treating sepsis

7/28/2019 Treating Sepsis

1/4

Copyright 2002 Massachusetts Medical Society.

This Week in the JournalSeptember 26, 2002

Warfarin, Aspirin, or Both after Myocardial Infarction

Antithrombotic therapy is routinely prescribed after myocardial in-farction. This study compared the effect of warfarin, aspirin, or thecombination of both medications on a composite end point of death,nonfatal reinfarction, or thromboembolic stroke. Both warfarin reg-imens were superior to the aspirin regimen. The combined-therapyregimen was somewhat more favorable than the warfarin-alone reg-imen but not significantly so.

Aspirin is the most commonly used antithrombotic drug after myo-cardial infarction, but this study suggests that warfarin or warfarinplus aspirin may be more effective in reducing coronary events. How-ever, the risk of bleeding episodes was higher with the warfarin reg-imens, a fact that must be considered in clinical decision making.

see page 969 (editorial, page 1019)

Peginterferon Alfa-2a plus Ribavirinfor Chronic Hepatitis C

Interferon-based therapies combined with ribavirin are effective forchronic hepatitis C, but many patients do not have a response and sideeffects are common. Pegylated interferons are more efficacious thanstandard interferons. In this large trial, peginterferon alfa-2a plus ri-bavirin resulted in a higher rate of sustained virologic response (56 per-cent) than interferon alfa-2b plus ribavirin (44 percent) and peginter-feron alfa-2a alone (29 percent). Side effects occurred less often withpeginterferon alfa-2a plus ribavirin than with interferon alfa-2b plusribavirin.

Peginterferon alfa-2a plus ribavirin appears to be better treatmentthan interferon alfa-2b plus ribavirin for chronic hepatitis C, becausethe regimen containing pegylated interferon is more effective withfewer side effects.

see page 975

N Engl J Med, Vol. 347, No. 13

September 26, 2002

www.nejm.org

965

1.0

0.7

0.8

0.9

30001000 20000

Days of Follow-up

Warfarinplus aspirin

Warfarin

P=0.003

AspirinEvent-free

Survival

100

80

60

40

20

0

29%

44%

56%

P


2/4

The New England Journal of Medicine

966


September 26, 2002

www.nejm.org

Treating Sepsis

epsis, a leading cause of deathin the United States, is now

viewed physiologically as aproinflammatory and procoagulantresponse to invading pathogens.There are three recognized stagesin the hierarchy of the inflammato-ry response, with progressively in-creased risk of end-organ failureand death: sepsis, severe sepsis, andseptic shock. Patients with infectionplus two or more elements of thesystemic inflammatory responsesyndrome meet the criteria for sep-sis; those who also have end-organfailure are considered to have severe

PERSPECTIVE

S

sepsis; and those who also have re-fractory hypotension are consideredto be in septic shock (see Figure).Because the crude mortality fromall stages of sepsis translates to ap-

proximately 210,000 deaths annu-ally, any adjunctive therapy thatled to improved outcomes wouldbe welcomed.

Clearly, the early use of appro-priate antibiotics can reduce mor-tality from sepsis. Thus, the skill ofthe clinician can be measured bythe effectiveness of empirical ther-apy that targets both the speciesand the antibiotic sensitivity of like-ly pathogens. For patients who arein septic shock, there are some datasuggesting that the early use of vas-opressors, bolus intravenous fluids,and physiologic doses of hydrocor-tisone favorably influences mortal-ity. However, the holy grail that has

eluded investigators for two dec-ades is a novel therapy targeting thebiologic triggers of sepsis.

Recently, it has been recognizedthat important responses to sepsis

occur on endovascular surfaces.Microorganisms stimulate macro-phages to elaborate a variety of pro-

vocative cytokines, which, in turn,target proteins located on small

vessels and thereby alter the nor-mally antiinflammatory and anti-coagulant ecology by causing in-flammation and clotting. A key

vascular protein orchestrating manyof the normal regulatory functionsis activated protein C. However, insevere sepsis and septic shock, lev-els of activated protein C are oftenreduced, with coincident procoag-ulation, failure of normal fibrinoly-sis, leaky capillaries, and other cor-relates of inflammation.

Crude

mortality

Number of

deaths annually

Total:

210,000

45% 90,000

20% 60,000

15% 60,000

Sepsis in the United States

Temperature, >38C or 90/min

Respirations, >20/min

White cells, >12,000

or 10% band forms

Systemic inflammatory

response syndrome

(2 of the following)

Septic

shock

(severe sepsis plus

refractory hypotension)

200,000 cases

Severe sepsis

(sepsis plus organ failure)

300,000 cases

Sepsis

(systemic inflammatory response syndrome

plus evidence of infection)

400,000 cases

Copyright 2002 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India.


