondioxide level. The presence of tissue hypoxia despite adequate systemic oxygen trans­port has been blamed on altered microhaemodynamics as well as in itochondrial dysfunction during sepsis [2] . However, the relative contributions
of disturbed micro-circulation and impaired mitochondrial function for sep­sis related tissue dysoxia are still debatable. The present review aims to highlight the former cause of tissue hy­poxia in sepsis i.e., involvement of the microcircula­tion. It moves from recapitulating relevant anatomy of microcirculation, to its current role in pathophysiology of sepsis, optimization during sepsis and lastly the mo­dalities for its assessment.

Functional anatomy of microcirculation

Anatomically, the in consists ofthe arterioles, terminal arterioles, capillaries, and post-cap­illary and collecting venules [3] . Rather than dwell on different vessels of the microcirculation as per their ana­tomical designations, it is clinically more relevant to di­vide the microvascular bed functionally into resistance, exchange and capacitance vessels.

Resistance vessels (Arterioles). Arteriole (<100­-200 µm in diameter) is the final branch ofthe arterial system and marks the beginning ofmicrocirculation. The arteriole and proximal part of its successor - terminal arteriole, are heavily infested with smooth muscle cells making them the mainstay of control ling the resistance in the microcirculation, by having the ability to change their caliber
due to presence of smooth muscle cells. Terminal arteriole is the last division ofarteriolar net­work and terminates into a capillary network without anastomosis with any other arterial or venous vessel.

Exchange vessels (Capillaries). Capillaries are essentially tubes lined by a single layer ofendothelium, containing no smooth muscle cells and thus being un­able to change their diameter actively. The structure is specialized to maintain their primary function as ex­change vessels. Endothelium lining the capillaries varies from being non-fenestrated to fenestrated or dis­continuous, in different
organs according to their meta­bolic requirements. There are over 10 billion capillar­ies (5-9µm) in the body. Capillary density refers to the number of capillaries present in a given area or volume of tissue. The body can cope up with increased meta­bolic demands by "capillary recruitment" i.e., increas­ing the proportion orperfused capillaries. The intrinsic ability for capillary recruitment also serves to decrease the total resistance, since capillary vessels are arranged in parallel rather than in series. This latter advantage of capillary recruitment is however offset by the rather small contribution of capillaries to resistance as com­pared to that offered by the arterioles. The more ben­eficial effect o leap illary recruitment is the increase in the exchange-vessel surface area exposed to flowing blood, enabling significant increase in the exchange of metabolites and gases. Recruitment primarily occurs by opening whole bundles orcapillaries, while the perfu­sion olconnections between already open vessels only plays a minor role. When two capillaries converge, a post-capillary venule is formed. Though slightly larger than a capillary (15-20 µm) it also lacks smooth muscles, and is unable to
regulate its caliber. Most of the ex­change of fluid, nutrients and end products occurs in this part of circulation and hence capillaries and non-muscular venules are termed as exchange vessels.Capacitance vessels (Venules). Venules with di­ameter greater than 30 µm start
acquiring smooth muscles cells. These muscular venules and veins are termed capacitance vessels' since they hold almost 70% ofthe total circulating blood volume while having negligible contribution to resistance.

Characteristics of microcirculation: The micro-circulation is endowed with certain peculiar characteris­tics. First and foremost, the microcirculation is heterog­enous with regard to rheologic and resistive properties in various organs and within the organ itself [4] . Heteroge­neity of flow helps to supply adequate oxygen to tis­sues based on their metabolic demands. However, it also leads to
microcirculatory units with unfavourable rheologic and/or resistive properties, making themweaker and thus more vulnerable to damage by hy­poxia as encountered during sepsis. Secondly, in al­most all vascular beds, there is a longitudinal and radial oxygen gradient such that the capillary pO 2 and hae­moglobin saturation are significantly lower than arterial values [5] . This results from oxygen unloading from arte­rial network to tissues, and the intrinsic oxygen con­sumption ofvessel wall to sustain endothelial functions and vascular tone. These properties again make the exchange segment more prone to hypoxic damage. The microvascular haematocrit is lower than the systemic haematocrit, and is also heterogenously distributed [6] . This decrease is due to the Fahreus effect that induces axial migration of erythrocytes near the centre of ves­sels, resulting in differential erythrocyte and plasma ve­locities, and a dynamic decrease in intravascular haematocrit. The end result of all the above character­istics is a heterogeneity of blood flow and oxygen de­livery in the microcirculation, resulting in vulnerable units prone to hypoxic damage.

