Acute Renal Failure ARF and Sepsis

1
Acute Renal Failure (ARF) and Sepsis

• ? ? ? ? ?
• ???????????
• Ref Robert W. Schrier, M.D., and Wei Wang, M.D.
  NEJM, Vol 351159-169, July 8, 2004, Number 2.

2
Outline

• Case Presentation and Introduction
• Hemodynamics and Hormones
• The Pressor Effect of AVP
• Effects of Systemic Arterial Vasodilatation on
  Body-Fluid Volume and Starling Forces
• Experimental Models of Endotoxemia and Sepsis
• Vasoactive Hormones
• Endothelial and Inducible NO Synthases
• Endotoxemia
•             Tumor Necrosis Factor and Reactive
  Oxygen Species
•             Nonspecific Inhibitors of NO Synthase
  
•             Cytokines, Chemokines, and Adhesion
  Molecules
• Disseminated Intravascular Coagulation
• Early Resuscitation
• Hyperglycemia and Insulin
• Glucocorticoids and Mechanical Ventilation
• Renal Replacement
• Conclusions

3
Toxic Neutrophils in Streptococcus pneumoniae
Sepsis

• A previously healthy, 37 Y/O woman presented to
  ER obtunded and hypotensive. The previous night,
  a cough and sore throat had developed, and the
  p't had awoken with a purpuric rash and abdominal
  pain.
• Lab. showed WBC was 20,180 per cubic millimeter,
  with 5 metamyelocytes, 6 bands, 88
  neutrophils, and 1 lymphocytes. PLT was 41,000
  per cubic millimeter.
• The tests also showed a depressed fibrinogen
  level and an elevated D-dimer level findings
  consistent with DIC.
• A peripheral-blood smear showed highly vacuolated
  neutrophils, some contained phagocytosed
  circulating diplococci (arrow).
• Despite ventilatory support and IV fluids, blood
  products, antibiotics, and vasopressive agents,
  the p't died five hours after presentation.
• One of two blood cultures pan-sensitive
  Strepto. pneumoniae.

4
(No Transcript)
5
Introduction (1)

• ARF occurs in 19 of p'ts with moderate sepsis,
  23 with severe sepsis, and 51 with septic
  shock when blood cultures are positive (Table 1
  and Table 2).
• A progressive increase in the acute respiratory
  distress syndrome (ARDS) also occurs with
  moderate and severe sepsis and septic shock.
• In the United States, an estimated 700,000 cases
  of sepsis occur each year, resulting in more than
  210,000 deaths this number accounts for 10 of
  all deaths annually and exceeds the deaths due to
  MI.

6
Introduction (2)

• Combination of ARF and sepsis is associated with
  a 70 mortality, as compared with a 45
  mortality among ARF alone.
• Combination of sepsis and ARF constitutes a
  particularly serious medical problem in the
  United States.
• Substantial progress has been made toward
  understanding the mechanisms whereby sepsis is
  associated with a high incidence of ARF.
• Recently identified clinical interventions may be
  able to decrease the occurrence of ARF and sepsis
  and the high associated mortality.

7
(No Transcript)
8
(No Transcript)
9
Introduction (3)

• The cytokine-mediated induction of NO synthesis
  that occurs in sepsis decreases systemic vascular
  resistance.
• This arterial vasodilatation predisposes sepsis
  to ARF, the need for mechanical ventilation, and
  increased mortality.
• In this article, we review the effects of
  NOmediated arterial vasodilatation on resistance
  to exogenous pressors and hypotension (Figure 1),
  and we discuss the use of AVP in septic shock.
• We also review the effects of increased plasma
  concentrations of several endogenous
  vasoconstrictor hormones, including
  catecholamines, angiotensin II, and endothelin,
  which support arterial pressure in sepsis who
  have vasodilatation but also cause renal
  vasoconstriction and predispose p'ts to ARF.

10
Figure 1. Arterial Vasodilatation and Renal
Vasoconstriction in Sepsis.

• Endotoxemia stimulates the induction of NO
  synthase, which leads to NOmediated arterial
  vasodilatation.
• The resultant arterial underfilling is sensed by
  the baroreceptors and results in an increase in
  sympathetic outflow and the release of AVP from
  the CNS, with activation of the
  reninangiotensinaldosterone system (RAAS).
• These increases in renal sympathetic and
  angiotensin activities lead to vasoconstriction
  with Na and water retention and a predisposition
  to ARF.

11
Figure 1. Arterial Vasodilatation and Renal
Vasoconstriction in Sepsis.
12
Introduction (4)

• Combination of sepsis and ARF may have some
  effects of systemic arterial vasodilatation, such
  as altered Starling forces in the capillaries,
  pulmonary edema, hypoxia, a need for mechanical
  ventilation, ARDS, and multiple-organ dysfunction
  syndrome, which together may increase mortality
  to more than 80 (Figure 2).
• We discuss interventions that may prevent this
  dire sequence of events. Finally, we review
  several prospective, randomized clinical trials
  of interventions that have the potential to
  prevent or attenuate ARF in sepsis and thus
  decrease mortality.
• Such trials have addressed anticoagulant therapy,
  early resuscitation, treatment of hyperglycemia,
  the use of corticosteroids, a shortened duration
  of mechanical ventilation, and various types of
  renal-replacement therapy.

