This document explains the complexities of sepsis, highlighting the critical role of microcirculatory and mitochondrial dysfunction in leading to shock, multiple organ failure, and death. It discusses various therapeutic interventions aimed at improving microcirculatory perfusion and oxygen delivery to tissues using measures like volume resuscitation and vasodilators. Monitoring tools for assessing tissue oxygenation and perfusion are also examined as essential in the management of septic patients.

2. Dr. Mridul M. Panditrao
CONSULTANT
Department of Anaesthesiology & Intensive Care
Public Hospital Authority’s Rand memorial
Hopsital
Freeport, Grand Bahama
Coomonwealth of The Bahamas

3. Introduction
Sepsis
A dynamic phenomenon progressing rapidly
 global tissue hypoxia
 cellular dysfunction
 cellular death
 shock
 organ failure
 death
Spronk PE, Zandstra DF, Ince C : Bench – to- bed side review: Sepsis is a disease of microcirculation. Criti. Care : 2004 – 8 :
462 – 468

4. Shock
 Disturbance of balance between
oxygen delivery and oxygen
consumption to the cells can be
defined as state of Shock

5.  Regional tissue distress caused by microcirculatory
dysfunction and mitochondrial depression are the
basic causes of Shock/ sepsis
 lead to regional hypoxia and oxygen extraction
deficit in spite of correcting systemic oxygen
delivery
 inhibition of mitochondrial respiratory chain and
decreased oxygen utilization
 immune mediated cytokine storm and systemic
inflammatory response syndrome
Ince C : The microcirculation is the motor of sepsis : Critical care 2005 : 9 (suppl-4) S13-S19.

6. MMDS
Microcirculatory & Mitochondrial Distress Syndrome
Systemic Inflammatory Response
Syndrome (SIRS), is the end point of
multiple aetio-pathogenic entities like
trauma/haemorrhage, major surgery
etc.
Harris A, Huet D, Duranteau J : Alterations of Mitochondrial function in Sepsis and Critical Illness : Curr . opin . Anaesthesiol, 2009 :
April 22(2) : 143-9.

7. 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 and
global tissue damage.
Bone R.C. The pathogenesis of sepsis . Ann. Intern. Med.1991.115.457-469
Fink M . Cytopatic Hypoxia in sepsis, Acta. Ananestheriol. Scandi. suppl. 1997 : 110 : 87-95

8. Global Indicators of
Oxygen Delivery
&
Role of Monitoring
In Sepsis

9. arterial side upto venous side starting
small sized arterial from end point of
divisions just prior to venules to form upto
formation of great veins
arterioles
Myocardium with its Vascular tree
chambers and valves
Microcirculation
Macrocirculation
Circulation

10. Microcirculation
 Structurally and to certain extent
functionally an entirely disparate entity.
 Although contiguous 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

11. Microcirculation
The microcirculation depends upon four main
determinants
 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

12. Microcirculation
Regulatory mechanisms:
1. Cellular : sensing stress & strain
2. Metabolic : regulation controlled by
oxygen, carbon dioxide, lactate, H+
3. Neuro humoral : various
neurotransmitters & mediators

13. Endothelial Cells lining inner wall of capillaries
 useful role by release of flow sensing substances
 govern the myogenic tone in arterioles
 more and more capillaries re-recruitement
 Endothelial cell-to-cell signalling system transmits
upstream information about haemodynamic conditions
downstream
 control coagulation and regulate immune function
Vallet B : Endothelial cell dysfunction and abnormal tissue perfusion; Crit Care Med 2002 : 30 ( Suppl 5) : s 229 – S 234

14. Main Characteristics of microcirculatory dysfunction
• Heterogeneous abnormalities in blood flow leading to
some capillary units being underperfused while
others having abnormally high blood flow leading to
disparity in oxygen delivery and oxygen extraction at
tissue level
• These underperfused units then become progressively
hypoxic which explains the deficit in oxygen extraction
associated 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

15. PO2 gap
 Thus microcirculatory partial pressure of oxygen
(µPO2 ) goes less than PVO2
 PaO2 may be adequate enough for providing
required amount of oxygen to the tissues, but
because of MMDS, the perfusion of oxygen
across the membrane, extraction, utilization and
regulation of intracellular activity dependent on
oxygen become totally imbalanced leading to the
disparity between µPO2 & PVO2
 This disparity has been termed as “ PO2 gap”
Lam 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

