1.From Evidence-BasedPractice of Critical Care Chapter 31Grainne McDermottPatrick J. Neligan

2. 1. SIRS Condition characterized by signs of systemic inflammation2. Sepsis SIRS because of an infection3. Severe sepsis Sepsis + one or more vital organ dysfunction4. Septic shock Severe sepsis + hypotension refractory to volume infusion5. MODS Abnormal fn in > one vital organ6. MOF Failure of > one vital organ 3. 1. Hemodynamic Derangement in Sepsis2. Vasopressor Therapy in Sepsis3. Individual Vasopressors4. Authors Recommendations 4. Early Sepsis- clinically analogous to hypovolemic shock1. Hypovolemia2. Lactic acidosis3. Increased oxygen extraction (Reduced SvO) GOAL-DIRECTED VOLUME RESUSCITATION(E.G.D.T.- Surviving Sepsis Campaign) 5. Late-stage septic shock1. Vasoplegia - loss of sympathetic tone, increased NO production, acute depletion of Vasopressin2. Reduced Stroke Volume - Circulating myocardial depressant factor - biventricular failure, decreased EF, myocardial edema & ischemia - CO maintained by a increased HR 6. Late-stage septic shock3. Microcirculatory failure - dysregulation & maldistribution of blood flow, AV shunting, capillary leak4. Mitochondrial dysfunction - tissue oxygen extraction is impaired (Increased SvO & serum lactate inspite of adequate oxygen delivery to tissues) 7. Renalinjury Hepatic dysfunction Delirium ARDSMULTI-ORGAN FAILURE 8. Indication: Hypotension, unresponsive tofluid therapy. The ideal pressor agent would restoreblood pressure while maintaining cardiacoutput and preferentially perfuse themidline structures of the body(brain, heart, splanchnic organs, andkidneys). 9. Noradrenaline Dopamine Dobutamine Adrenaline Phenylephrine Vasopressin Others like Milrinone, Enoximone & Levosimendan 10. CARDIOVASCULAR Tachyarrhythmias Ischemia: digital, cardiac, and mesenteric Thrombogenic effect Increased myocardial work yet decreased metabolic efficiency Increased oxygen expenditure Thermogenic effectsIMMUNOLOGIC Cellular injury Increased generation of reactive oxygen species Increased cytokine generation; this later declines Reduced antioxidative defenses Increased superoxide radical production Promotion of bacterial growth Biofilm formation Monocyte dysfunction Increased risk for nosocomial infectionSPLANCHNIC HYPOPERFUSION Mesenteric ischemia Ileus Malabsorption Stress ulceration Deranged liver functionMETABOLIC (PARTICULARLY EPINEPHRINE) Aerobic glycolysis, lactic acidosis Insulin resistance and hyperglycemia Enhanced lipolysis leading to hepatic steatosisDOPAMINE SPECIFIC Interference with pituitary function, particularly thyroid Dysregulation of prolactin metabolism and immunosuppression 11. Presentlythe agent of choice in sepsis 1- and 1-adrenergic receptor agonist Increases organ perfusion by increasingvascular tone & MAP 2-12 g/min upto 30 g/min IV Does not increase heart rate Vs. Dopamine, studies have shown betterimprovements in Oxygen delivery, perfusion &consumption with Noradrenaline. 12. Potent1-adrenergic receptor agonist Increases Oxygen delivery and consumption byincreasing myocardial contractility, SV, CO 2-20 g/kg/min upto 40 g/kg/min IV Less increase in HR than Dopamine Vs Dopamine & Adrenaline, better splanchnicblood flow & reduction in lactate production 13. 1- and 1-adrenergic receptor agonist Mixed inotrope & vasoconstrictor 1-50 g/kg/min IV Potent chronotrope & more arrhythmogenic Potent diuretic (neither saves nor damages thekidneys) Complex neuroendocrine & immunosuppressiveeffects 14. SOAP study - The authors divided patients into those who received dopamine alone or in combination, and those who never received dopamine. The dopamine group had higher ICU (42.9% versus 35.7%; P = .02) and hospital (49.9% versus 41.7%; P = .01) mortality rates. 15. A syndrome of dopamine-resistant septicshock (DRSS) has beendescribed, defined as MAP less than70mm Hg despite administration ofDopamine @ 20g/kg per minute.In one study, the incidence of DRSS was60%, and those patients had a mortalityrate of 78%, compared with 16% in thedopamine-sensitive group. 16. 