13
Figure 2. Effects of Systemic Arterial
Vasodilatation in Sepsis and ARF.

• Sepsis and endotoxemia with ARF can lead to early
  noncardiogenic pulmonary edema, hypoxia, and the
  need for mechanical ventilation.
• With prolonged ventilatory support, ARDS,
  multiple-organ dysfunction syndrome, and an
  extremely high mortality can occur.
• The goal is to intervene early to prevent
  excessive fluid administration and essen fluid
  overload by hemofiltration.
• This will prevent the need for long-term
  mechanical ventilation that could lead to damage
  to the pulmonary capillaries.
• It could also prevent tissue hypoxia and the ARDS
  and reduce the risk of death.

14
(No Transcript)
15
????????,????????????,??????,??????????!
???????????,??????----?,????,??!??
???????!!!!
16
Hemodynamics and Hormones (1)

• The hemodynamic hallmark of sepsis is generalized
  arterial vasodilatation with decrease in systemic
  vascular resistance.
• Arterial underfilling due to arterial
  vasodilatation occurs in several clinical
  circumstances, including sepsis, and is
  associated with activation of the neurohumoral
  axis and an increase in CO secondary to the
  decreased cardiac afterload.
• Activation of the sympathetic nervous system and
  the reninangiotensinaldosterone axis, the
  nonosmotic release of vasopressin, and an
  increase in CO are essential in maintaining the
  integrity of the arterial circulation in severe
  sepsis and septic shock (Figure 1) but may lead
  to ARF.

17
Hemodynamics and Hormones (2)

• The arterial vasodilatation that accompanies
  sepsis is mediated, at least in part, by
  cytokines that up-regulate the expression of
  inducible NO synthase in the vasculature.
• The release of NO with inducible NO synthase, as
  compared with constitutive endothelial NO
  synthase, is more profound and prolonged.
• Vascular resistance to the pressor response to
  NEP and angiotensin II occurs during sepsis and
  is attributable in part to the potent
  vasodilatory effect of NO.
• In addition, an increase in plasma concentrations
  of hydrogen ions and lactate and a decrease in
  ATP in vascular smooth-muscle cells during septic
  shock activate the ATP-sensitive K channels (KATP
  channels).

18
Hemodynamics and Hormones (3)

• The resultant K efflux through the KATP channels
  causes hyperpolarization of the vascular
  smooth-muscle cells with closure of the
  voltage-gated Ca channels in the membrane.
• Since the vasoconstrictor effects of NEP and
  angiotensin II depend on open Ca channels,
  vascular resistance to these pressor hormones can
  occur along with lactic acidosis in sepsis.
• Furthermore, the high endogenous levels of these
  vasoactive hormones during sepsis may be
  associated with down-regulation of their
  receptors, which would result in a lessening of
  their effects on the vasculature.

19
Pressor Effect of arginine vasopressin (AVP) (1)

• Administration of AVP in sepsis-related
  vasodilatory shock may help maintain BP despite
  the relative ineffectiveness of other vasopressor
  hormones such as NEP and angiotensin II.
• Specifically, AVP may inactivate the KATP
  channels and lessen vascular resistance to NEP
  and angiotensin II.
• AVP also decreases the synthesis of NO (as a
  result of a decrease in the expression of
  inducible NO synthase) as well as cyclic
  guanosine monophosphate (cGMP) signaling by NO,
  thus attenuating the arterial vasodilatation and
  pressor resistance during sepsis.

20
The Pressor Effect of AVP (2)

• The degree of vasoconstriction in response to AVP
  relates to its plasma levels and occupancy of the
  V1a AVP receptors on vascular smooth-muscle
  cells.
• Initially, in septic or hemorrhagic shock, the
  plasma AVP concentrations increase to 200 to 300
  pg/ml, but after approximately an hour, the
  neurohypophysial stores of vasopressin are
  depleted and plasma concentrations may fall to 30
  pg/ml.
• At that time and in the presence of unoccupied
  V1a receptors, the administration of exogenous
  AVP can increase BP by 25 to 50 mm Hg by
  returning the plasma concentrations of ADH to
  their earlier high levels.

21
The Pressor Effect of AVP (3)

• AVP is also known to be synergistic with the
  pressor hormones NEP and angiotensin II, since
  all three hormones have in common intracellular
  signaling that involves an increase in the
  cytosolic Ca concentration.
• Another advantage of using AVP as a pressor agent
  in sepsis is that the sites of major arterial
  vasodilatation in sepsis the splanchnic
  circulation, the muscles, and the skin are
  vascular beds that contain abundant V1a AVP
  receptors.

