Transcript Document

Severe Sepsis: Recent Advances in Management and the Need
to do More
Kimberly E Fenton and Margaret M Parker
Department of Pediatrics, Stony Brook University, Stony Brook, NY, USA
The past two decades have seen a marked increase in our
understanding of the pathophysiology of sepsis and septic
shock.
Standard management, such as appropriate early antibiotic
therapy, and aggressive fluid resuscitation remains the
mainstay of therapy.
Early goal-directed therapy has been shown to reduce the
mortality rate. Newer approaches include the use of
drotrecogin alfa (activated), low tidal volume ventilation for
patients with acute respiratory distress syndrome, control of
hyperglycemia in critically ill patients, and the use of steroids
in patients with relative adrenal insufficiency.
Implementation of a combination of approaches, with
attention to critical care, will hopefully bring about the
decreases in mortality that have been long sought.
ADVANCES IN SEPSIS
Advances in Sepsis 2004;3(3):75-82
Introduction
• Severe sepsis is one of the most common causes of death in
intensive care units (ICUs).
• Over the past two decades, there have been major advances
in the understanding of the pathophysiology of sepsis and
septic shock, as well as numerous new approaches to
treatment.
• Despite improved understanding of the pathophysiology of
sepsis, novel therapies, and better ICU care all contributing to
better survival rates, sepsis remains one of the top 10 leading
causes of death in the US.
ADVANCES IN SEPSIS
Epidemiology
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The incidence of severe sepsis and septic shock is difficult to
determine accurately. There are an estimated 750 000 cases of severe
sepsis leading to 215 000 deaths per year in the US alone.
Incidence in Europe just as high, with >21% of all ICU admissions
resulting from sepsis.
Longitudinal data indicate that the incidence of sepsis continues to
rise [3]. The increasing incidence of sepsis is due to:
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Better survival of patients whose chronic diseases put them at increased
risk for sepsis, such as diabetics.
The use of invasive devices for monitoring and treatment of critically ill
patients.
The increasing use of therapies that improve survival from underlying
diseases but result in immunosuppression.
Sepsis carries a substantial morbidity from secondary organ failure,
the most common organ failures are respiratory and renal [3].
ADVANCES IN SEPSIS
Epidemiology continued…
• Sepsis is not just a disease of the elderly. Although it occurs
with less frequency in children, sepsis spans across all age
groups.
• Most cases of pediatric sepsis occur in the very young (<1
year of age), with a smaller percentage occurring in children
aged 1–19 years.
• While the morbidity is similar to that seen in adults, the risk of
mortality is significantly less in children, at approximately
10% [1].
• Increasing numbers of patients in the US are being discharged
to rehabilitation facilities. While this may reflect shorter
lengths of hospital stay and patients who would not have
previously survived, the costs are great, with a national
average hospitalization for sepsis costing US$22 100 per
patient.
ADVANCES IN SEPSIS
Pathophysiology
• The syndrome of sepsis is a complex interaction between
microorganisms, toxins, and the immune system, which
results in activation of the systemic inflammatory response
syndrome, characterized by:
• Cytokine production.
• Prostaglandin activation.
• Activation of the coagulation cascade.
• The resultant effects to the host are generalized endothelial
injury, increased capillary permeability, distributive
hemodynamic compromise, coagulopathy, tissue anoxia, and
ischemia, all of which can lead to the development of
multiorgan system failure.
ADVANCES IN SEPSIS
Specific therapies
Antimicrobial therapy
• Many agents that block one or more of the mediators of sepsis
have failed to demonstrate a reduction in mortality in clinical
trials.
• Antimicrobial therapy is the mainstay of treatment, using
broad-spectrum therapy empirically upon diagnosis of septic
shock.
• Removal or drainage of the source of infection, if possible, is
also important.
• Numerous studies demonstrate a substantially lower mortality
rate in patients who receive prompt and appropriate
antimicrobial therapy compared with those who do not.
ADVANCES IN SEPSIS
Specific therapies
Drotrecogin alfa (activated)
• Drotrecogin alfa (activated) (recombinant human Activated
Protein C) is a novel specific therapy for severe sepsis that
has been shown to decrease mortality.
• Protein C requires conversion to its active form by complexing
with thrombin and endothelial cell thrombomodulin.