Importance of the microcirculatory endothe­lium: The major cell types constituting the microcircu­lation include endothelial cells lining inside of the microvessels,smooth muscle cells present mostly in the arterioles, and components or blood i.e., erythrocytes, leucocytes, and plasma components. The endothelial cell surface in the microcirculation is the lamest endot­helial surface of the body -
the largest 'organ' in the human body. The total endothelial surface area is ap­proximately 4000 to 7000 m 2 with most ofthe elements being within the microcirculation [7] .

By virtue of its anatomical location i.e., being a divide between the flowing blood within and the extra-cellular space beyond, the endothelium forms an inter­face between inflammation and coagulation [8] . It thus mediates and controls trans-endothelial exchanges be­tween blood plasma and interstitial fluid, regulates the vasomotor tone by releasing vasodilating and vasoconstricting substances, maintains an anticoagulant state, and regulates transmigration of
leukocytes into surrounding tissues.The endothelium also plays a central role in regu­lation of microcirculatoiy perfusion[9] by sensing flow, metabolic, and other regulating substances to alter
ar­teriolar tone and capillary recruitment. Importantly, this endothelial sensing is capable of detecting downstream haemodynamic conditions e.g., lactate levels, and trans­mitting information upstream by cell to cell signaling, to adjust the perfusion accordingly.

Pathophvsiology of microcirculation in sepsis

The inflammatory mediators that herald sepsis, and the changes they induce in the macrohaemodynamics i.e., blood pressure, heart rate and oxygen extraction are well known. The ensuing section highlights the changes induced in the microcirculation by sepsis.Five to fifteen minutes after its (endotoxin) intra­venous administration, there
were strong waves oicon­traction along the small arteries, arterioles, and metaarterioles. These could arrest flow and last for sev­eral minutes. There Would afterwards be a phase of dilation, followed by a strong contraction. As time went on, the phases of relaxation became more prominent until preagonally there was a general and permanent vasodilation. The circulation would slow progressively until death."

This early description[10] of response of microvessels to endotoxin in guinea pig and mouse mesentery demonstrates the immediate arteriolar vaso­constriction response to endotoxin followed by the sub­sequent phases of changing microvascular tone and ul­timate cardiovascular collapse.
The release of endotoxin or proinflammatory cytokines initiates a cascade of cellular and mediator changes in sepsis[11]. The cornerstone of impaired ho­meostasis in sepsis is an inflamed microcirculation. It is clogged with microthrombi and leaks extensively and the central role in this microcirculatory
dysfunction is in turn played by the endothelium[12]. It is damage to the endothelium that turns the usual water tight blood ves­sels into sieves allowing large amounts of protein rich fluid to leak into the subcutaneous tissues, causing ex­tensive tissue oedema and intravenous dehydration. Activation ofthe coagulation cascade leading to intra­vascular thrombosis is also a result of the damaged
endothelium that starts liberating progoabulant factors. Besides these
alterations, the endothelium also fails to perform its regulatory functions, and its nitric oxide (NO) system is severely disturbed. There is a heterog­enous expression of inducible nitric oxide synthase (iNOS) in the endothelium of different areas of organ beds. Areas that lack iNOS have less NO induced vasodilation and become underperfused resulting in pathological shunting of blood flow[13],[14].