22
The Pressor Effect of AVP (4)

• Glomerular filtration is determined by the net
  difference in arterial pressure between the
  afferent and efferent arterioles across the
  glomerular capillary bed (termed transcapillary
  filtration pressure).
• NEP profoundly constricts the glomerular afferent
  arteriole, dropping the filtration pressure, and
  thus may contribute to and prolong the course of
  ARF in sepsis.
• In contrast, AVP has been shown to constrict the
  glomerular efferent arteriole and therefore can
  increase the filtration pressure and,
  consequently, the glomerular filtration rate
  (GFR).

23
The Pressor Effect of AVP (5)

• The decision to use AVP as a pressor agent, must
  involve consideration of several additional
  physiological properties.
• Increased concentrations of AVP constrict the
  coronary arteries and have been reported to cause
  MI.
• In contrast to NEP and angiotensin II, AVP does
  not have a cardiac inotropic effect the increase
  in cardiac afterload during the infusion of AVP
  can decrease CO.
• Moreover, during sepsis, the increased CO that
  generally occurs may be suboptimal for the p't,
  given the diminished systemic vascular resistance
  and cardiac afterload, because circulating
  cytokines such as TNF that are induced by the
  septic state have myocardial depressant
  properties.

24
The Pressor Effect of AVP (6)

• Furthermore, interstitial myocarditis and
  diastolic dysfunction have also been reported to
  occur during sepsis.
• Since AVP is a very potent venoconstrictor that
  decreases splanchnic compliance, excessive fluid
  that is administered is distributed more
  centrally, including in the lung, and therefore
  can lead to noncardiogenic pulmonary edema
  (pseudoARDS).
• Administration of AVP may be effective in septic
  shock who have vasodilatation and relative
  resistance to other pressor hormones.

25
????(SPHINX),??????????????,????????????,??!??????
?,???????,????????!
26
Effects of Systemic Arterial Vasodilatation on
Body-Fluid Volume and Starling Forces (1)

• The difference between the oncotic and
  hydrostatic pressures within the vasculature and
  interstitium (Starling forces) determines whether
  plasma water remains within the vasculature or
  leaks out into the interstitium.
• Experimental studies in rats have examined the
  effect of arterial vasodilatation on Starling
  forces, albumin distribution, and body-fluid
  volume in normal animals.
• Administration of the potent arterial vasodilator
  minoxidil was shown to cause Na and water
  retention with resultant expansion of plasma and
  interstitial volume.
• With the use of Guyton's subcutaneous capsule,
  which is able to measure interstitial pressure,
  arterial vasodilatation in a rat model was shown
  to reverse the normally negative pressure within
  the interstitium.

27
Effects of Systemic Arterial Vasodilatation on
Body-Fluid Volume and Starling Forces (2)

• Moreover, during IV saline loading, interstitial
  pressure increased in animals without
  vasodilatation, whereas the elevated interstitial
  pressure in the animals that had vasodilatation
  did not increase further.
• The fall in interstitial pressure that occurred
  with IV hyperoncotic albumin in the normal
  animals did not occur in the animals with
  vasodilatation. This latter effect may be due to
  the increased distribution of albumin within the
  interstitial space that occurs with arterial
  vasodilatation. The pulmonary bed is particularly
  prone to collect interstitial fluid in this
  situation.
• If applied to humans, these findings indicate
  that sepsis who have vasodilatation are
  susceptible to noncardiogenic pulmonary edema.
  There is indeed evidence that this is the case.

28
Effects of Systemic Arterial Vasodilatation on
Body-Fluid Volume and Starling Forces (3)

• Neveu et al. performed a prospective study
  involving 345 p'ts who had ARF with or without
  sepsis.
• The most dramatic differences were the increased
  requirement for mechanical ventilation (70 vs.
  47 , P0.001) and the higher mortality (74.5
  vs. 45.2 , Plt0.001) in the p'ts with sepsis.
• Figure 2 depicts a sequence of events that can
  occur with overly aggressive fluid
  administration, which results in increases in
  interstitial volume in sepsis and ARF who have
  vasodilatation.

29
Experimental Models of Endotoxemia and Sepsis
Vasoactive Hormones (1)

• There is experimental evidence that early in
  sepsis-related ARF, the predominant pathogenetic
  factor is renal vasoconstriction with intact
  tubular function, as demonstrated by increased
  reabsorption of tubular Na and water. Thus,
  intervention at this early stage may prevent
  progression to acute tubular necrosis.
• For example, if endotoxin is infused into a
  conscious-rat model, the early events include a
  fractional excretion of Na of less than 1 ,
  indicating good tubular function.
• Fractional excretion of Na is calculated as
  (urine Na x plasma Cr) (plasma Na x urine Cr)
  x 100.
• This level of fractional excretion may result in
  prerenal azotemia.
• If this prerenal azotemic state is permitted to
  persist, the fractional excretion of Na
  increases, indicating tubular dysfunction that
  may progress to established acute tubular
  necrosis.