• The activated form of protein C modulates inflammation,
coagulation, and endothelial cell function via its antiinflammatory activity and antithrombotic and fibrinolytic
properties.
• Coagulation abnormalities, specifically Activated Protein C
deficiency, are well described in sepsis.
• Lower protein C concentrations in adult patients with sepsis
correlate with an increased mortality rate.
ADVANCES IN SEPSIS
Specific therapies
Drotrecogin alfa (activated)continued…
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The PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) trial
was a Phase III, randomized, double blind, placebo-controlled clinical
trial that studied the effect of 96 h of continuous infusion of
drotrecogin alfa (activated) in 1690 patients with severe sepsis.
Compared with those treated with a placebo, patients treated with
drotrecogin alfa (activated) demonstrated a 6.1% absolute reduction
in mortality (19.4% adjusted relative decrease in risk of mortality).
Subgroup analysis of the PROWESS trial demonstrated a beneficial
effect of drotrecogin alfa (activated) on the reduction of organ system
failure.
Patients treated with drotrecogin alfa (activated) showed a significant
improvement in both cardiovascular and respiratory function and a
prevention or delay in hematological dysfunction as assessed by
Sequential Organ Failure Assessment (SOFA) scores.
ADVANCES IN SEPSIS
Specific therapies
Drotrecogin alfa (activated)continued…
• In the more recent ENHANCE (Baseline Characteristics and
Survival of Adult Severe Sepsis Patients Treated with
Drotrecogin Alfa in a Global, Single-Arm, Open-Label Trial),
2378 adult patients with sepsis were treated in an open-label
study using similar entry criteria to the PROWESS trial.
• Patients were treated early in the course of severe sepsis
(<48 h of symptoms). The reduction in mortality (25.3%) was
similar to PROWESS (24.7%), compared with the placebo
treated group in PROWESS (30.8%).
• It is likely that earlier treatment will be associated with better
outcome. The major side effect of drotrecogin alfa (activated)
is a slightly increased risk of serious bleeding (3.5% incidence
in the treated group compared with 2% incidence in the
placebo group).
ADVANCES IN SEPSIS
Specific therapies
Drotrecogin alfa (activated)continued…
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ADVANCES IN SEPSIS
Supportive therapies
Early goal-directed therapy
• Of all the supportive therapies, early goal-directed therapy
(EGDT) has demonstrated the most substantial impact on
outcome.
• While prior studies aimed at hemodynamic optimization to
both normal and supranormal values have failed to
demonstrate a significant benefit, these studies have been
performed in ICUs in patients with established critical illness
and not at the onset of illness.
• Early identification of patients with sepsis, and prompt
initiation of goal oriented therapy to achieve adequate oxygen
delivery in patients with severe sepsis and septic shock is very
important.
ADVANCES IN SEPSIS
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ADVANCES IN SEPSIS
Supportive therapies
Inotropic and vasopressor therapy
• Hypotension that persists despite adequate fluid resuscitation
characterizes septic shock, and results from impaired cardiac
contractility as well as altered systemic vascular resistance.
• As a result of of these pathophysiological responses,
vasopressor and inotropic therapies play an important role in
restoring blood pressure and maintaining oxygen delivery to
tissues.
• Typically employed agents are the catecholamines and their
synthetic derivatives, which include dopamine,
norepinephrine, phenylephrine, epinephrine, and dobutamine.
ADVANCES IN SEPSIS
Supportive therapies
Adrenal replacement therapy
• Anti-inflammatory therapy with corticosteroids has been
widely studied in the treatment of septic shock.
• However, studies of high-dose, short-term corticosteroid
therapy in sepsis have failed to demonstrate an improved
outcome.
• Recently, the concept of a relative adrenal insufficiency or an
induced glucocorticoid receptor resistance has been
introduced.
• Relative adrenal insufficiency occurs commonly in patients
with septic shock, and adrenal replacement therapy should be
initiated in patients with refractory septic shock.
• An ACTH stimulation test should be considered to guide the
duration of therapy.
ADVANCES IN SEPSIS
Supportive therapies
Glycemic control
• Hyperglycemia associated with insulin resistance occurs
commonly in critically ill patients, including those with sepsis,
and in the past has been considered an adaptive response.