The endothelium is not the only component of microcirculation to be altered. All other cellular com­ponents oithe microcirculation also undergo deterio­ration during sepsis. Smooth muscle cells lining the arterioles loose their adrenergic sensitivity and tone[15],[16]. The red blood cells become more rigid thus increasing the blood viscosity[17]. The percentage of activated neu­trophils with decreased deformability and increased agreeability, due to upregulation of
adhesion molecules also increases.Recently, endothelial glycocalyx has also been shown to be involved in sepsis induced microcircula­tory dysfunction[18]• The glycocalyx is a layer covering the endothelium and consists of endothelial cell derived proteoglycans, hyal uronan
glycosam inoglycans, and selectively adsorbed plasma proteins [19],[20],[21] . It is the first interface between blood and tissue, and is involved in physiological processes such as maintenance of vascu­lar tone, mechanotransduction, and transport along vessels [20],[21] . Its thickness regulates the organ blood flow and red blood cell velocity [22],[23],[24] . It has been suggested that glycocalyx
destruction occurs during endotoxemia, and this may participate in causing microvascular per­fusion deficit[18].

The aforesaid cellular alterations in the in icrocir­culation lead to impairment of all three functional ele­ments of the microvascular network. The arterioles are hyporesponsive to vasoconstrictors and vasodilators despite the elevated levels of catecholamines[25], perfused capillaries are reduced in number, and venu les are
obstructed by the sequestered neutrophi ls. In the capillaries, besides a decreased density, there also oc­curs increased heterogeneity and an increase in the pro­portion ofstopped and intermittently perfused capillar­ies[26],[27],[28], [29],[30]. This shut-down ofthe vulnerable microcircula­tory units in the organ
beds promotes the shunting of blood and hence oxygen, from arterial to venous com ­partment leaving the microcirculation hypoxic, along with a decrease in oxygen extraction. The local micro-circulatory partial pressure ofoxygen drops below the venous oxygen pressure. This dillerence has been termed the "pO 2 gap" and is an indicator ofthe severity offunc­tional shunting[9]. The systemic manifestation of
this pathologic shunting is seen as a deficit ofoxygen ex­traction by tissues with an apparently normal delivery, and raised venous pO 2 , lactate, and gastric CO 2, lev­els. In addition, the blood flow regulation of microcirculation is severely disrupted.

Microcirculatory perfusion as an endpoint
Much ofthe research pertaining to resuscitation during sepsis has focused on restoring the macrodynamics ofcirculation such as blood pressure, oxygen delivery and oxygen extraction ratio. The patho­logic shunting occurring in the microcirculation is not depicted by systemic haemodynamic derived and oxy­gen derived variables. The difference between macrocirculation and microcirculation was recognized very early on [10] when it was pointed that changes in total peripheral resistance could not provide informa­tion regarding local vascular
resistance changes since "dilation in one vascular bed may be accompanied by constriction elsewhere". Also, the cause of alterations in the macrohaemodynamics lies in the microcircula­tion e.g., the decrease in systemic vascular resistance and hypotension result from arteriolar vasodilatation and hypovolemia from capillary leak. Thus, it needs to be answered whether resuscitating the microcirculation rather than the macrocirculation will finally answer the quest
for improving survival in sepsis.
There is previous evidence that resuscitating the macrohaemodynamics is not always associated with improved microhaemodynamics, organ function, or survival [31], [32],[33],[34],[35] . A study by LeDoux and colleagues [35] ob­served the effect of norepinephrine on global haemodynamic parameters and measures oftissue oxy­genation during septic shock. While the mean blood pressure increased from 65 to
85 mmHg along with expected increase in heart rate and cardiac index (p<0.05), there was no improvement in organ Iiinction or tissue oxygenation as evidenced by decrease in urine output, no change in capillary red blood cell velocity, fall in capillary blood flow and increase in gastric pCO 3 . The authors thus concluded that resuscitation ofmean blood pressure or cardiac output alone in septic shock is inadequate. Microcirculatory independence from ar­terial blood pressure in septic shock has also been proven using direct imaging of microcirculation [33], [34] . DeBacker et al [33] reported a significant decrease in ves­sel density and proportion ofsmall perfused vessels in septic patients, the alterations being more
severe in non-survivors and were not related to the mean arterial pres­sure. Sakr and colleagues [34] further explored these find­ings by studying the microcirculation in 49 septic pa­tients. The small vessel perfusion was seen to improve rapidly in survivors as compared to non-survivors, with no difference in the global haemodynamic variables. Together with the evidence showing that organ
func­tion improves and mortality decreases when resuscita­tion boosts
microcirculatory flow [36] , the microcircula­tion does appear to be a new target for resuscitation during sepsis [6] .

