From Evidence-BasedPractice of Critical Care Chapter 31 Grainne McDermott Patrick J. Neligan
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
1. Hemodynamic Derangement in Sepsis2. Vasopressor Therapy in Sepsis3. Individual Vasopressors4. Author’s Recommendations
Indication: Hypotension, unresponsive to fluid therapy. The ideal pressor agent would restore blood pressure while maintaining cardiac output and preferentially perfuse the midline structures of the body (brain, heart, splanchnic organs, and kidneys).
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
Presently the agent of choice in sepsis α1- and β1-adrenergic receptor agonist Increases organ perfusion by increasing vascular tone & MAP 2-12 μg/min upto 30 μg/min IV Does not increase heart rate Vs. Dopamine, studies have shown better improvements in Oxygen delivery, perfusion & consumption with Noradrenaline.
Potent β1-adrenergic receptor agonist Increases Oxygen delivery and consumption by increasing myocardial contractility, SV, CO 2-20 μg/kg/min upto 40 μg/kg/min IV Less increase in HR than Dopamine Vs Dopamine & Adrenaline, better splanchnic blood flow & reduction in lactate production
α1- and β1-adrenergic receptor agonist Mixed inotrope & vasoconstrictor 1-50 μg/kg/min IV Potent chronotrope & more arrhythmogenic Potent diuretic (neither saves nor damages the kidneys) Complex neuroendocrine & immunosuppressive effects
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.
A syndrome of dopamine-resistant septic shock (DRSS) has been described, defined as MAP less than 70mm Hg despite administration of Dopamine @ 20μg/kg per minute.In one study, the incidence of DRSS was 60%, and those patients had a mortality rate of 78%, compared with 16% in the dopamine-sensitive group.
β1-,β2-, and α1-adrenergic receptor agonist The increase of MAP in sepsis is mainly from an increase in cardiac output (SV) 2-20 μg/min IV Drawbacks (1) it increases myocardial oxygen demand, (2) it increases serum glucose and lactate, (3) appears to have adverse effects on splanchnic blood flow, redirecting blood peripherally
Pure α1-adrenergic receptor agonist In sepsis, less effective vasoconstrictor than noradrenaline or adrenaline. 40-60 μg/min upto 180 μg/min IV Least likely to cause tachycardia Compared to NA, it reduces splanchnic blood flow, O₂ delivery & lactate uptake
Hormone that is released in response to decreased intravascular volume and increased plasma osmolality. Directly acts on V1 receptors Causes vasoconstriction & also increases the responsiveness of the vasculature to catecholamines 0.01- 0.04 units/min IV
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.
VASST trial -Vasopressin+steroids, when compared with NA, was associated with significantly decreased mortality (35.9% vs 44.7%). Conversely, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality as compared with NA(33.7% vs 21.3%). Thus a beneficial synergy, between vasopressin and corticosteroids in patients who had septic shock, was demonstrated.
Phosphodiesterase inhibitors1. Milrinone2. EnoximoneCalcium sensitizers LevosimendanThere are currently inadequate data on these agents to recommend their use in septic shock.
Itis essential that patients are fluid- resuscitated before commencement of vasopressor therapy. Few data are available suggesting the primacy of one agent over another; however, catecholamines continue to be the agent group of first choice.
Norepinephrine is a potent vasoconstrictor that maintains cardiac output and restores midline blood flow. It is not metabolically active, and this would appear beneficial.
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.
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.
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.
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.
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.
Vasopressors Maintain MAP ≥ 65mmHg.(1C) Norepinephrine or dopamine centrally administered are the initial vasopressors of choice.(1C) Epinephrine, phenylephrine or vasopressin should not be administered as the initial vasopressor in septic shock.(2C) Vasopressin 0.03 units/min maybe subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone. Use epinephrine as the first alternative agent in septic shock when BP is poorly 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)