Download ARF in Sepsis

Prevention and Treatment of
Acute Renal Failure in Sepsis
AN S. DE VRIESE
J 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
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.

Prevention and Treatment of
Acute Renal Failure in Sepsis
 Treatment
with Fluids, Vasopressors,
and Diuretics
 Specific Pharmacologic Treatment
 Dialytic Treatment
 Conclusion
Treatment with Fluids,
Vasopressors, and Diuretics
I.
II.
III.
IV.
Volume Expansion
Vasopressors
Low-Dose Dopamine
Diuretics
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.

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.

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.

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
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.
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.

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.

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.
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)
Specific Pharmacologic Treatment









Anti-TNF-α Therapy
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
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
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.
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.
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.
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.
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
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
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.

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
Activated Protein C




Protein C is activated by the thrombinthrombomodulin 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
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
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.
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.
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
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.

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.
Dialytic Treatment
Intermittent Hemodialysis (IHD) Versus
Continuous Renal Replacement Therapy
(CRRT)
 Extracorporeal Inflammatory Mediator
Removal

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 24h 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
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.
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.
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)
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.
The END
Thank You !