Therapies for optimizing microcirculation

Even though several experimental data are avail­able regarding effect of various therapeutic interven­tions on microcirculation, human data is still limited [37] .The ideal modality to resuscitate the microcirculation and the endpoints to be achieved still remain to be de­fined. Against this background, the following section explores the suggested modalities for microcirculatory therapy.
The commonly practiced combination therapy developed by Rivers and colleagues [38] in their protocol of "early goal directed therapy" involves achieving macrohaemodynamic end-points i.e., central venous pressure of mmHg, addition olvasopressor to maintain mean arterial pressure ≥65 mmHg, measure­ment of central venous oxygen saturation, red cell transfusion, and/or inotropic agents to increase central venous oxygen saturation to 70%. It has also however, been shown
to improve the microcirculatory flow, or­gan function and ultimately the survival.

Intravascular resuscitation. Both crystalloid and colloid infusions recruit vessels, and improve barrier function and oxygen transport in the microcirculation[39],[40],[41],[42],[43]. Although prospective studies regarding the choice of fluid for resuscitation in patients with septic shock are lacking, a large prospective, controlled, random­ized, double-blind study comparing 4 percent human albumin solution with 0.9 percent sodium chloride in critically ill patients
requiring fluid resuscitation (the Saline vs. Albumin Fluid Evaluation (SAFE) study) has re­cently been published[44]. The results ofthis study show identical mortality rate in patients receiving albumin or 0.9 percent sodium chloride. However, subgroup analysis reveals that albumin might have some (albeit not statistically significant) benefit in patients with se­vere sepsis.Blood is a better oxygen carrier and hence im­proves oxygen delivery to microcirculation more than with either crystalloid or colloid. Certain data however suggests that erythrocyte transfusion may not improve the microcirculatory
perfusion due to the 2-3-DPG depletion, poor erythrocyte deformability, and eryth­rocyte interaction with endothelium and other blood cells[6]. Given the variable effects of erythrocyte transfusion it is emphasized that use of erythrocyte transfusion needs to be analyzed according to the baseline haematocrit, while also keeping in mind the storage time and presence or absence of residual leukocytes in trans­fused products.

Nitric Oxide Synthase (NOS) inhibitors. The concept of NO inhibition therapy for sepsis is debatable at present[45], with the role of NO itself being equivo­cal with respect to its effect on microcirculation [46] . Im­provement in microvascular blood flow has been shown with both, NO donors [47] , and iNOS inhibitors[48],[49].

In sepsis, overproduction of NO from endothe­lial cells through the upregulation of iNOS has been associated with impaired vascular reactivity, capillary leak, erythrocyte deformiability and refractoryhypoten­sion [50] . This is also known to inhibit mitochondrial res­piration, reversibly or irreversibly, depending on
the duration of NO exposure and the mitochondrial com­plex inhibited[51],[52], [53],[54].

Early data in septic shock patients treated with NOS inhibitors showed increasing blood pressure and decreasing dose of vasopressors[55]. However, a sub­sequent randomized controlled multicenter phase III trial had to he stopped when interim analysis showed in­creased mortality with the NO synthase inhibitor 546C88 [56] .Other authors have also noted raised mor­tality despite an improvement in the
general haemodynamic parameters with usage of NOS inhibitors[57],[58] .Certain authors also suggest that completely in­hibiting vasodilation is not the appropriate answer to sepsis. A more specific approach by inhibiting the in­ducible form of NOS has been studied. Following the application of 1400W (a synthetic blocker of inducible NOS) in a pig endotoxemia model, microvascular per­fusion was restored by a redistribution within the gut wall and/or an amelioration ofthe cellular respiration[59].