30
Experimental Models of Endotoxemia and Sepsis
Vasoactive Hormones (2)

• Activation of the neurohumoral axis during the
  arterial vasodilatation that occurs in sepsis is
  critical in maintaining arterial circulatory
  integrity, it is associated with renal
  vasoconstriction (Figure 1).
• Plasma catecholamines and activation of the RAAS
  are known to be heightened in cases of sepsis and
  septic shock.
• This pattern of hormonal activation has been
  observed in a normotensive murine model of
  endotoxemia induced with lipopolysaccharide (5
  mg/kgw).
• In this same model, renal denervation afforded
  considerable protection against the decrease in
  GFR during the initial 16 hours of endotoxemia.
• Such studies indicate that the effects of these
  vasoactive hormones on the kidney are, at least
  in some measure, neurally mediated and may
  contribute to the ARF seen in cases of sepsis.

31
Experimental Models of Endotoxemia and Sepsis
Vasoactive Hormones (3)

• Another pressor hormone that has been observed to
  be elevated in sepsis is endothelin, a potent
  vasoconstrictor.
• Renal vasoconstriction in sepsis seems to be due,
  at least in part, to the ability of TNF to
  release endothelin.
• Indeed, an intrarenal injection of antiserum to
  endothelin-1 in a rat model was capable of
  reversing the decrease in the GFR induced by
  endotoxin.
• During endotoxemia, endothelin may also cause a
  generalized leakage of fluid from the capillaries
  and thereby diminish plasma volume.

32
Endothelial and Inducible NO Synthases (1)

• The vasodilatory effect of constitutive
  endothelial NO synthase within the kidney might
  be expected to lessen the renal vasoconstriction
  induced by NEP, angiotensin II, and endothelin
  during sepsis.
• However, the results of in vitro studies showed
  that the increase in the plasma NO stimulated by
  inducible NO synthase during endotoxemia
  down-regulated endothelial NO synthase within the
  kidney.
• When cytokines activated inducible NO synthase,
  however, not only did the plasma NO increase, but
  also the expression of inducible NO synthase
  increased in the renal cortex.
• In association with this increased expression of
  inducible NO synthase, a progressive increase in
  cGMP in the renal cortex occurred during the
  initial 16 hours after exposure to endotoxin.

33
Endothelial and Inducible NO Synthases (2)

• At 24 hours, however, the plasma NO remained
  high, though renal cGMP had decreased. Since cGMP
  is the secondary messenger for NOmediated
  arterial vasodilatation, the down-regulation of
  this enzyme at 24 hours may also contribute to
  renal vasoconstriction during sepsis.
• Endothelial damage occurs during sepsis and may
  be associated with microthrombi and an increased
  von Willebrand factor in the circulation.
• Sepsis-related impairment of the endothelium may
  also attenuate or abolish the normal effect of
  endothelial NO synthase in the kidney to
  counteract the vasoconstrictor effects of NEP,
  endothelin, and angiotensin II.

34
Endothelial and Inducible NO Synthases (3)

• The study of knockout mice, in which the
  expression of either endothelial NO synthase or
  inducible NO synthase has been ablated, has been
  helpful in elucidating the importance of
  endothelial damage during sepsis.
• Since there is no specific inhibitor of
  endothelial NO synthase, the effect of endotoxin
  (lipopolysaccharide) was tested in endothelial NO
  synthaseknockout mice, which have a significant
  increase in BP and renal vascular resistance as
  compared with normal (control) mice.
• A small dose of endotoxin, which did not alter
  the GFR in the control mice, caused a profound
  decrease in the GFR in these knockout mice.

35
EndotoxemiaTNF and Reactive Oxygen Species (1)

• Studies have also been undertaken in inducible NO
  synthaseknockout mice to determine the role of
  the high plasma NO in the ARF that is associated
  with endotoxemia.
• A dose of endotoxin (lipopolysaccharide) of 5
  mg/kg causes a large and progressive rise in the
  plasma NO in the normotensive mouse model by
  means of inducible NO synthase. However, in mice
  in which inducible NO synthase is ablated, this
  same dose of endotoxin fails to cause an increase
  in plasma NO.
• Nevertheless, these knockout mice still have a
  decrease in the GFR after receiving endotoxin,
  suggesting that cytokines such as TNF can cause
  renal vasoconstriction even in the absence of
  inducible NO synthase.
• Although a soluble TNF receptor (TNFsRp55)
  afforded renal protection in murine endotoxemia,
  a prospective, randomized study of a monoclonal
  Ab against TNF (the MONARCS Monoclonal
  Anti-TNF A Randomized Controlled Sepsis trial)
  did not show any improvement in the survival of
  p'ts.

36
EndotoxemiaTNF and Reactive Oxygen Species (2)

• Endotoxemia is known to be associated with the
  generation of oxygen radicals and thus may
  contribute to the early vasoconstrictor phase of
  ARF. Endogenous scavengers of reactive oxygen
  species can attenuate renal tubular injury or
  renal vascular injury (or both) that is caused by
  reactive oxygen species during endotoxemia.
• However, the levels of the mRNA and protein of
  the endogenous scavenger extracellular superoxide
  dismutase, which is found predominantly in blood
  vessels and the kidney, have been noted to be
  decreased in mice during endotoxemia.
• In contrast, the mitochondrial scavenger
  manganese superoxide dismutase and the
  cytoplasmic scavenger copperzinc superoxide
  dismutase were observed to be unaltered during
  endotoxemia.
• Exogenous oxygen-radical scavengers were shown to
  protect against ARF in this normotensive mouse
  model of endotoxemia.