16.  Can be used as a measurement of severity of
functional shunting, which has been found to be
highly significant indicator in conditions like
sepsis, haemorrhage & trauma
 This is the main reason why there remains a
paradox, when monitoring systemic
haemodynamic based and oxygen derived
variables in the terms of predicting severity
leading 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

17. 2. More de-recruitement of endothelial cells & Inablity
to perform-leads to
 disturbed signal transductional pathways
 loss of electrophysiological communication and
smooth muscle control
 leading to severe tissue dysoxia / and hypoxia
Mechanism:
 NO system imbalance caused by unequal expression
of inducible nitric oxide synthase (iNOS) in different
microcirculatory beds, resulting in pathological
shunting of flow
 areas which are lacking iNOS, automatically have
less NO- induced vasodilatation and remain
underperfused 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

18. 3. Myogenic cells of the arteriolar walls, lose their
sensitivity to adrenergic factors in sepsis.
4. The red blood cells in the presence of hypoxia
release NO and lead to vasodilatation and thus
increased perfusion
5. Red blood cells become less deformable, more
rigid and start aggregating more, leading to
severe disturbances of coagulation, activation of
coagulation cascade, fibrin deposition and
formation of microthrombi, further impeding
microcirculatory perfusion, function and oxygen
delivery.
 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 et’al’ : Red blood cells deformity in 2 different doses of LPS in a porcine model of
Endotoxemia : Intensive Care Med . (1999). 25. S21.

19. 6. Leucocytes activated due to systemic inflamatory
response start generating free radicals of reactive
oxygen species, which directly start acting and
destroying microcirculatory structures, cellular
interactions and coagulatory functions, leading to
altered permeability, structural defects and tissue
oedema, culminating into further deterioration of
oxygen extraction deficit, parenchymal /cellular
respiratory distress and resultant organ failure
7. MMDS: Defined as persistent failure of microcirculatory
perfusion and mitochondrial oxygen utilizations in spite
of correction of systemic, hemodynamic and oxygen
derived 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

21. Ultimately culminating into cellular dysoxia, regional
disequilibrium in oxygen delivery and utilization
leading to cellular hypoxia and multiple organ failure
and 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 liver
B. Disturbed acid- base balance
C. High gastric or oral CO2 levels
D. Clinical parameters : colour, capillary refill, temperature
in periphery
De Backer D . Lactic Acidosis : Intensive care Medicine 2003 : 2a : 699-702.

22. E. Due to “Down stream” assessment : mixed venous oxygen
saturation (SVO2), measurement of available oxygen (DO2)
due to altered regional NO responsivness, and resultant
microcirculatory shunting, normal SVO2 levels may be
found in spite of severe local tissue dysoxia
F. Tonometric CO2 Assessment: seems promising
 is a modification of previously used tool of regional intestinal
capnography
 measurement of difference between gastric/intestinal PCO2 and
arterial PCO2 is better than that of pH alone because PCO2 is
dynamically variable in all the ventilated patients
 gastric intramucosal tonometry & sublingual PCO2 : baseline
difference in sublingual PCO2 and PaCO2 values appear to be
better and more suitable predictor of survival than changes in
lactate levels or SVO2 levels
Marik 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.

23. G. Intravital Microscopy (IVM) : direct method
 The size of IVM equipment makes it useful only
in eye, skin, or nail fold in humans
 Thus 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 humans
F. Orthogonal Polarization Spectral imaging (OPS): a new
method to study microcirculation
 No need of fluorescent dyes.
 The machine being hand held & can be used bed side
Saetzlar RK, Harris AG et’al’ : Intra Vital Flouroscence Microscopy : Impact of light induced phototoxicity on adhesion of floroscently
labelled leucocytes : J Histochem Cytochem : 1997 : 45 – 505-513.
Grover W et’al’ :orthogonal polarisation spectral imaging : a new method for study of the micro circulation . Nat. Med. 1999 : 5 : 1209-1212.