• A recent study has demonstrated that hyperglycemia is
associated with an increased length of ICU stay and increased
morbidity and mortality.
• Intensive insulin therapy also was associated with:
• Reduced morbidity.
• A 46% reduction of sepsis.
• Decreased length of stay among patients requiring ICU care for
>5 days.
• Decreased renal failure.
• Less polyneuropathy of critical illness.
ADVANCES IN SEPSIS
Supportive therapies
Low tidal volume ventilation
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Acute respiratory distress syndrome (ARDS) occurs commonly in
severe sepsis and septic shock, and is associated with a mortality rate
as high as 50%.
Optimal mechanical ventilation is therefore a necessary inclusion in
the armamentarium of supportive therapies of severe sepsis and
septic shock.
It has been increasingly recognized that mechanical ventilation itself
can inflict further injury on already damaged lungs, through oxygen
toxicity, high pressures, and high volumes.
Alveolar overdistension leads to alveolar capillary leak and
inflammatory activation, which can exacerbate sepsis-induced
inflammation further and increase the risk of multi-system organ
dysfunction.
Lung protective strategies have been developed to reduce ventilatorassociated volutrauma and barotrauma.
ADVANCES IN SEPSIS
Supportive therapies
Renal replacement and blood purification
therapies
• Acute renal failure is a frequent consequence of severe sepsis
and septic shock and often necessitates renal replacement
therapy with either continuous hemofiltration or intermittent
hemodialysis.
• Hemofiltration has been investigated as a supportive therapy
in severe sepsis to treat acute renal failure as well as to
remove inflammatory mediators.
• Several studies have sought to find the ideal filtration rate
with the theory that higher filtration rates will remove
inflammatory mediators and improve hemodynamics more
efficiently.
• The results, however, have been inconsistent, with the largest
study demonstrating no impact of high volume hemofiltration
on hemodynamics or survival.
ADVANCES IN SEPSIS
Conclusion
• Despite the numerous advances in the understanding of the
pathophysiology of sepsis, there has been only a modest
improvement in survival over the past decade.
• Several very promising strategies have been reported in the
past few years, and it is likely that diligent critical care,
combining these strategies as applicable in individual patients,
will lead to significant improvements in outcome over the next
few years.
• There is a great need for the broader education of healthcare
personnel about sepsis and for the standardization of care for
patients with severe sepsis or septic shock if we are to make
significant advances in outcome.
ADVANCES IN SEPSIS
Conclusion
• It is clear that early diagnosis and aggressive initial treatment
with appropriate antibiotics and aggressive fluid resuscitation,
with prompt restoration of normal hemodynamic function, are
essential for the successful management of severe sepsis and
septic shock.
• Numerous vasoactive agents are available, but there is
insufficient evidence to support the use of one agent over
another in most patients with septic shock.
• The clinician should understand the hemodynamic effects of
the available agents, and treat according to the hemodynamic
profile of the individual patient.
• For patients with a high risk of mortality, the use of
drotrecogin alfa (activated) should be considered as it has
been demonstrated to reduce mortality.
ADVANCES IN SEPSIS
Conclusion
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Detailed attention to all aspects of patient care includes attention to
multiple organ systems.
In patients with shock refractory to catecholamines, relative adrenal
insufficiency should be considered.
Attention to glycemic control is also important since hyperglycemia is
associated with a higher mortality, although the optimal glucose
target level is not yet well defined.
Mechanical ventilation strategies that provide adequate oxygenation
and ventilation, and yet minimize further ventilator-induced damage
to the lungs using limited lung volumes and peak pressures, are
important considerations.
While renal replacement therapy may be essential for the patient with
acute renal failure, there is not enough evidence to support the use of
renal replacement strategies or plasmapheresis for the purpose of
removing mediators or for blood purification.
ADVANCES IN SEPSIS
Conclusion
• Continued collaboration between institutions will allow
successful multicenter trials, which are large enough to
continue to answer important questions about the
management of patients with sepsis and move us to the next
step in improving the outcome from severe sepsis and septic
shock.
• Collaborative efforts in both education and research are
critical for lowering mortality from sepsis and septic shock.
ADVANCES IN SEPSIS