- 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
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
- 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
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.
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.
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
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