A new perspective in the debate regarding the role of iNOS/NO in septic shock has recently been put for­ward by the study of Batem an and colleagues [45] . The authors noted that timing as well as degree of iNOS/ NO inhibition may be an important determinant in al­tering prognosis in septic shock. They found increased oxygen consumption by inhibiting iNOS/NO overpro­duction at the onset ofhypotensive sepsis. In contrast to earlier trials, the therapy was initiated very early in sepsis and no attempt was made to normalize the mean arterial
pressure, rather the aim was to maintain the NO level at baseline value.In recent animal studies it has been observed that combination of fluid therapy with iNOS inhibition was successful in recruiting vulnerable microcirculation in the intestine, while fluid therapy alone was unable to do so[41],[59] .

Steroids. Use of steroids in sepsis represents a non-specific approach towards modulation ofthe sys­temic inflammatory response, and inhibition of iNOS. However, this is a time dependent phenomenon since sepsis evokes NO induced inhibition of glucocorticoid receptor. Following the recent large, European multicenter trial [60] which failed to show any mortality benefit with steroids in septic shock, never recommen­dations [61] suggest that only adult septic shock patients in whom blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy should receive steroid therapy. For improvement of autoregulation of microcirculation, relatively higher doses are required and thus not recommended for clinical use in sepsis. These recommendations have dampened the earlier enthusiasm created by the study of Annane et al [62] re­garding the use of steroids in septic shock. The authors had found adrenal insufficiency in greater than 50% patients of septic shock and these patients had re­sponded well to low dose hydrocortisone therapy.

Statins. The role of statins in sepsis has been re­viewed in great detail elsewhere [63] . Statins are widely used as cholesterol-lowering agents but appear to have an anti-inflammatory action during sepsis. The primary mechanism of their action in sepsis is by increasing ex­pression of eNOS (endothelial nitric oxide synthase - constitutive enzyme), along with a down-regulation of iNOS. Together,
this increases NO levels, restoring the endothelial functions. Other beneficial effects of statins in sepsis may also include its antioxidant activity and alterations in development of vascular atherosclerosis [63] . The future promise of statins in sepsis is a subject of great interest and current research [64],[65].

Vasodilators. As per the shunting theory of sep­sis, correction of the condition should occur by recruit­ment of the shunted microcirculatory units. Applying strategies to `open the microcirculation' by vasodila­tion is thus expected to promote microcirculatory flow by increasing the driving pressure at the entrance of the microcirculation and/or decreasing the capillary afterload [66] . In the very early stages of sepsis although eNOS decreases causing impaired endothelium- depen­dent vasodilation, the iNOS release contributing to hy­potension may take several hours [67] . Thus, an early ad­ministration of a NO donor may be beneficial to pre­serve tissue perfusion. In a recent trial by Assadi et al [68] the use of sodium nitroprusside (SNP), a NO donor, during early severe sepsis was observed to improve the hepatosplanchnic microcirculatoiy blood flow. Re­cruitment
of microcirculation by vasodilator therapy in the form of NO donors [41] , nitroglycerin [47] , prostacyclin [69] and even topical acetylcholine [33] has been found to be effective for microcirculatory recruitment. Pending how­ever, is the usefulness of these approaches in clinical course [37].

