Prevention and Treatment of Acute Renal Failure in Sepsis AN S. DE VRIESE J Am Soc Nephrol 14: 792–805, 2003

1. Prevention and Treatment of Acute Renal Failure in SepsisAN S. DE VRIESEJ Am Soc Nephrol 14: 792–805, 2003 Supervisor:主治醫師 李博仁 Reporter :住院醫師 巫文平 VGHTC-9211

2. Introduction • ARF: Common complication of sepsis and carries an ominous prognosis. • Mortality of ARF: Septic ARF: 74.5% ARF not related to sepsis: 45.2% • ARF: Increases morbidity and mortality of sepsis.

3. Prevention and Treatment of Acute Renal Failure in Sepsis • Treatment with Fluids, Vasopressors, and Diuretics • Specific Pharmacologic Treatment • Dialytic Treatment • Conclusion

4. Treatment with Fluids, Vasopressors, and Diuretics • Volume Expansion • Vasopressors • Low-Dose Dopamine • Diuretics

5. I. Volume Expansion • Optimization of systemic hemodynamics and effective intravascular volume • important to prevent ARF in pts with sepsis. • What constitutes optimal hemodynamics • remains largely undefined.

6. I. Volume Expansion • 3 systematic reviews of randomized controlled trials comparing crystalloids with colloids • yielded conflicting results. • The nature and targets of an optimal fluid resuscitation regimen • continue to be an unresolved issue.

7. II. Vasopressors • When appropriate volume expansion fails to restore BP in pts with sepsis, • vasopressors are indicated. • Physicians have been concerned about their use for fear that intrarenal vasoconstriction would abrogate the benefits of increased BP.

8. Norepinephrine • In a pt with sepsis, characterized by systemic vasodilatation and impaired renal autoregulation, • Norepinephrine administration may be expected to improve RBF. • Several non-controlled studies in pts with sepsis • Norepinephrine augmented urine output & GFR • A prospective observational study in 97 pts with septic shock • lower mortality in pts treated with norepinephrine than those with other vasopressors mainly high-dose dopamine

9. Vasopressin • Vasopressin, a hormone secreted by the posterior pituitary, increases systemic vascular resistance through activation of V1a-receptors on vascular smooth muscle cells. • A randomized trial in 24 pts with septic shock demonstrated that a 4-h infusion of arginine vasopressin • Improved urine output & creatinine clearance with similar effects on BP and cardiac output, as compared with norepinephrine.

10. II. Vasopressors • Vasopressors can be used safely to restore BP without compromising renal function in patients with septic shock. • Norepinephrine is preferable to dopamine. • In patients refractory to norepinephrine, early use of arginine vasopressin is recommended.

11. III. Low-Dose Dopamine • Low-dose dopamine (1 to 3 μg/kg/ min) • increases RBF, diuresis, and natriuresis in healthy animals & humans • may be of potential benefit in pts with ARF. • Side effect of Dopamine: • Depress respiratory drive • Trigger tachyarrhythmias & myocardial ischemia. • Suppress all anterior pituitary-dependent hormones, except for cortisol • decrease T cell function.

12. III. Low-Dose Dopamine • Low-dose dopamine in different models of experimental ARF, including ischemic ARF and septicemia => protective or no beneficial effects • Low-dose dopamine for renoprotective purposes should be abandoned, due to • No evidence supporting its effectiveness • Precipitate serious cardiovascular & metabolic complications in critically ill pts.