1-,2-, and 1-adrenergic receptor agonist The increase of MAP in sepsis is mainly froman increase in cardiac output (SV) 2-20 g/min IV Drawbacks (1) it increases myocardial oxygendemand, (2) it increases serum glucose andlactate, (3) appears to have adverse effectson splanchnic blood flow, redirecting bloodperipherally 17. Pure 1-adrenergic receptor agonist In sepsis, less effective vasoconstrictorthan noradrenaline or adrenaline. 40-60 g/min upto 180 g/min IV Least likely to cause tachycardia Compared to NA, it reduces splanchnicblood flow, O delivery & lactate uptake 18. Hormone that is released in response todecreased intravascular volume andincreased plasma osmolality. Directly acts on V1 receptors Causes vasoconstriction & also increasesthe responsiveness of the vasculature tocatecholamines 0.01- 0.04 units/min IV 19. Vasopressin has emerged as an additive vasoconstrictor in septic patients who have become resistant to catecholamines. There appears to be a quantitative deficiency of this hormone in sepsis, and admin of vasopressin in addition to NA increases splanchnic blood flow and urinary output. 20. VASSTtrial -Vasopressin+steroids, whencompared with NA, was associated withsignificantly decreased mortality (35.9% vs44.7%). Conversely, in patients who did notreceive corticosteroids, vasopressin wasassociated with increased mortality ascompared with NA(33.7% vs 21.3%). Thus a beneficial synergy, betweenvasopressin and corticosteroids in patientswho had septic shock, was demonstrated. 21. Phosphodiesterase inhibitors1. Milrinone2. EnoximoneCalcium sensitizers LevosimendanThere are currently inadequate data onthese agents to recommend their use inseptic shock. 22. Itis essential that patients are fluid-resuscitated before commencement ofvasopressor therapy. Few data are available suggesting theprimacy of one agent over another;however, catecholamines continue to bethe agent group of first choice. 23. Norepinephrine is a potent vasoconstrictor that maintains cardiac output and restores midline blood flow. It is not metabolically active, and this would appear beneficial. 24. Dobutamine is a potent inotrope that is a useful adjunct to fluid resuscitation in early sepsis. In late septic shock, dobutamine is widely used in combination with norepinephrine as an inotrope. 25. There is an absolute deficiency of Vasopressin in septic shock, and combination therapy with catecholamines should be considered. Few data support the use of vasopressin as first-line therapy. Corticosteroids appear to have an additive effect with vasopressin and may improve outcomes. 26. Dopamine is a problematic agent. It has a variety of nonhemodynamic effects that may affect neurohormonal and immune function. It is an unpredictable vasoconstrictor; a significant cohort of patients are dopamine resistant and require changeover to epinephrine and norepinephrine. 27. Epinephrine is a potent vasoconstrictor and inotrope. When commenced, it causes an early lactic acidosis secondary to aerobic glycolysis and may reduce splanchnic blood flow. The clinical significance of this is unclear, and both of these effects appear to be time limited. 28. Phenylephrine has little or no value in the management of the patient in septic shock.There are inadequate data available to recommend the use of calcium sensitizers or phosphodiesterase inhibitors in septic shock. 29. Thank You for your attention. 30. Vasopressors Maintain MAP 65mmHg.(1C) Norepinephrine or dopamine centrally administered are the initialvasopressors of choice.(1C) Epinephrine, phenylephrine or vasopressin should not be administered asthe initial vasopressor in septic shock.(2C) Vasopressin 0.03 units/min maybe subsequently added to norepinephrinewith anticipation of an effect equivalent to norepinephrine alone. Use epinephrine as the first alternative agent in septic shock when BP ispoorly responsive to norepinephrine or dopamine.(2B) Do not use low-dose dopamine for renal protection.(1A) In patients requiring vasopressors, insert an arterial catheter as soon as practical.(1D)Inotropic therapy Use dobutamine in patients with myocardial dysfunction as indicated byelevated cardiac filling pressures and low cardiac output.(1C) Do not increase cardiac index to predetermined supranormal levels(1B)