Vasopressors/Inotropes. Commonly recom­mended vasopressors/inotropes in sepsis include dopamine, norepinephrine, epinephrine and dobutamine. While these are potent for correcting sys­temic haemodynamics, their use should be viewed with caution for intent of improving microcirculation. Their detrimental effects on regional perfusion are well de­scribed [70],[71],[72] . Dobutamine can improve but not fully re­verse microcirculatoiy alterations in patients with sep­tic shock[73] . Vasopressin, a more recently investigated vasopressor in sepsis, has been shown to increase urine output while raising the blood pressure [74],[75] , but it has also been seen to cause microcirculatory shutdown [76] . It appears that further studies are required to deter­mine the best vasopressor for microcirculatory septic shock [36] .

Cinhinution therapy. Combination of fluid therapy with vasoactive and inotropic support is effective in restoring the microcirculation [77] . Non-respond­ers to this therapy have a poor prognosis. A seemingly contradictory combination of NO donor and iNOS in­hibitor may also prove to be successful in recruitment of microcirculatio [77] .

Activated Protein C (APC). Protein C, a com­ponent of the natural anticoagulation system, is an antithrombotic serine protease that is activated to APC in the body by thrombin thrombomodulin complex. Deficiency of APC has been shown to increase mor­bidity and mortality in patients of sepsis and septic shock [78],[79] . Therapy withA PC aims directly at the pivot ofsepsis, the endothelium, by a multimodal mechanism possessing anti-inflammatory properties independent of its
anti-coagulation properties. It inhibits iNOS expres­sion [80] , decreases level of TNF á[81] , reduces leucocyte activation and release of - reactive oxygen species, im­proves capillary density [82] , and acts on coagulatory pathways[83] by inhibiting factors Va and VIIIa, as well as by promoting fibrinolysis. The only adverse effect to be considered was the risk of bleeding. Despite the en­couraging
report of successful use of APC [84] ,the most recent guidelines however, limit its use only to very sick patients of sepsis [61] . Lehmann et al [85] have published a very elegant study regarding the effect of - APC on the microcirculation and cytokine release, during experi­mental endotoxemia in rats.
The authors observed APC to attenuate deterioration ofmicrovascular blood flow by decreasing leucocyte adherence, plasma extrava­sation and a decrease in systemic cytokine IL-Iâ. These findings are consistent with those of earlier trials re­garding, effect of APC on m icrocirculation [82],[86],[87] . APC also decreases the oxidative stress and glycocalyx de­struction during endotoxemia [18] .

Other pharmacologic interventions. Arachi­donic acid metabolites are powerful lipid mediators playing a key role in microcirculatory failure. They in­crease interleukin- 1 release by macrophages in sepsis. It has been demonstrated that pharmacologic inhibition of leukotrienes [88],[89] and thromboxane A2 [90] , and usage of thromboxane receptor antagonists is beneficial dur­ing sepsis. On the
other hand, prostaglandin El infu­sion for 7 days improved survival and decreased organ failure in patients of ARDS [9] .

Preliminary animal data has shown benefits of cholinesterase inhibition with physostigmine or neostig­m ine in survival during sepsis [92] . The probable mecha­nism of action is the activation ofthe cholinergic anti-inflammatory pathway [93] . However, there is no data re­garding its effect on the microcirculation as yet.

Levosimendan is a never vasoactive drug that acts by Ca +2 sensitization in the myocardium and the open­ing of the K ATP , channels in vascular smooth muscle cells. It has been shown to improve the cardiac dysfunction ofsepsis at the "macro" level, and also improve the tissue pO 2 without much alterations in the microcircu­lation [94] .

Assessment of microcirculation

Till date, there is no single objective gold stan­dard to assess the
microcirculation. In clinical practice, microcirculatory perfusion has been traditionally judged by the color, capillary refill and temperature of the dis­tal parts of the body (i.e., finger, toes, earlobes and nose). Amongst the investigational modalities available to assess microcirculation, both indirect indicators as well as direct techniques exist [6] , even though any single objective reliable method is still not recognized. Indi­rect techniques involve
measurement of 'downstream' global derivatives of microcirculatory dysfunction such as lactate, carbondioxide, and oxygen saturation. The direct imaging of microcirculatory perfusion seems a superior approach to assessment ofm icrocirculation. Invention of microscope is perhaps the single most im­portant advancement in technology linked to discover­ing the microcirculation, since experimental investiga­tion ofthe microcirculation began soon after its advent.
Studies of human microcirculation began at the end of 19 th century, with Hueter using a microscope with re­flected light to investigate vessels on inner border of lower lip.

