1.Dr. Mridul M. Panditrao CONSULTANTDepartment of Anaesthesiology & Intensive Care Public Hospital Authoritys Rand memorialHopsital Freeport, Grand BahamaCoomonwealth of The Bahamas

2. IntroductionSepsisA dynamic phenomenon progressing rapidly global tissue hypoxia cellular dysfunction cellular death shock organ failure deathSpronk PE, Zandstra DF, Ince C : Bench to- bed side review: Sepsis is a disease of microcirculation. Criti. Care : 2004 8 : 462 468 3. Shock Disturbance of balance between oxygen delivery and oxygen consumption to the cells can be defined as state of Shock 4. Regional tissue distress caused by microcirculatorydysfunction and mitochondrial depression are thebasic causes of Shock/ sepsis lead to regional hypoxia and oxygen extractiondeficit in spite of correcting systemic oxygendelivery inhibition of mitochondrial respiratory chain anddecreased oxygen utilization immune mediated cytokine storm and systemicinflammatory response syndrome Ince C : The microcirculation is the motor of sepsis : Critical care 2005 : 9 (suppl-4) S13-S19. 5. MMDSMicrocirculatory & Mitochondrial Distress SyndromeSystemic Inflammatory ResponseSyndrome (SIRS), is the end point ofmultiple aetio-pathogenic entities liketrauma/haemorrhage, major surgeryetc.Harris A, Huet D, Duranteau J : Alterations of Mitochondrial function in Sepsis and Critical Illness : Curr . opin . Anaesthesiol, 2009 :April 22(2) : 143-9. 6. MMDS In sepsis same phenomenon is seen causing: increased oxygen consumption decreased systemic vascular resistance altered distribution of blood flow in tissues acute shutdown of microcirculation Multy Organ Failure Syndrome(MOFS) Cytopatic hypoxia : relentless, progressive andglobal tissue damage.Bone R.C. The pathogenesis of sepsis . Ann. Intern. Med.1991.115.457-469Fink M . Cytopatic Hypoxia in sepsis, Acta. Ananestheriol. Scandi. suppl. 1997 : 110 : 87-95 7. Global Indicators of Oxygen Delivery &Role of Monitoring In Sepsis 8. arterial side upto venous side starting small sized arterial from end point ofdivisions just prior to venules to form upto formation ofgreat veins arteriolesMyocardium with its Vascular treechambers and valvesMicrocirculation MacrocirculationCirculation 9. Microcirculation Structurallyand to certain extentfunctionally an entirely disparate entity. Althoughcontiguous with the macrocirculation, the factors controlling it, indicators of its function and therapeutic measures for its manipulation, vary to certain extent from those in macrocirculation 10. MicrocirculationThe microcirculation depends upon four maindeterminants Driving pressure Arteriolar tone Hemorheology Capillary network Spronk PE, Zandstra DF, Ince C : Bench to- bed side review: Sepsis is a disease of microcirculation. Criti. Care : 2004 8 : 462 468 11. MicrocirculationRegulatory mechanisms:1. Cellular : sensing stress & strain2. Metabolic : regulation controlled by oxygen, carbon dioxide, lactate, H+3. Neuro humoral : various neurotransmitters & mediators 12. Endothelial Cells lining inner wall of capillariesuseful role by release of flow sensing substancesgovern the myogenic tone in arteriolesmore and more capillaries re-recruitement Endothelial cell-to-cell signalling system transmits upstream information about haemodynamic conditions downstream control coagulation and regulate immune functionVallet B : Endothelial cell dysfunction and abnormal tissue perfusion; Crit Care Med 2002 : 30 ( Suppl 5) : s 229 S 234 13. Main Characteristics of microcirculatory dysfunction Heterogeneous abnormalities in blood flow leading tosome capillary units being underperfused whileothers having abnormally high blood flow leading todisparity in oxygen delivery and oxygen extraction attissue level These underperfused units then become progressivelyhypoxic which explains the deficit in oxygen extractionassociated with sepsis.Bateman R M , Sharpe M D , Ellis CG : Benet Bedside review : Microvascular dysfunction in sepsis haemodynamics, oxygen transport and Nitric Oxide. Crit. Care . 2003, 7 : 359-373 14. PO2 gap Thus microcirculatory partial pressure of oxygen(PO2 ) goes less than PVO2 PaO2 may be adequate enough for providingrequired amount of oxygen to the tissues, butbecause of MMDS, the perfusion of oxygenacross the membrane, extraction, utilization andregulation of intracellular activity dependent onoxygen become totally imbalanced leading to thedisparity between PO2 & PVO2 This disparity has been termed as PO2 gapLam C, Tyml K , et al: Microvascular perfusion is impaired in rat model of normotensive sepsis , J Clin invest 1994 . 94 :2077-2083.Ince C, Singasappel M : Microcirculatory oxygenation in Shunting and Shock. Crit Care Med. 1999 . 