37
Endotoxemia TNF and Reactive Oxygen Species (3)

• In a murine model of septic shock and ARF,
  administration of a superoxide dismutase mimetic
  that had properties of oxygen-radical scavengers
  decreased deaths in the animals.
• Oxygen radicals also scavenge NO to produce
  peroxynitrite, an injurious reactive oxygen
  species.
• Furthermore, the decrease in endothelial NO
  synthase in the kidney when there is
  oxidant-related endothelial damage may contribute
  to the early vasoconstrictor phase of ARF.
• Figure 3 depicts the potential good and bad
  effects of NO during sepsis.

38
Figure 3. Good and Bad Effects of NO on the
Kidney during Sepsis.

• The induction of NO synthase and the generation
  of oxygen radicals during sepsis cause
  peroxynitrite-related tubular injury, systemic
  vasodilatation, and down-regulation of renal
  endothelial NO synthase.
• Endotoxemia, however, may increase renal cortical
  inducible NO synthase, with a resultant increase
  in NO. The NO may afford protection to the kidney
  by inhibiting platelet-aggregationrelated
  glomerular microthrombi and causing cGMP
  mediated vasodilatation to counteract renal
  vasoconstriction with increased activity of the
  sympathetic nervous system and angiotensin II
  during sepsis.
• Solid arrows indicate activation, and the dashed
  arrow and T bar inhibition.

39
(No Transcript)
40
??????---?????????????
41
Nonspecific Inhibitors of NO Synthase

• Studies in animals and humans have further
  examined the role of NO synthase in the decrease
  in the GFR during endotoxemia.
• No renal protection was found with the
  administration of a nonspecific inhibitor of NO
  synthase, NG-nitro-L-arginine methyl ester, in an
  endotoxemic rat model of ARF.
• In humans, the use of another nonspecific
  inhibitor of NO synthase, NG-monomethyl-L-arginine
  , was found to increase mortality in septic
  shock.
• Since this nonspecific inhibitor of NO synthase
  blocks both inducible and endothelial NO
  synthases, further studies with an inhibitor
  specific for inducible NO synthase,
  N6-(1-iminoethyl)-L-lysine, which would preserve
  any renal protective effect of endothelial NO
  synthase, were undertaken in the rat model.
• N6-(1-iminoethyl)-L-lysine appeared to be
  protective experimentally however, these results
  require confirmation in clinical trials in
  humans.

42
Cytokines, Chemokines, and Adhesion Molecules (1)

• The early vasoconstrictor phase of ARF during
  endotoxemia may be followed by a proinflammatory
  phase, although there is probably an overlap in
  these processes.
• It is known that caspase activates both
  interleukin-1 and interleukin-18 cytokines, and
  the resultant up-regulation of adhesion molecules
  contributes to neutrophil infiltration during
  endotoxemia.
• The importance of caspase in endotoxemia has been
  underscored by the observation that
  caspase-1knockout mice are protected against
  renal failure that is induced by either ischemia
  or endotoxemia.
• Several chemokines are also expressed during
  endotoxemia in association with neutrophil and
  macrophage infiltration into the glomeruli and
  interstitium.

43
Cytokines, Chemokines, and Adhesion Molecules (2)

• The complex composed of a lipopolysaccharide and
  the lipopolysaccharide-binding protein activates
  the membrane-CD14 and toll-like receptors on
  cells, which up-regulate nuclear factor- B (NF-
  B), a nuclear transcription factor for the
  promoters of multiple cytokines, chemokines, and
  adhesion molecules.
• Activation of NF- B may therefore be a critical
  factor in the proinflammatory phase that involves
  a cytokine, chemokine, and adhesion molecule
  "storm," which leads to ARF and an increased rate
  of death.
• Blocking agents for NF- B exist that could
  protect against endotoxemia better than targeting
  any individual cytokine, chemokine, or adhesion
  molecule.
• These substances need to be studied both in
  experimental models and in clinical studies in
  humans with concurrent sepsis and ARF.

44
Cytokines, Chemokines, and Adhesion Molecules (3)

• Complement pathways are activated during sepsis
  by bacterial products such as lipopolysaccharide,
  CRP, and other stimuli.
• Complement C5a that is generated during sepsis
  seems to have procoagulant properties, and
  blocking C5a and C5a receptor in a rodent model
  of sepsis has been shown to improve survival.
• Although animal models of endotoxemia and sepsis
  have provided insights into sepsis and ARF, the
  translation of these experimental results to p'ts
  with sepsis must be made with caution.
• Also, the mouse models in which sepsis was
  induced by the administration of
  lipopolysaccharide differed from the models
  achieved by cecal ligation and puncture.