Indirect assessment of microcirculation:

Lactate levels in the blood are thought to reflect anaerobic metabolism associated with tissue dysoxia and hence may predict the prognosis and response to therapy.
However, the balance between lactate pro­duction due to global (shock, hypoxia),local (tissue ischemia), and cellular(mitochondrial dysfunction) fac­tors on the one hand, and lactate clearance depending on metabolic liver function on the other hand, make the interpretation of lactate levels uncertain and difficult [95] .
Recent evidence also suggests that blood lactate con­centration may be affected by other factors such as altered pyruvate dehydrogenase, Na+, K+-ATPase activity and increased glycolysis rate. Even so, increased lactate levels do help to identify patients with tissue hypoperl usion, and if levels are markedly elevated, serve as a trigger for initiating early goal directed therapy [61] . The current recommendations [96] advocate use of se­rum lactate levels to identify patients with "crytic shock" i.e., preserved macrohaemodynamics with altered mi­crocirculation.fixed venous oxygen saturation (Sv02) can be measured using a pulmonary artery catheter and is thought to reflect the average oxygen saturation of all perlused microvascular beds. But in sepsis, microcir­culatory shunting can cause normal Sv02 despite ex­istence of severe local tissue dysoxia [9] . Even though
maintaining Sv02>65% is advocated as a recommen­dation to treat severe sepsis and septic shock, it may not reflect restoration of local tissue oxygenations [97] .An appealing alternative to the evaluation oltis­sue dysoxia is the use tonometry of gastrointestinal tract. Tonometry is based on the principle that during hypoxia, anaerobic metabolism leads to production of acids which are buffered by
bicarbonate ions leading to increased carbondioxide tension in tissues. The op­timal site for monitoring tissue pCO 2 is unclear [37] . In­testinal, gastric,oesophageal and rectal pCO 2 have all been investigated. Recently, sublingual mucosa and skin, which are not a part of splanchnic circulation have been investigated and appear promising. Sublingual capnometry has numerous advantages
over gastric tonometry. It is simple to perform, non-invasive, pro­duces immediate result, and can be used at the bed­side. It does not require premedication and acid sup­pression therapy, and patients do not have to be with­held from enteral feeding. The earlier index ofmeasur­ing tissue dysoxia by tonometry was pHi wherein a value of<7.32 indicated ischaemia. However, measurement ofthe difference
between tissue (intestinal) pCO 2 , and arterial pCO 2 has been found to be a better indicator since the arterial pCO, fluctuates in ventilated patients. In the stomach, normal gastric-arterial pCO 2 gradient is<7 mmHg. Sublingual pCO 2 values have been found to correlate well with gastric intramucosal pCO 2 val­ues [98] .
The baseline difference between sublingual pCO 2 and arterial pCO 2 values is a better predictor of sur­vival than the change in lactate or SvO2 [99] .

Direct assessment of microcirculation:

Intravital microscopy (IVM) depends on trans or epi-illumination and thus observations are limited to superficial layers of thin tissues only. By using fluores­cent dyes a higher contrast is possible as well as spe­cific cells can be labeled for visualization and quantifi­cation. Its use has been primarily limited to animal stud­ies because of the potentially toxic effects of dyes, and the limited access of tissues allowed with its usage. Its use in humans is usually
restricted to the eye, skin and the nail fold.

