Acute Renal Failure And Sepsis


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Acute Renal Failure And Sepsis

  1. 1. Acute Renal Failure and Sepsis Michael Fernando M.D. PGY-3 Cleveland Clinic July 18, 2007
  2. 2. Clinical Definition of Sepsis
  3. 3. RIFLE classification of Acute Renal Failure <ul><li>(R)isk - Increase in serum creatinine level X 1.5 or decrease in GFR by 25%, or UO <0.5 mL/kg/h for 6 hours </li></ul><ul><li>(I)njury - Increase in serum creatinine level X 2.0 or decrease in GFR by 50%, or UO <0.5 mL/kg/h for 12 hours </li></ul><ul><li>(F)ailure - Increase in serum creatinine level X 3.0, decrease in GFR by 75%, or serum creatinine level > 4 mg/dL; UO <0.3 mL/kg/h for 24 hours, or anuria for 12 hours </li></ul><ul><li>(L)oss - Persistent ARF, complete loss of kidney function >4 wk </li></ul><ul><li>(E)nd Stage Kidney Disease - Loss of kidney function >3 months </li></ul>
  4. 4. Occurrence of Acute Renal Failure in Sepsis
  5. 5. Objectives <ul><li>Hemodynamics and Hormones </li></ul><ul><li>Pressor Effect of Vasopressin </li></ul><ul><li>Effects of arterial vasodilatation on fluid volume </li></ul><ul><li>Models of endotoxemia and sepsis </li></ul><ul><li>Early Resuscitation </li></ul><ul><li>Glucose control </li></ul><ul><li>Glucocorticoids </li></ul><ul><li>Renal Replacement </li></ul>
  6. 6. Hemodynamics and Hormones <ul><li>The hemodynamic hallmark of sepsis is generalized arterial vasodilatation with  SVR </li></ul><ul><li>- leads to activation of sympathetic nervous system </li></ul><ul><li>- renin-angiotensin-aldosterone axis </li></ul><ul><li>- nonosmotic release of vasopressin </li></ul><ul><li>- increase in cardiac output 2 ° to  afterload </li></ul><ul><li>Maintaining the integrity of arterial circulation in pts. with severe sepsis and septic shock may lead to ARF </li></ul>
  7. 7. Pathophysiology
  8. 8. Pathophysiology II <ul><li>Arterial vasodilatation in sepsis is mediated by: </li></ul><ul><li>- cytokines  upregulate expression of inducible NO synthase </li></ul><ul><li>- vasodilatory effect of inducible NO synthase is more profound and prolonged than constitutive NO synthase </li></ul><ul><li>-  [H+] and lactate and  ATP in vascular smooth muscle cells in sepsis activate K+ channels  hyperpolarization of smooth muscle making cells refractory to pressor effects of Norepinephrine and Angiotensin II </li></ul>
  9. 9. Importance of Vasopressin <ul><li>Vasopressin in septic shock may maintain BP despite ineffectiveness of other pressors (ie Norepinephrine, and angiotensin II) </li></ul><ul><li>- inactivate K+ channels lessening resistance to norepinephrine and angiotensin II </li></ul><ul><li>-  synthesis of NO (via inducible NO synthase and its signaling pathway cGMP) </li></ul><ul><li>- via Arginine Vasopressin ®eceptor V1A </li></ul><ul><li>Neurohumoral response </li></ul><ul><ul><li>- in septic and hypovolemic shock vasopressin concentrations  300 pg/ml but after 1 hour fall to 30 pg/ml. Exogenous vasopressin may return plasma concentrations to higher levels  BP from 25 -50 mm Hg </li></ul></ul>
  10. 10. Vasopressin and GFR <ul><li>Norepinephrine </li></ul><ul><ul><li>- profoundly constricts afferent arteriole decreasing filtration pressure prolonging ARF </li></ul></ul><ul><li>Vasopressin increases GFR </li></ul><ul><ul><li>- Via constriction of efferent arteriole which increases filtration pressure thereby  GFR </li></ul></ul>
  11. 11. Effects of Systemic Arterial Vasodilation on Starling forces <ul><li>Studies have shown administration of potent arterial vasodilators cause sodium and water retention w/ expansion of plasma & interstitial volume –reversing the normally negative interstitial pressure. </li></ul><ul><li>IV hyperoncotic albumin produced a fall in interstitial pressures non-vasodilated animals however interstitial pressures remained the same in vasodilated animals. </li></ul><ul><li>Effect may be due to increased distribution of albumin w/i the interstitial space of vasodilated animals. </li></ul>
  12. 12. Effects of systemic arterial vasodilatation (cont.’d) <ul><li>Pulmonary vasculature is particularly prone to collect interstitial fluid. </li></ul><ul><li>Extrapolated to humans, pts. in sepsis with vasodilatation may be susceptible to noncardiogenic pulmonary edema. </li></ul><ul><li>Prospective study showed that pts. with ARF with sepsis had a dramatically higher requirement for mech. ventilation and higher mortalities. (Neveu et al.) 70% vs. 47% and 74.5% vs. 45.2% </li></ul>
