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July 17, 2001
Controlling Sepsis
Efficacy and
safety of recombinant human activated Protein C for severe sepsis.
Bernard GR, Vincent J-L, et al. N Engl
J Med 2001; 344:699-709.
Severe sepsis
- a new treatment with both anticoagulant and antiflammatory properties.
Matthay MA. N Engl J Med 2001; 344:759-761.
Commentary by Douglas
Coursin, M.D.
Sepsis remains a major
cause of life threatening illness affecting approximately 750,000 Americans
annually and resulting in at least 225,000 deaths. Sepsis is a leading cause
of the acute respiratory distress syndrome and the major cause of morbidity,
mortality, and prolonged length of stay in surgical intensive care units in
the U.S. The etiology of sepsis continues to evolve and is related, in part,
to an aging population, co-morbidities, antibiotic use and resistance, increased
interventional therapy, and wider administration of potent immunosuppresants.
Gram positive cocci are the leading cause of bacteria-induced sepsis, followed
by enteric gram negative rod infections. The incidence of fungemia also continues
to increase as we care for an older and more frequently immunosuppresed population.
As facets of a complex
response to sepsis, generalized inflammation, activation of the procoagulant
response and inhibition of fibrinolysis lead to diffuse endovascular insult
resulting in microthrombosis and inhibited fibrinolysis. In severe cases of
sepsis, this endovascular injury causes multiple organ dysfunction and death.
Modern medicine and critical care have witnessed a tremendous therapeutic
assault against sepsis. This attack includes aggressive current supportive
care with resuscitation directed by minute-to-minute monitoring, hemodynamic
intervention, nutrition, ventilatory support, and application of a growing
armamentarium of antimicrobials. The overall sepsis-induced mortality remains
frighteningly high at 30 - 50%, however, despite appropriate care.
Over the past twenty years
a host of promising therapies have been evaluated and anticipated with great,
but unrealized, expectations. These failed approaches included administration
of high dose steroids; polyclonal and monoclonal antibodies against endotoxin
and various inflammatory mediators such as tumor necrosis factor alpha; receptor
antagonists; anti-inflammatories; inhibitors of nitric oxide; anti-oxidants;
and others. Some of these promising potential approaches lacked successful
animal models and/or appeared appealing based on inadequately controlled,
under powered or non-randomized studies.
The Protein C Worldwide
Evaluation in Severe Sepsis (PROWESS) study is the first effective therapeutic
intervention against sepsis since the introduction of antibiotics. This multinational
study was performed in eleven countries at one hundred sixty four centers
and included 1690 patients with severe sepsis. It showed a dramatic -- almost
20% -- decrease in overall mortality at twenty-eight days in patients treated
with a 96 hour continuous infusion of a recombinant human activated protein
C (APC) [drotrecogin alfa (activated)TM Eli Lilly].
APC is a serine protease
and part of the natural anticoagulant system. It promotes fibrinolysis and
inhibits inflammation and thrombosis. APC is an important modifier of coagulant
and inflammatory cascades that are activated during severe sepsis. Its potential
for success in severe sepsis was based on:
- APC levels are diminished
in most patients with sepsis because of cytokine-induced down regulation
of thrombomodulin, which is required to promote activation of protein
C.
- APC inhibits factors V and
VIII and decreases the formation of thrombin.
- APC activates fibrinolysis
by reducing the formation of tissue plasminogen activator-1 (t-PA-1),
which is overproduced during sepsis.
- Infused APC reversed procoagulant
and inflammatory effects in baboons with gram negative sepsis. Treated
baboons also had improved survival.
- A small phase II trial in
humans treated with drotrecogin alfa resulted in reductions in the plasma
levels of D-dimer and interleukin-6 (IL-6), markers of coagulation and
inflammation, respectively.
- A recent report that treatment
with APC improved clinical outcome in patients with severe meningococcemia
(Blood 2000; 96:3719-24).
The PROWESS study was
developed to monitor the effect of a prolonged infusion of drotrecogin alfa
on D-dimer and IL-6, on end-organ function, and on outcome at twenty-eight
days in patients with severe sepsis. Patients were also assessed for development
of an antibody to APC. Severe sepsis was defined as known or suspected infection
along with three or more signs of systemic inflammation (see Chest
1992; 101:1644-55) and sepsis-induced end-organ dysfunction that lasted no
longer than twenty four hours. Study patients were enrolled and randomized
within twenty four hours of identification to receive an infusion of APC or
placebo. The groups were well matched in demographic characteristics, severity
of illness (similar baseline APACHE II scores), incidence of positive cultures,
etiology and site of infection, baseline levels of D-dimer and IL-6, and presence
of protein C deficiency at study onset. Over half of the study patients had
a pulmonary source of infection (53.6%) while an abdominal focus was identified
in an additional 19.9%. Blood cultures were positive in approximately a third
of all patients with Staph aureus, Strep pneumonia, and
enteric gram negative rod infections being the leading causes of identifiable
bacteremias.
Nine out of ten patients
were protein C deficient while almost all patients had increased D-dimer and
IL-6 levels at the time of enrollment. None of the APC treated patients developed
a neutralizing antibody response to APC. The vast majority of treated patients
had decreased D-dimer and IL-6 levels and increased APC levels during study
drug infusion. There was a greater incidence of serious bleeding, however,
in treated patients (3.5%) vs. control patients (2.0), but not an increased
risk of second infection, thrombotic events or other major side effect.
Anesthesia care providers
should take note of the exclusion criteria and concerns over risk of bleeding
for enrolled patients undergoing procedures, surgeries, or developing coagulopathy.
Along with classic exclusion criteria, thrombocytopenic patients (platelet
count < 30,000); patients undergoing surgery with general or spinal anesthesia
within 12 hours of beginning study infusion; patients with recent CNS surgery,
trauma, or pathology; and patients with a history of hypercoaguable states
such as AT, protein C, or S deficiencies or those with anticardiolipin antibody
or lupus anticoagulant were excluded. Patients receiving therapeutic anticoagulation
were also excluded.
This study provides the
first active therapy to have a positive impact on the outcome from severe
sepsis in the current era of critical care. This improved survival was potentially
secondary to APC limiting the enhanced coagulation and inflammation that develops
in severe sepsis. APC provided a significant benefit with only modest increase
in bleeding complications. Drotrecogin alfa (activated) is currently under
active review by the FDA for possible release later this year. More data is
necessary to completely establish the risk/benefit for septic patients with
significant coagulopathy and to determine subsets of patients who may benefit
from longer duration of infusion than the 96 hours used in the current study.
The financial impact of this therapy may be marked depending on the cost and
frequency of use.
A recent abstract report
from a French multicenter study showed significant improvement in mortality
in septic shock patients with relative adrenal insufficiency who were treated
with low dose hydrocortisone, 50 mg every six hours, for a week. This was
a very select population. The potential of additive benefit if APC and corticosteroids
were concurrently administered is an interesting possibility that requires
further study.
ABSTRACT
Efficacy and
safety of recombinant human activated Protein C for severe sepsis.
AUTHORS:
Bernard GR, Vincent J-L, et al.
SOURCE:
N Engl J Med 2001; 344:699-709
ABSTRACT:
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 patients with
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 microg per kilogram of body
weight per hour) 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.
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
(P=0.005). 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,
P=0.06).
CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces
mortality in patients with severe sepsis and may be associated with an increased
risk of bleeding.
Severe sepsis
- a new treatment with both anticoagulant and antiflammatory properties.
AUTHOR:
Matthay MA
SOURCE:
N Engl J Med 2001; 344:759-761
ABSTRACT:
No abstract available.
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