13. IV. Diuretics • Intravascular volume depletion should be carefully corrected • as an already damaged kidney may be profoundly injured by a relatively mild decrease in perfusion pressure. • In pts with sustained oliguria despite high doses of loop diuretics=> treatment should be withdrawn. • In responders=>continuous infusions are preferred ( more effective & associated with less toxicity)

15. Specific Pharmacologic Treatment • Anti-TNF-αTherapy • Inhibition of Platelet-Activating Factor • Inhibition of Nitric Oxide Synthase • Endothelin Antagonism • Inhibitors of Arachidonic Acid Metabolism • Natriuretic Peptides • Inhibition of Leukocyte Adhesion • Inhibitors of Coagulation-Activate protein C • Growth Factors

16. Anti-TNF-Therapy • TNF-affects the kidney • Indirect: inducing hypotension and releasing inflammatory mediators in the circulation • Direct: TNF- mediated renal damage in sepsis. • Success of anti-TNF therapies in animal models with prevention of both mortality and RF the • but not in humans • A more profound knowledge of cytokine profiles in septicemia • better selection of pts that will most likely benefit from these therapies

17. Inhibition of Platelet-Activating Factor • A large phase III trial with PAF acetylhydrolase (a recombinant form of the endogenous human enzyme that hydrolyzes PAF) has been initiated in pts with severe sepsis. • Although experimental studies are encouraging, no firm conclusions on the value of PAF antagonism in septic ARF can be drawn in the absence of information from clinical trials.

18. Inhibition of Nitric Oxide Synthase • The ubiquitous nature and the pleiotropic effects of the NO system & its complex alterations in sepsis and ARF=> explain why NOS inhibition fails to show laudable effects. • NO: essential to counterbalance the vasoconstricton and maintain RBF => inhibit infiltration of leukocytes & to prevent thrombosis. • Excessive NO production : Exacerbates the injurious effects of ischemia on tubular cells.

19. Endothelin Antagonism • Effective in experimental models of sepsis • A nonselective ET antagonist increased the risk of contrast nephropathy in patients with chronic renal failure undergoing coronary angiography. • The mixed results in experimental models of sepsis and the deleterious effects in human contrast nephropathy • Reexamine the rationale for ET antagonism before embarking on clinical trials in patients with ARF and sepsis.

20. Inhibitors of Arachidonic Acid Metabolism • In pts with sepsis, cyclooxygenase inhibition with ibuprofen • Reduced the synthesis of thromboxane and prostacyclin, • No effect on the development of shock or renal failure • No improvement of survival. • Clinical studies with selective thromboxane or leukotriene inhibitors have not been performed.

21. Natriuretic Peptides • In a noncontrolled study of 11 pts who developed ARF after cardiac surgery, long-term (48-h) ANP infusion • improved RBF and GFR • In 3 randomized placebo-controlled trials in critically ill pts with ARF, a infusion of ANP (anaritide or urodilatine) • did not improve renal function • No convincing evidence to support the use of natriuretic peptides as adjunctive treatment in ARF

22. Inhibition of Leukocyte Adhesion • Inhibition of leukocyte recruitment is a potential promising approach in the treatment of septic ARF, but data in humans are required before relevant conclusions can be drawn

23. Inhibitors of Coagulation -Rationale • DIC is common in septic pts and is associated with an adverse prognosis. • It is characterized by a generalized activation of the coagulation cascade, • resulting in the intravascular formation of fibrin clots & endothelial damage. • Impaired tissue blood supply contributes to organ dysfunction, including ARF.

24. Inhibitors of Coagulation -Rationale • Tissue Factor Pathway Inhibitor : tissue factor inhibited by a natural anticoagulant, tissue factor pathway inhibitor (TFPI). • Antithrombin: blocks several proteases involved in coagulation, but its inhibitory effect is most powerful against factor Xa and thrombin • Plasma levels of antithrombin are usually markedly reduced in pts with sepsis, which is associated with an increased mortality • Activated Protein C

25. Activated Protein C • Protein C is activated by the thrombin-thrombomodulin complex on endothelial cells. • Activated protein C inhibits thrombin generation by inactivating factor Va and factor VIIIa. • Activated protein C has direct antiinflammatory properties, including impairment of leukocyte adhesion to the endothelium by binding selectins and inhibition of the production of inflammatory cytokines by monocytes. • It stimulates the fibrinolytic response by inhibiting plasminogen-activator inhibitor type 1