24. MONITORING
 Routine hemodynamic : MAP, CVP, PCOP
 Oxygen extraction / saturation parameters :
SPO2, ScVO2, SVO2, Falling venous oxyhemoglobin
saturation
 Lactate levels > 4 mmol/L & increasing can inversely
correlate with ScVO2 and SVO2
 Anion gap , base deficits , bicarbonate levels as indirect
indicator of lactate levels can be misleading
 Other routine parameters : RFTs, LFTs, coagulation
profile , PT, PTT, INR, blood platelet levels
 Sublingual, buccal and subcutaneous CO2 levels
 Absorbance, refractoriness and near infrared
spectroscopy (NIRS)

25. Early Goal Directed Therapy (EGDT) and Other Therapeutic
Interventions to improve Oxygenation
Rivers study : criteria were the same as Society of Critical Care
Medicine 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 vasopressors
and / or dilators.
• If ScVO2 fell less than 70%, red blood cell transfusion to achieve
haematocrit of 30%.
• dobutamine (2.5-20µg/kg/min) was administered to bring ScVO2 to
70% or above.
Significantly lower in hospital mortality even at 28 and 60 days
Mean hospital stay was significantly lesser (14.6 days versus 18.4 days)
Rivers E , Nguyen B et’al’ , Early goal directed therapy in the treatment of severe sepsis and septic shock : N Engl. J. Med. 2001 : 1368-1377

27. Principles of Therapy to “improve microcirculatory
perfusion as the goal”: available evidence
 Vasodilators: Like Prostacycline; by vasodilatation of
the microcirculatory networks, which had been de-
recruited, are re-recruited, thus making oxygen available
to these previously hypoxic tissues.
 Vasoconstrictors: normal sublingual microcirculatory
perfusion has been achieved in septic patient with
hepatic failure on high doses nor adrenalin or with
vasopressin
Bihari D , Smithies M et’al’ : 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 et’al’ Microvascular blood flow is altered in patients with sepsis . Am. J. Respir. Criti.
Care. Med. 2002 : 166 . 98-104.

28. Principles of Therapy to “improve
microcirculatory perfusion as the goal”.
NO
Conflicting 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 baseline
Best mid-ground strategy :
Improvement of oxygen supply to tissues by manipulating the
microcirculatory and hemodynamic goals of
 Optimised cardiac output
 Adequate haemoglobin concentration and saturation
 Physiological range of CVP / Pulmonary arterial wedge pressure
 Approximate level of (<70%) ScVO2
Pittner A, Nalos M et’al’ Mechanism of inducible nitric oxide synthase (iNOS) inhibition – related improvement of Gut
mucosal acidosis during hyperdynamic porcine endo-toxemia. Intensive care med. 2003 : 29 :312-316.

29.  When no further improvement using volume
resuscitation and or Dobutamine infusion can be
achieved, the gastric pH can be improved after
starting prostacyclin, due to improvement in
splanchnic circulation / microcirculation
Radermarcher P , Buhl R et’al’ : The effects of prostacyclin on gastric intramucosal PH in patients with septic shock :
Intensive care med. 1995 . 21 : 414-421.

30. THERAPEUTIC OPTIONS FOR
IMPROVING OXYGENATION
 Intravascular volume manipulation:- Use of
crystalloids / non homogenous colloids
 Blood transfusion has been found to improve oxygen
delivery to the microcirculation
 Vasodilators or vasopressors or both?: Nitric Oxide
(NO) donors used as adjuncts with fluids
 As it is a “distributive defect”: nitroglycerin to improve
oxygen delivery at the tissue level
 Vasopressors :conflicting and controversial
:vasopressin showed promising result in one study,
while same drug produced derangement of oxygen
delivery and death in another
Spronk PE, Ince C et’al’ : Nitroglycerin promotes microvascular recruitment in septic shock after intravascular volume
resuscitation. Lancet 2002 : 360 : 1395-96.
Boerma EC. Van der Voort PHJ. Ince C. : Sublingual microcirculatory flow is impaired by vasopressin–analog
terlipressin in a patient with cathecolamine resistant septic shock. Acta. Anaesth. Scand. 2005, 74: 200-8

31.  iNOS inhibitors :newer promising area is iNOS
inhibitors, can cause re-recruitment of various
microcirculatory units, improved auto regulatory
dysfunction, and protect barrier function of
microcirculation.
 steroids :in relatively higher doses have been
found very effective as iNOS inhibitors,
especially if given early on, by preventing NO
induced inhibition of glucocorticoid receptors
Duma D, Silva–Santos JE : Inhibition of glucocorticoid receptor binding by nitric oxide by endo toxemic rats . Crit.
Care. Med 2004 : 32 : 2304-2310.

