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Acute Renal Failure and Sepsis

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Acute Renal Failure and Sepsis

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    1. Acute Renal Failure and Sepsis Michael Fernando M.D. PGY-3 Cleveland Clinic July 18, 2007

    2. Clinical Definition of Sepsis

    3. RIFLE classification of Acute Renal Failure (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 (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 (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 (L)oss - Persistent ARF, complete loss of kidney function >4 wk (E)nd Stage Kidney Disease - Loss of kidney function >3 months

    4. Occurrence of Acute Renal Failure in Sepsis

    5. Objectives Hemodynamics and Hormones Pressor Effect of Vasopressin Effects of arterial vasodilatation on fluid volume Models of endotoxemia and sepsis Early Resuscitation Glucose control Glucocorticoids Renal Replacement

    6. Hemodynamics and Hormones The hemodynamic hallmark of sepsis is generalized arterial vasodilatation with ? SVR - leads to activation of sympathetic nervous system - renin-angiotensin-aldosterone axis - nonosmotic release of vasopressin - increase in cardiac output 2 to ? afterload Maintaining the integrity of arterial circulation in pts. with severe sepsis and septic shock may lead to ARF

    7. Pathophysiology

    8. Pathophysiology II Arterial vasodilatation in sepsis is mediated by: -cytokines ? upregulate expression of inducible NO synthase - vasodilatory effect of inducible NO synthase is more profound and prolonged than constitutive NO synthase - ? [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

    9. Importance of Vasopressin Vasopressin in septic shock may maintain BP despite ineffectiveness of other pressors (ie Norepinephrine, and angiotensin II) - inactivate K+ channels lessening resistance to norepinephrine and angiotensin II - ? synthesis of NO (via inducible NO synthase and its signaling pathway cGMP) - via Arginine Vasopressin eceptor V1A Neurohumoral response - 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

    10. Vasopressin and GFR Norepinephrine - profoundly constricts afferent arteriole decreasing filtration pressure prolonging ARF Vasopressin increases GFR - Via constriction of efferent arteriole which increases filtration pressure thereby ? GFR

    11. Effects of Systemic Arterial Vasodilation on Starling forces 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. IV hyperoncotic albumin produced a fall in interstitial pressures non-vasodilated animals however interstitial pressures remained the same in vasodilated animals. Effect may be due to increased distribution of albumin w/i the interstitial space of vasodilated animals.

    12. Effects of systemic arterial vasodilatation (cont.d) Pulmonary vasculature is particularly prone to collect interstitial fluid. Extrapolated to humans, pts. in sepsis with vasodilatation may be susceptible to noncardiogenic pulmonary edema. 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%

    13. Excessive fluid administration in the setting of Sepsis and ARF Sequelae of excess fluids in sepsis w/ ARF 1) redistribution of albumin and altered starling forces 2) Pulmonary edema and hypoxia 3) need for mechanical ventilation 4) progression to sepsis related ARDS 5) ? mortality

    14. Experimental models of Sepsis induced ARF 1) Experiments w/ endotoxin infused rats showed that early in course FENa <1% indicating good tubular function in prerenal azotemic state. As the state persists FENa ? indicating tubular dysfunction ? ATN 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. -results showed that renal denervation afforded considerable protection against decreased GFR during first 16 hours of endotoxemia. -this suggests that neurally mediated vasoactive hormoes contribute to ARF in sepsis 3) Antiserum to endothelin in a rat model showed that reduced GFR in endtoxemia can be temporarily reversed. - suggesting that TNF ? released endothelin is partially responsible for renovasoconstriction.

    15. Benefits of Early Fluid Resuscitation 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) Goal directed therapy Early volume expansion and vasopressors titrated to MAPs 65mm Hg Transfusion of pRBCs to maintain Hct above 30 if SvO2 <70% If SvO2 < 70% despite the above interventions dobutamine was started.

    16. Glucose Control 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. In theory hyperglycemia impairs the overall function of leukocytes and macrophages

    17. Benefits Glucorticoids It has been known that glucorticoids enhance the pressor effects of catecholamines 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. Withdrwal of vasopressors was also significantly better 40% vs. 57%

    19. Renal Replacement Therapy 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. 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

    20. Peak Concentration Hypothesis

    21. Renal Replacement Therapy 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. RCT using CVVHD w/ ultrafiltration rate of 35-45ml/kg/hr compared w/ 20ml/kg/hr improved survival in ARF. (Ronco et. al.)

    22. Conclusions Vasopressin has been shown to have greater therapeutic value compared to other pressors. Mortality rates of pts. w/ sepsis and ARF have decreased with early judicious resuscitative measures, glucocorticoid therapy, as well as tight glucose control. Frequency of renal replacement therapy when needed has improved survival outcomes.

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