Laser Doppler involves the principle of detec­tion of frequency shift in laser light alter it encounters flowing erythrocytes. It measures the velocity of mi­crocirculatory flow in a small area of microcirculation, being an average ofthe velocities in all the vessels present in the measured volume. It can be used to measure the flow in skin, muscle, gastric mucosa, rectum and va­gina. It has been
validated in experimental models and gives an accurate assessment ofchanges in velocity in­duced by pharmacologic interventions. The limitations of Laser Doppler include the estimation of an average flow in aboutonly about 1 mm 3 of tissue, disregard of the morphology ofmicrovessels, the direction of flow, and heterogeneity of blood flow in the microcircula­tion, as well as failure to account for any changes in haematocrit.

The scanning Laser Doppler technique is an advancement over the conventional technique that allows two dimensional visualization ofthe microcircula­tion. It has been used to assess perfusion for oesoph­ageal or colonic anastomosis, and cutaneous perfusion of the loot during arterial cannulation in critically ill patients.

Orthogonal Polarization Spectral (OPS) lmagin is a newer noninvasive method for direct visual­ization of microcirculation using green polarized light to illuminate the area of study [100] . The polarized light is scat­tered by the tissue and collected by an objective lens. A polarization filter or analyzer oriented orthogonal to the polarized light is placed in front of the imaging camera. This analyzer eliminates the reflected light which is scattered at or near
the surface ofthe tissue, while de­polarized light scattered deeper within the tissue passes through the analyzer. When this depolarized light corn­ing from deeper tissues passes through absorbing struc­tures close to the surface, such as blood vessels, high contrast images ol - nlicrocirculation are formed. It is especially useful for studying the tissues protected by a thin epithelial layer,
such as mucosal surfaces. Incor­porated in a hand held type of microscope, OPS imag­ing was introduced clinically to first identify pathologies during surgery. The sublingLial area is the most frequently investigated mucosal surface. That the
sublingual site indeed represents microcirculation of other areas finds favour with certain authors [37] .

Limitations of OPS imaging in sublingual region include movement artifacts such as respiration, and presence of various secretions such as blood and sa­liva.Also, patients have to be cooperative or adequately sedated such that they do not bite the device. The tech­nique can investigate only those tissues that are cov­ered
with a thin epithelial layer, and of course internal organs are not available except during intraoperative conditions. It does not (live the exact measurement o1 - red blood cell flow velocity in individual vessels. What it does allow, is prediction ofa semiquantitative flow score based on average score over a maximum of 12 quadrants (three regions X four quadrants per region), derived from the
overall flow impression of all vessels with a particular range of diameter in a given quadrant.

The flow score is a semi-quantitative one, and whether the flow score from 0 to 3 [101] is actually a linear rela­tionship with the actual flow is also not established. With repeated measures, selecting the exact site as before is also a difficult task. An improvement in the OPS imag­ing is the sidestream dark-field (SDF) imaging. It con­sists of a light guide surrounded by 530 nm light-emit­ting diodes, a wavelength of light that is absorbed by haemoglobin of erythrocytes,
allowing their observa­tion as dark cells flowing in the microcirculation. As compared to OPS it offers the advantage ofimproved image quality, relative technical simplicity, and lack of - need of a high-powered light source [94] .

Future aspects

With several clinical and laboratory indicators of identi Eying hypoperf ision due to the nlicrocirculation dysfunction being available, it is perhaps time to recog­nize shock in sepsis keeping tissue hypoperfusion as distinct from hypotension. A perfusion based scoring system has been proposed by Spronk et al [97] . It emphasizes the need of - extending recognition of shock severity to include
microcirculatory parameters, besides global haemodynamic and oxygen-derived parameters.

Therapy in shock should be aimed at optimizing cardiac function, arterial hemoglobin saturation, and tis­sue perfusion. This not only includes correction of hy­povolemia, but the restoration of an evenly distributed nlicrocirculatory flow and adequate oxygen transport as well. The role of vasodilators in recruiting the micro-circulation will need to be looked into further.

Direct monitoring of sublingual microcirculation monitoring appears to be a promising endpoint for re­suscitating the microcirculation. An integrative approach incorporating both macrocirculatory and microcircula­tory haemodynamic data may indeed hold the answer to resuscitation in sepsis.

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