27 : 1369 1377 15. Can be used as a measurement of severity offunctional shunting, which has been found to behighly significant indicator in conditions likesepsis, haemorrhage & trauma This is the main reason why there remains aparadox, when monitoring systemichaemodynamic based and oxygen derivedvariables in the terms of predicting severityleading to morbidity and mortality. This is termed as masking of ongoing process. Ince C, Singasappel M : Microcirculatory oxygenation in Shunting and Shock. Crit Care Med. 1999 . 27 : 1369 1377 16. 2. More de-recruitement of endothelial cells & Inablityto perform-leads to disturbed signal transductional pathways loss of electrophysiological communication andsmooth muscle control leading to severe tissue dysoxia / and hypoxiaMechanism: NO system imbalance caused by unequal expressionof inducible nitric oxide synthase (iNOS) in differentmicrocirculatory beds, resulting in pathologicalshunting of flow areas which are lacking iNOS, automatically haveless NO- induced vasodilatation and remainunderperfused leading to hypoxia in these areas.Morin MJ , Unno N, Hodin RA , Fink MP : Differential expression of inducible nitric oxide synthase messenger RNA along the Longitudinal and crypt villus axes of the intestine in endotoxic rats ; Crit. Care med . 1998 : 26 : 1258- 1264 17. 3. Myogenic cells of the arteriolar walls, lose theirsensitivity to adrenergic factors in sepsis.4. The red blood cells in the presence of hypoxiarelease NO and lead to vasodilatation and thusincreased perfusion5. Red blood cells become less deformable, morerigid and start aggregating more, leading tosevere disturbances of coagulation, activation ofcoagulation cascade, fibrin deposition andformation of microthrombi, further impedingmicrocirculatory perfusion, function and oxygendelivery. Singel D J , Stamler JS : Chemical physiology of blood flow regulation by red blood cells : the role of nitric oxide and S nitrosohemoglobin. Annu. Rev. Physiol . 2005. 67 : 99 145. Siegemund M, Hardemann MR etal : Red blood cells deformity in 2 different doses of LPS in a porcine model ofEndotoxemia : Intensive Care Med . (1999). 25. S21. 18. 6. Leucocytes activated due to systemic inflamatoryresponse start generating free radicals of reactiveoxygen species, which directly start acting anddestroying microcirculatory structures, cellularinteractions and coagulatory functions, leading toaltered permeability, structural defects and tissueoedema, culminating into further deterioration ofoxygen extraction deficit, parenchymal /cellularrespiratory distress and resultant organ failure7. MMDS: Defined as persistent failure of microcirculatoryperfusion and mitochondrial oxygen utilizations in spiteof correction of systemic, hemodynamic and oxygenderived variables in the presence of sepsis Victor, VM, Rocha M, De.la.Fuente M. Immune cells : Free radicals and antioxidants in sepsis. Int. Immuno pharmacol 2004 : 4 : 327-347. Fink M.P : Intestinal epithelial Hyper permeability : update on the pathogenesis of Gut mucosal barrier dysfunction in critical illness in Curr . Opin .Crit . Care 2003 : a : 143-151 19. Ultimately culminating into cellular dysoxia, regionaldisequilibrium in oxygen delivery and utilizationleading to cellular hypoxia and multiple organ failureand death. The indicators which point to this are A. Increased lactate levels : indicator of anaerobic metabolism i. Global : sepsis, shock, hypoxia ii. Regional : tissue ischemia iii.Cellular : mitochondrial dysfunction and clearance by liverB. Disturbed acid- base balanceC. High gastric or oral CO2 levelsD. Clinical parameters : colour, capillary refill, temperaturein periphery De Backer D . Lactic Acidosis : Intensive care Medicine 2003 : 2a : 699-702. 20. E. Due to Down stream assessment : mixed venous oxygensaturation (SVO2), measurement of available oxygen (DO2)due to altered regional NO responsivness, and resultantmicrocirculatory shunting, normal SVO2 levels may befound in spite of severe local tissue dysoxiaF. Tonometric CO2 Assessment: seems promising is a modification of previously used tool of regional intestinalcapnography measurement of difference between gastric/intestinal PCO2 andarterial PCO2 is better than that of pH alone because PCO2 isdynamically variable in all the ventilated patients gastric intramucosal tonometry & sublingual PCO2 : baselinedifference in sublingual PCO2 and PaCO2 values appear to bebetter and more suitable predictor of survival than changes inlactate levels or SVO2 levelsMarik PE : Sublingual PCO2 : a clinical validation study . Chest : 2001 : 120 : 923 927.Marik PE , Bankov A : Sublingual Capnography vs traditional markness of tissue oxygenation in critically ill patients : Crit. Care. Med.2003 : 31 : 818-822. 