32. Multimodal approach
 Intravascular volume resuscitation combined with crystalloids /
colloids , vasoactive and inotropic support improves
microcirculatory perfusion and oxygen delivery.
 NO donor can open microcirculation
steroids or specific iNOS inhibitors decrease pathological
shunting and cause recruitment of multiple microcirculatory
units
NOVEL APPROACH: COMBINATION OF BOTH
 Drugs with multiple sites of action
Activated Protein C (APC) (PROWESS STUDY)
Sakr Y. Dubois MJ et’al’ : Persistant microcirculatory alterations are associated with organ failure and
death in patients with septic shock. Crit . Care . Med . 2004-32 : 1825-1831.
Bernard GR, Vincent JL et’al’ Recombinant human protein C, world wide evaluation in severe sepsis
(PROWESS) study group: Efficaey and safety of recombinant human activated protein C for sepsis.
N. Engl. J. Med. 2001 ; 344 : 699-709.

33. Activated Protein C
(XIGRIS)
Has integrated and variety of mechanisms viz.
 APC inhibits iNOS induction and ill effects of NO
 APC reduces levels of TNF alpha.
 Decreases leucocyte activation and free oxygen radicals release
 Prevents abnormalities of coagulation cascade
exogenous application of APC and antithrombin shows
promising results
 Yamaji K , Wang Y et’al’ : Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibit
lipid peroxidation and glycation end prodnets formation. Thrombs Res. 2005 : 115 : 319-325.
 Hoffmann JN, Fertmann JM, Jaunch KW : Microcirculatory disorders in sepsis and transplantation : therapy with
natural coagulants inhibitors antithrombin and activated protein C . Current Opin. in Crit Care : 2006 : 12 : 5 : 426-430.

34. “EGDT revisited: 2006
 Same group again reassessed the original concept with
newer diagnostic and therapeutic interventions.
Findings and Recommendations
 Monitoring of ScVO2 and /or SVO2 both are useful
 If not suitable to pass PAC (Pulmonary Artery Catheter)
then one may depend upon SVO2. SVO2 upto 65% and
ScVO2 of 70% seems to be suitable end points
 Crystalloids: in initial 6 hours aggressive fluid management
followed by 7 – 72 hours of conservative fluid management
seems to be optimum adjunct to vasopressor therapy.
 more amenable to vasopressor use, lesser refractoriness,
improved survival.
 longer the need for vasopressor more the mortality.
Otero RM, Nguyen HB : Early goal directed therapy in severe sepsis and septic shock revisited : Chest : 2006 : 130 (5) : 1579-
95.

35.  Vasodilator therapy ( decreasing afterload)
Nitroglycerin is the drug of choice because of its effects
on preload, afterload and coronary vasodilatation. The
patients with pre-existing cardiac problem or already in
CHF will be benefitted
 Inotropic support: Inspite of conflicting reports about
Dobutamine therapy and associated mortality
recommendation is:
Dobutamine in small doses (2.5 microgram /kg/min )
in already adequated volume preloaded, but still
hypotensive patients. Then rate increased by 2.5
microgram/kg/min titrating it every 15 – 20minutes to
keep MAP > 90 mm Hg. Appearance of sinus
tachycardia would be the indication for stopping
dobutamine and switching over to alpha agonists like
phenylepherine or nor adrenlaine.

36.  RBC transfusion: In an adequate volume
resuscitated patient, RBCs may be transfused
so as to keep hematocrit of < 30 % which allows
the ScVO2 of > 70 % in nearly 79 – 80 %
patients:
 Appropriate system support
Antibiotic support
Monitoring
Physiologic scoring systems
APACHE II
MODS
Mechanical ventilation
EGDT results in significant reduction in
mortality, morbidity, vasopressor use and
health care resource consumption.

37. Conclusion
 The Microcirculation plays the pivotal role
 clinically the macrovasculature (Cardio-
vascular/Haemodynamic) parameters may
appear to be near normal
 at the cellular level, there is an emergent crisis
due to imbalance between the oxygen
delivery, extraction and consumption
(MMDS, Cytopathic hypoxia, Dysoxia)

38.  To plan precise modalities for “Optimising the
Oxygen Delivery” in such patients, it requires
one to have a thorough understanding about
the various aetio-pathogenic factors, Patho-
physiologic processes involved at the level of
Microcirculation.
 The monitoring which can help in
identifying, detecting and assessing the
efficacy of therapeutic measures.
 EGDT is still valid with suitable modifications
 Newer Modalities with promising results are
now available!