45
Disseminated Intravascular Coagulation (DIC)

• Sepsis affects the expression of complement,
  coagulation, and the fibrinolytic cascade. Sepsis
  can be viewed as a procoagulant state that can
  lead to DIC with consumptive coagulopathy,
  thrombosis, and ultimately, hemorrhage.
• DIC has been associated with glomerular
  microthrombi and ARF.
• Prospective, randomized trials have been
  undertaken to evaluate methods of intervening in
  the procoagulant process associated with sepsis.
• A major prospective, randomized study, the
  PROWESS (Recombinant Human Activated Protein C
  Worldwide Evaluation in Severe Sepsis) trial,
  showed that recombinant human activated protein C
  (drotrecogin alfa, Xigris) significantly improved
  survival in severe sepsis, as compared with those
  given placebo (75.3 vs. 68.3 , P0.006).
• Results of renal-function tests were not reported
  in this trial.

46
Proposed Actions of Activated Protein C in
Modulating the Systemic Inflammatory,
Procoagulant, and Fibrinolytic Host Responses to
Infection
Bernard, G. R. et al. N Engl J Med
2001344699-709
47
Efficacy and Safety of Recombinant Human
Activated Protein C for Severe Sepsis

• Background Drotrecogin alfa (activated), or
  recombinant human activated protein C, has
  antithrombotic, antiinflammatory, and
  profibrinolytic properties. In a previous study,
  drotrecogin alfa activated produced
  dose-dependent reductions in the levels of
  markers of coagulation and inflammation in severe
  sepsis. In this phase 3 trial, we assessed
  whether treatment with drotrecogin alfa activated
  reduced the rate of death from any cause among
  patients with severe sepsis.
• Methods We conducted a randomized, double-blind,
  placebo-controlled, multicenter trial. Patients
  with systemic inflammation and organ failure due
  to acute infection were enrolled and assigned to
  receive an intravenous infusion of either placebo
  or drotrecogin alfa activated (24 µg/kgw/hr) for
  a total duration of 96 hours. The prospectively
  defined primary end point was death from any
  cause and was assessed 28 days after the start of
  the infusion. Patients were monitored for adverse
  events changes in vital signs, laboratory
  variables, and the results of microbiologic
  cultures and the development of neutralizing
  antibodies against activated protein C.

N Engl J Med 2001344699-709.
48

• Results A total of 1690 randomized patients were
  treated (840 in the placebo group and 850 in the
  drotrecogin alfa activated group). The mortality
  rate was 30.8 percent in the placebo group and
  24.7 percent in the drotrecogin alfa activated
  group. On the basis of the prospectively defined
  primary analysis, treatment with drotrecogin alfa
  activated was associated with a reduction in the
  relative risk of death of 19.4 percent (95
  percent confidence interval, 6.6 to 30.5) and an
  absolute reduction in the risk of death of 6.1
  percent (P0.005). The incidence of serious
  bleeding was higher in the drotrecogin alfa
  activated group than in the placebo group (3.5
  percent vs. 2.0 percent, P0.06).
• Conclusions Treatment with drotrecogin alfa
  activated significantly reduces mortality in
  patients with severe sepsis and may be associated
  with an increased risk of bleeding.

N Engl J Med 2001344699-709.
49
???????
50
Early Resuscitation (1)

• Since the early vasoconstrictor phase of sepsis
  and ARF is potentially reversible, it should be
  an optimal time for intervention.
• However, clinical studies performed in p'ts up to
  72 hours after admission to ICU, in which
  attempts were made to optimize hemodynamics and
  monitor the p'ts with a pulmonary-artery
  catheter, not only were negative but showed
  increased mortality among p'ts with sepsis.
• In contrast, a randomized study of 263 p'ts with
  a mean serum Cr of 2.6 mg/dl (230 µmol/l) on
  admission to ER showed that early goal-directed
  therapy during the first six hours after
  admission was effective.

51
Early Resuscitation (2)

• The central venous oxygen saturation was
  continuously monitored as goal-directed therapy
  was instituted in p'ts assigned to such
  interventions, the multiorgan dysfunction score
  decreased significantly and in-hospital mortality
  decreased (30.5 , as compared with 46.5 in the
  control p'ts, who received standard care
  P0.009).
• The goal-directed approach included early volume
  expansion and administration of vasopressors to
  maintain mean BP at or above 65 mm Hg and
  transfusion of red cells to increase the Hct to
  30 or more if central venous oxygen saturation
  was less than 70 .
• If these interventions failed to increase central
  venous oxygen saturation to greater than 70 ,
  then therapy with dobutamine was instituted.

52
Hyperglycemia and Insulin (1)

• Hyperglycemia impairs the function of leukocytes
  and macrophages.
• A randomized study of 1548 p'ts compared the use
  of insulin to control blood glucose levels
  tightly (maintaining blood glucose levels between
  80 and 110 mg/dl 4.4 and 6.1 mmol/l) with
  conventional treatment (the use of insulin only
  if the blood glucose levels exceeded 215 mg/dl
  11.9 mmol/l, with the aim of maintaining
  glucose levels between 180 and 220 mg/dl 10.0
  and 12.2 mmol/l).