21. G. Intravital Microscopy (IVM) : direct methodThe size of IVM equipment makes it useful only in eye, skin, or nail fold in humansThus observations limited only to the superficial layers of body & Potential toxicity of fluorescent dyes which have to be used, make it difficult to use it in humansF. Orthogonal Polarization Spectral imaging (OPS): a newmethod to study microcirculationNo need of fluorescent dyes. The machine being hand held & can be used bed sideSaetzlar RK, Harris AG etal : Intra Vital Flouroscence Microscopy : Impact of light induced phototoxicity on adhesion of floroscentlylabelled leucocytes : J Histochem Cytochem : 1997 : 45 505-513.Grover W etal :orthogonal polarisation spectral imaging : a new method for study of the micro circulation . Nat. Med. 1999 : 5 : 1209-1212. 22. MONITORING Routine hemodynamic : MAP, CVP, PCOP Oxygen extraction / saturation parameters :SPO2, ScVO2, SVO2, Falling venous oxyhemoglobinsaturationLactate levels > 4 mmol/L & increasing can inverselycorrelate with ScVO2 and SVO2 Anion gap , base deficits , bicarbonate levels as indirectindicator of lactate levels can be misleading Other routine parameters : RFTs, LFTs, coagulationprofile , PT, PTT, INR, blood platelet levels Sublingual, buccal and subcutaneous CO2 levels Absorbance, refractoriness and near infraredspectroscopy (NIRS) 23. Early Goal Directed Therapy (EGDT) and Other TherapeuticInterventions to improve OxygenationRivers study : criteria were the same as Society of Critical CareMedicine and American College of Chest Physicians randomized, 263 patients with suspected sepsis into two groups: either to get standard care or early goal directed therapy (EGDT)by using central SVO2 & PVO2 to adjust cardiac pre load, after load and contractility half hourly 500ml bolus of crystalloid CVP of 8-12mm of Hg. MAP was maintained between 65-90 mm of Hg using vasopressorsand / or dilators. If ScVO2 fell less than 70%, red blood cell transfusion to achievehaematocrit of 30%. dobutamine (2.5-20g/kg/min) was administered to bring ScVO2 to70% or above.Significantly lower in hospital mortality even at 28 and 60 daysMean hospital stay was significantly lesser (14.6 days versus 18.4 days)Rivers E , Nguyen B etal , Early goal directed therapy in the treatment of severe sepsis and septic shock : N Engl. J. Med. 2001 : 1368-1377 24. Principles of Therapy to improve microcirculatoryperfusion as the goal: available evidence Vasodilators: Like Prostacycline; by vasodilatation ofthe microcirculatory networks, which had been de-recruited, are re-recruited, thus making oxygen availableto these previously hypoxic tissues. Vasoconstrictors: normal sublingual microcirculatoryperfusion has been achieved in septic patient withhepatic failure on high doses nor adrenalin or withvasopressinBihari D , Smithies M etal : The effect of Vasodilation with prostacyclin on oxygen delivery and uptake in critically ill patients . N. Engl. J. Med. 1987. 317 : 397-403.De Backer D, Dubois MJ etal Microvascular blood flow is altered in patients with sepsis . Am. J. Respir. Criti. Care. Med. 2002 : 166 . 98-104. 25. Principles of Therapy to improve microcirculatory perfusion as the goal.NOConflicting evidence as the culprit or the saviour of sepsis undebatable that completely inhibiting vasodilatation is not the proper answer to sepsis, but specifically inhibiting only the inducible form of nitric oxide synthase (iNOS) may improve the outcome, thus improving PO2 and bringing intraluminal gastric PCO2 levels to a baselineBest mid-ground strategy : Improvement of oxygen supply to tissues by manipulating themicrocirculatory and hemodynamic goals of Optimised cardiac output Adequate haemoglobin concentration and saturation Physiological range of CVP / Pulmonary arterial wedge pressure Approximate level of ( 90 mm Hg. Appearance of sinustachycardia would be the indication for stoppingdobutamine and switching over to alpha agonists likephenylepherine or nor adrenlaine. 33. RBC transfusion: In an adequate volumeresuscitated patient, RBCs may be transfusedso as to keep hematocrit of < 30 % which allowsthe ScVO2 of > 70 % in nearly 79 80 %patients: Appropriate system support Antibiotic support Monitoring Physiologic scoring systemsAPACHE IIMODSMechanical ventilationEGDT results in significant reduction in mortality, morbidity, vasopressor use and health care resource consumption. 34. Conclusion The Microcirculation plays the pivotal role clinically the macrovasculature (Cardio-vascular/Haemodynamic) parameters mayappear to be near normal at the cellular level, there is an emergent crisisdue to imbalance between the oxygendelivery, extraction and consumption(MMDS, Cytopathic hypoxia, Dysoxia) 35. To plan precise modalities for Optimising theOxygen Delivery in such patients, it requiresone to have a thorough understanding aboutthe various aetio-pathogenic factors, Patho-physiologic processes involved at the level ofMicrocirculation. The monitoring which can help inidentifying, detecting and assessing theefficacy of therapeutic measures. EGDT is still valid with suitable modifications Newer Modalities with promising results arenow available!