3/4

THIS WEEK IN THE JOURNAL


September 26, 2002

www.nejm.org

967

In March 2001, Bernard and col-

leagues presented data in theJour-nalfrom their pivotal study, show-ing a reduction in 28-day mortalityamong patients with severe sepsisand septic shock who received re-combinant human activated pro-tein C. The death rate was 30.8 per-cent among controls and 24.7percent in the group receiving ac-tivated protein C (P=0.005). Sub-sequently, 10 members of an advi-sory panel of the Food and Drug

Administration (FDA) voted forapproval of the drug and 10 voted

against it, but drotrecogin was li-censed in November 2001.Controversy surrounds both the

study and the FDA approval. In thelatter half of the study, the sponsor(Eli Lilly) not only modified the el-igibility criteria but also used a dif-ferent cell line for the productionof human recombinant activatedprotein C. In terms of outcomes,the absolute difference in mortality 6.1 percent seemed small tosome, and there was an increasedrisk of serious bleeding (an abso-

lute difference of 1.4 percent) as-sociated with activated protein Ctherapy. Subsequently, the FDAperformed a post hoc analysis ofthe data and found that activatedprotein C benefited primarily themost seriously ill patients those

with scores of 25 or more on theAcute Physiology and ChronicHealth Evaluation (APACHE II).

The FDAs analysis became the ba-

sis of an unprecedented indicationfor a drug: a score calculated on thebasis of current physiological mark-ers and chronic health status hasnever before been a criterion forapproved treatment. Furthermore,the cost of activated protein C is ap-proximately $7,000 per course asubstantial investment at a time ofbudget constraints in critical careunits.

In this issue of theJournal, threearticles and a letter to the editorframe the issues of the debate over

the value of activated protein C. Ina Sounding Board article (see pages10301034), Siegel, from theCenter for Biologics Evaluation andResearch, argues that the changesin eligibility criteria created incon-sistencies over time only in thelower-risk population (patients with

APACHE II scores of 24 or less).Concluding that the amendedprotocol did not account for thesubsequently improved study out-comes, he defends the FDA ap-proval. In another Sounding Board

article (see pages 10271030), War-ren and colleagues (all of whomwere consultants to the FDAs Anti-Infective Drugs Advisory Commit-tee) argue that the results of posthoc analyses require confirmationin a new study. They conclude thatthe existing data fail to support theuse of activated protein C as thestandard of care. Manns and col-

leagues (see pages 9931000), who

created mathematical models of theeconomic value of activated pro-tein C, estimate that the cost of alife-year gained with the use of thedrug would be about $28,000.However, in patients with an

APACHE II score of less than 25,the cost could exceed $500,000 perlife-year gained.

In a letter to the editor (see pages10351036), Ely and colleagues,authors of the original study, pro-

vide some updated information: al-most 2800 patients have received

activated protein C, with a crudemortality of 25 to 26 percent the same figure observed in thetreated group in the pivotal study.Furthermore, of the 13 patients

with intracranial hemorrhage (0.5percent), 9 had meningitis, markedthrombocytopenia (a platelet countof less than 30,000 per cubic mil-limeter), or both. From these fourpieces, those of us who are review-ing the arguments surrounding thecurrent debate on the value of ac-tivated protein C will gain insights

that may guide us in answeringthe key clinical question: Whichpatients with severe sepsis or septicshock should receive recombinanthuman activated protein C?

R

ICHARD

P. W

ENZEL

, M.D.

Virginia Commonwealth UniversityRichmond, VA 23298

Nephrolithiasis and Osteoporosiswith Hypophosphatemia Caused by Mutationsin the Type 2a SodiumPhosphate Cotransporter

Familial aggregation occurs among persons with renal calcium stonesor bone demineralization, suggesting a genetic propensity toward thesedisorders. In this study of 14 patients with stones and 6 with bonedemineralization, all of whom also had hypophosphatemia and de-creased renal phosphate reabsorption, 2 patients were found to haveunique mutations in the type 2a sodiumphosphate cotransporter.

Considering additional phenotypic features in persons with commonclinical conditions can aid in selecting candidate genes in which mu-tations may explain the clinical abnormalities.

see page 983 (editorial, page 1022)

Functional variants

of theNPT2a

gene

provide genetic evidence

that a defect in renal

phosphate reabsorption

may contribute to these

two common disorders.

Copyright 2002 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India.


4/4

treating sepsis

Documents