  13. 13. Excessive fluid administration in the setting of Sepsis and ARF <ul><li>Sequelae of excess fluids in sepsis w/ ARF </li></ul><ul><li>1) redistribution of albumin and altered starling forces </li></ul><ul><li>2) Pulmonary edema and hypoxia </li></ul><ul><li>3) need for mechanical ventilation </li></ul><ul><li> 4) progression to sepsis related ARDS </li></ul><ul><li> 5)  mortality </li></ul>
  14. 14. Experimental models of Sepsis induced ARF <ul><li>1) Experiments w/ endotoxin infused rats showed that early in course FENa <1% indicating good tubular function in prerenal azotemic state. </li></ul><ul><li>As the state persists FENa  indicating tubular dysfunction  ATN </li></ul><ul><li>2) Given  plasma concentrations of catechols and activation of RAAS in sepsis and septic shock, experiments were conducted infusing mice with endotoxin 5mg/kg with normotensive vs. renally denervated mice. </li></ul><ul><li>-results showed that renal denervation afforded considerable protection against decreased GFR during first 16 hours of endotoxemia. </li></ul><ul><li>-this suggests that neurally mediated vasoactive hormoes contribute to ARF in sepsis </li></ul><ul><li>3) Antiserum to endothelin in a rat model showed that reduced GFR in endtoxemia can be temporarily reversed. </li></ul><ul><li>- suggesting that TNF  released endothelin is partially responsible for renovasoconstriction. </li></ul>
  15. 15. Benefits of Early Fluid Resuscitation <ul><li>Randomized control trial (RCT) of 263 pts. w/ mean serum Cr 2.6 on admission showed a significant decrease in in-hospital mortality vs. controls (30.5% vs. 46.5%) if goal directed therapy was instituted (Rivers et. al) </li></ul><ul><li>Goal directed therapy </li></ul><ul><ul><li>Early volume expansion and vasopressors titrated to MAPs 65mm Hg </li></ul></ul><ul><ul><li>Transfusion of pRBCs to maintain Hct above 30 if SvO2 <70% </li></ul></ul><ul><ul><li>If SvO2 < 70% despite the above interventions dobutamine was started. </li></ul></ul>
  16. 16. Glucose Control <ul><li>RCT of 1548 pts. compared use of insulin to tightly control glucose levels (80-110) vs conventional control –insulin use only if BS >180-220. Tight control group showed a  in mortality 4.6% vs. 8% and a 41% decrease in ARF requiring dialysis or hemofiltration. </li></ul><ul><li>In theory hyperglycemia impairs the overall function of leukocytes and macrophages </li></ul>
  17. 17. Benefits Glucorticoids <ul><li>It has been known that glucorticoids enhance the pressor effects of catecholamines </li></ul><ul><li>RCT 229 pts. With negative corticotropin stim test were tx w/ Hydrocortisone 50mg IV q6 and fludrocortisone 50  g qd had a decrease in mortality at 28 days. 53% vs. 63% compared w/ placebo. </li></ul><ul><li>Withdrwal of vasopressors was also significantly better 40% vs. 57% </li></ul>
  18. 19. Renal Replacement Therapy <ul><li>Pts. in sepsis and ARF are hypercatabolic. Pts. placed on renal replacement therapy have been shown to have a mortality benefit, particularly if renal replacement is instituted on a more frequent basis. </li></ul><ul><li>Peak Concentration hypothesis - non specific removal of soluble pro and anti inflammatory mediators, which normally exist in a state of immune homeostasis but when dysregulated are likely responsible for the malignity of sepsis or SIRS </li></ul>
  19. 20. Peak Concentration Hypothesis
  20. 21. Renal Replacement Therapy <ul><li>Schiffl et. Al showed that daily hemodialysis as compared with alternate-day HD was associated with less SIRS or sepsis (22% vs. 46%), lower mortality (28% vs. 46%) and shorter duration of ARF. </li></ul><ul><li>RCT using CVVHD w/ ultrafiltration rate of 35-45ml/kg/hr compared w/ 20ml/kg/hr improved survival in ARF. (Ronco et. al.) </li></ul>
  21. 22. Conclusions <ul><li>Vasopressin has been shown to have greater therapeutic value compared to other pressors. </li></ul><ul><li>Mortality rates of pts. w/ sepsis and ARF have decreased with early judicious resuscitative measures, glucocorticoid therapy, as well as tight glucose control. </li></ul><ul><li>Frequency of renal replacement therapy when needed has improved survival outcomes. </li></ul>