26. Proposed Actions of Activated Protein C in Modulating the Systemic Inflammatory, Procoagulant, and Fibrinolytic Host Responses to Infection--N Engl J Med, Vol. 344, No. 10·March 8, 2001 TAFI: thrombin-activatable fibrinolysis inhibitor ; PAI-1: plasminogen-activator inhibitor 1

27. Activated Protein C • In a randomized, multicenter trial conducted in 1690 pts with severe sepsis, recombinant human activated protein C significantly reduced mortality. • Treatment with drotrecogin alfa activated (24 μg/ kg of body weight/ hour for a total duration of 96 hours)=>Reduces mortality in pts with severe sepsis & Increases risk of bleeding. • More efficacy=> in the seriously ill pts, as assessed by the APACHE II score, the number of failing organs & the presence of shock.

28. Kaplan–Meier Estimates of Survival among 850 Patients with Severe Sepsis in the Drotrecogin Alfa Activated Group and 840 Patients with Severe Sepsis in the Placebo Group.

29. Inhibitors of Coagulation -Conclusion • Several strategies to inhibit coagulation have been evaluated as adjunctive therapies in sepsis • only activated protein C has proved successful. • The success of activated protein C may hinge on its combined effects on coagulation, fibrinolysis, & inflammation, rather than anticoagulation alone. • Activated protein C is currently the first biologic agent approved by the FDA for the treatment of sepsis. • The FDA has restricted its use to pts with an APACHE score of 25 or more

30. Growth Factors • Despite ample evidence that growth factors accelerate renal recovery in experimental ARF in the rat. • A study in a large animal model more representative for human ARF as well as several clinical studies in critically ill pts => no beneficial or even detrimental effects.

31. Potential Treatments of ARF -Conclusion • Several researches successful in unraveling the complex pathophysiology of sepsis & ARF • different pharmacologic interventions that are effective in ameliorating experimental ARF • failed to come up with a treatment that works in humans. • The success of activated protein C, by virtue of its combined actions on the inflammatory, coagulation, and fibrinolytic cascades • The complex & multifactorial nature of septic ARF =>require multitargeted interventions.

32. Dialytic Treatment • Intermittent Hemodialysis (IHD) Versus Continuous Renal Replacement Therapy (CRRT) • Extracorporeal Inflammatory Mediator Removal

33. Dialytic Treatment • Benefit of CRRT=> better hemodynamic tolerance, due to a more gradual fluid and solute removal. • A randomized crossover trial compared 24-h continuous arteriovenous hemofiltration with a 24-h period encompassing a 4-h IHD session in 27 critically ill patients and found no difference in the incidence of BP drops and vasopressor requirements

34. Dialytic Treatment • Although physicians intuitively prefer CRRT to IHD in critically ill pts with severe fluid overload and cardiovascular instability, • No conclusive evidence to support the superiority of either technique. • As for today, a reasonable approach is to choose a technique according to individual pt characteristics, nursing proficiency, and technical resources.

35. Extracorporeal Inflammatory Mediator Removal • Assuming that effective clearance of humoral mediators of inflammation were achievable, it is far from clear which mediators should be removed at which time point and under which conditions this might be advantageous for the pt. • Side effect: =>deplete valuable nutrients, albumin, hormones, vitamins, trace elements, & antibiotics, with potential detrimental effects for the pt.

36. The 5 of TNF-α, IL-1β, & IL-6 that was removed after the start of CVVH in 15 pts with septic shock & ARF.(change filter at 12hrs)

37. Conclusion • Unfortunately, treatment of ARF in sepsis is as yet exclusively supportive. • Thousands of pts have been randomized in industry-sponsored trials of sophisticated pharmacologic therapies, yielding very little or no tangible results, with the exception of activated protein C. • Clear guidelines on basic therapeutic attitudes such as the optimal fluid resuscitation regimen, use of diuretics, dose of dialysis, and timing of initiation of dialysis are still lacking.

38. The END Thank You !