53
Hyperglycemia and Insulin (2)

• The group assigned to tight control of blood
  glucose levels showed a decrease in mortality in
  the intensive care unit as compared with the
  group receiving conventional treatment (4.6 vs.
  8 , Plt0.04), a 46 decrease in positive blood
  cultures, and a 41 decrease in ARF requiring
  dialysis or hemofiltration.
• Multiple-organ failure with a proven focus of
  sepsis was also decreased (8 cases vs. 33 cases,
  P0.02).
• Recent studies further support the importance of
  controlling blood glucose in critically ill p'ts
  but suggest a less stringent goal of maintaining
  blood glucose at a level of 145 mg/dl (8.0
  mmol/l) or less.

54
Glucose Control and Mortality in Critically Ill
Patients

• Context  Hyperglycemia is common in critically
  ill patients, even in those without diabetes
  mellitus. Aggressive glycemic control may reduce
  mortality in this population. However, the
  relationship between mortality, the control of
  hyperglycemia, and the administration of
  exogenous insulin is unclear.
• Objective  To determine whether blood glucose
  level or quantity of insulin administered is
  associated with reduced mortality in critically
  ill patients.
• Design, Setting, and Patients  Single-center,
  prospective, observational study of 531 patients
  (median age, 64 years) newly admitted over the
  first 6 months of 2002 to an adult ICU in a UK
  national referral center for cardiorespiratory
  surgery and medicine.
• Main Outcome Measures  The primary end point was
  ICU mortality. Secondary end points were hospital
  mortality, ICU and hospital length of stay, and
  predicted threshold glucose level associated with
  risk of death.

JAMA 20032902041-2047.
55

• Results  Of 531 patients admitted to the ICU, 523
  underwent analysis of their glycemic control.
  Twenty-fourhour control of blood glucose levels
  was variable. Rates of ICU and hospital mortality
  were 5.2 and 5.7, respectively median lengths
  of stay were 1.8 (interquartile range, 0.9-3.7)
  days and 6 (interquartile range, 4.5-8.3) days,
  respectively. Multivariable logistic regression
  demonstrated that increased administration of
  insulin was positively and significantly
  associated with ICU mortality (odds ratio, 1.02
  95 confidence interval, 1.01-1.04 at a
  prevailing glucose level of 111-144 mg/dL
  6.1-8.0 mmol/L for a 1-IU/d increase),
  suggesting that mortality benefits are
  attributable to glycemic control rather than
  increased administration of insulin. Also, the
  regression models suggest that a mortality
  benefit accrues below a predicted threshold
  glucose level of 144 to 200 mg/dL (8.0-11.1
  mmol/L), with a speculative upper limit of 145
  mg/dL (8.0 mmol/L) for the target blood glucose
  level.
• Conclusions  Increased insulin administration is
  positively associated with death in the ICU
  regardless of the prevailing blood glucose level.
  Thus, control of glucose levels rather than of
  absolute levels of exogenous insulin appear to
  account for the mortality benefit associated with
  intensive insulin therapy demonstrated by others.

JAMA 20032902041-2047.
56
Glucocorticoids and Mechanical Ventilation (1)

• Glucocorticoids have been known to enhance the
  pressor effects of catecholamines, but older
  studies in which septic shock was treated with
  large doses of glucocorticoid hormones for a
  short period of time did not show any benefit.
• However, a recent study in septic shock showed
  that p'ts without a response to corticotropin (as
  defined by a rise in plasma free cortisol of less
  than 9 µg/dl at 30 or 60 mins) who were treated
  for 7 days with IV boluses of 50 mg of
  hydrocortisone every 6 hrs plus daily oral
  fludrocortisone (a 50-µg tablet) had a decrease
  in mortality at 28 days as compared with placebo
  (63 vs. 53 , P0.02).
• In this randomized study, 229 of the 299 p'ts
  with septic shock who were enrolled were
  classified as not having a response.
• There was no difference in mortality among the 70
  p'ts with a response to the short corticotropin
  study.

57
Glucocorticoids and Mechanical Ventilation (2)

• Withdrawal of vasopressors was also significantly
  better at 28 days in those without a response (40
  vs. 57 , Plt0.001). Although this study did not
  report renal function results, it is known that
  septic shock is associated with ARF in 38 of
  p'ts with negative cultures and 51 of p'ts with
  positive cultures.
• Other studies show that the longer the duration
  of mechanical ventilation, the higher the
  mortality in p'ts with sepsis and ARF.
• One study showed that daily interruption of a
  continuous infusion of sedatives in critically
  ill p'ts who were undergoing mechanical
  ventilation shortened the time needed on the
  ventilator (7.3 vs. 4.9 days, P0.004) and time
  in the intensive care unit (9.9 vs. 6.4 days,
  P0.02).

58
Effect of Treatment With Low Doses of
Hydrocortisone and Fludrocortisone on Mortality
in Patients With Septic Shock

• Context  Septic shock may be associated with
  relative adrenal insufficiency. Thus, a
  replacement therapy of low doses of
  corticosteroids has been proposed to treat septic
  shock.
• Objective  To assess whether low doses of
  corticosteroids improve 28-day survival in
  patients with septic shock and relative adrenal
  insufficiency.
• Design and Setting  Placebo-controlled,
  randomized, double-blind, parallel-group trial
  performed in 19 intensive care units in France
  from October 9, 1995, to February 23, 1999.
• Patients  Three hundred adult patients who
  fulfilled usual criteria for septic shock were
  enrolled after undergoing a short corticotropin
  test.

JAMA. 2002288862-871.
59

• Intervention  Patients were randomly assigned to
  receive either hydrocortisone (50-mg intravenous
  bolus every 6 hours) and fludrocortisone (50-µg
  tablet once daily) (n 151) or matching placebos
  (n 149) for 7 days.
• Main Outcome Measure  Twenty-eight-day survival
  distribution in patients with relative adrenal
  insufficiency (nonresponders to the corticotropin
  test).
• Results  One patient from the corticosteroid
  group was excluded from analyses because of
  consent withdrawal. There were 229 nonresponders
  to the corticotropin test (placebo, 115
  corticosteroids, 114) and 70 responders to the
  corticotropin test (placebo, 34 corticosteroids,
  36). In nonresponders, there were 73 deaths (63)
  in the placebo group and 60 deaths (53) in the
  corticosteroid group (hazard ratio, 0.67 95
  confidence interval, 0.47-0.95 P .02).
  Vasopressor therapy was withdrawn within 28 days
  in 46 patients (40) in the placebo group and in
  65 patients (57) in the corticosteroid group
  (hazard ratio, 1.91 95 confidence interval,
  1.29-2.84 P .001). There was no significant
  difference between groups in responders. Adverse
  events rates were similar in the 2 groups.
• Conclusion  In our trial, a 7-day treatment with
  low doses of hydrocortisone and fludrocortisone
  significantly reduced the risk of death in
  patients with septic shock and relative adrenal
  insufficiency without increasing adverse events.

JAMA. 2002288862-871.
60
Renal Replacement (1)

• Pts with sepsis and ARF are hypercatabolic.
• Studies suggesting that increased doses of
  dialysis improve survival in p'ts who are
  hypercatabolic and have ARF are persuasive. For
  example, survival was markedly improved with
  aggressive hemodialysis as compared with
  peritoneal dialysis in p'ts who had heatstroke,
  rhabdomyolysis, and ARF.
• Hemofiltration has been shown to produce better
  survival rates than peritoneal dialysis in p'ts
  with ARF associated with malaria and other
  infections.
• A recent study showed that daily hemodialysis as
  compared with alternate-day hemodialysis was
  associated with less systemic inflammatory
  response syndrome or sepsis (22 vs. 46 ,
  P0.005), lower mortality (28 vs. 46 , Plt0.01)
  and a shorter duration of ARF (mean SD, 92
  vs. 166 days P0.001).

61
Renal Replacement (2)

• Continuous renal-replacement therapy has
  increasingly been used to treat ARF. A randomized
  study using continuous venovenous hemofiltration
  suggested that the ultrafiltration rate of 35 or
  45 ml/kg/hr as compared with 20 ml/kg/hr improves
  survival in ARF (Plt0.001).
• Moreover, in p'ts with sepsis-related ARF, better
  survival was observed with an ultrafiltration
  rate of 45 ml/kg/hr than with a rate of 35
  ml/kg/hr. Meta-analysis of hemodialysis as
  compared with continuous renal-replacement
  therapy in ARF, however, has not yet shown an
  advantage for either mode of renal-replacement
  therapy.
• The benefit of the removal of cytokines by
  continuous renal-replacement therapy also remains
  to be proven as a method for improving survival
  in sepsis and ARF.

62
Conclusions

• ARF is a common complication of sepsis and septic
  shock.
• P'ts who have sepsis-related ARF have much higher
  mortality than p'ts with ARF who do not have
  sepsis.
• Experimental models of endotoxemia and sepsis
  have provided insights into the pathogenesis of
  sepsis-related ARF, but results from such models
  should be examined stringently before applying
  them to p'ts with sepsis.
• As shown in Figure 4, recent clinical studies
  indicate that interventions based on several
  proposed pathogenetic factors in sepsis-related
  ARF may have a favorable effect on both the
  incidence of ARF and the mortality of p'ts with
  ARF.

63
Figure 4. Methods of Attenuating or Preventing
Sepsis-Related ARF

• AVP (AVP) and hydrocortisone (50 mg every six
  hours for seven days) may be effective therapy
  for pressor-resistant hypotension and may
  decrease the likelihood of ARF during septic
  shock.
• Early directed resuscitation of p'ts with sepsis
  may prevent the progression from prerenal
  azotemia to acute tubular necrosis.
• Maintenance of blood glucose levels below 145
  mg/dl (8.0 mmol/l) may decrease the incidence of
  ARF, multiple-organ dysfunction syndrome, and
  death.
• Finally, activated protein C can decrease DIC
  with glomerular and microvascular thrombi and
  thereby decrease mortality.
• T bars indicate inhibition.

64
(No Transcript)
65
Thank You Awfully For Your Great Attention !
?????----????