Understanding the Inflammatory Cytokine Response in Pneumonia and Sepsis: Kellum JA, Lan K, Fink MP,...

correlation coefficient of 0.22, 95% confidence interval [CI]0.20–0.24; p � 0.001) and individual study centers (interclasscorrelation coefficient of 0.66, 95% CI 0.62–0.70; p � 0.001).Patients treated with AEDs had significantly higher odds ofhaving an unfavorable outcome relative to those without AEDuse based on Glasgow Outcome Scale score after adjustmentfor study center, neurological grade, age, and systolic bloodpressure on admission (odds ratio [OR] 1.56, 95% CI 1.16–2.10; p � 0.003). The odds ratios of all in-hospital complica-tions were higher in patients treated with AEDs compared tothose without AED use, and included cerebral vasospasm (OR1.87, 95% CI 1.43–2.44; p � 0.001), neurological deterioration(OR 1.61, 95% CI 1.25–2.06; p � 0.001), cerebral infarction(OR 1.33, 95% CI 1.01–1.74; p � 0.04), and elevated temper-atures (OR 1.36, 95% CI 1.03–1.80; p � 0.03). The authorsconclude that prophylactic AED treatment in patients withSAH is common, follows an arbitrary prescribing pattern basedon institution and physician, and may be associated with in-creased in-hospital complications and possible worse outcome.

[Brad Talley, MD,

Denver Health Medical Center, Denver, CO]

Comment: The use of antiepileptic drugs is common yetarbitrary, varying by institution and individual neurosurgeonpreference. Given the lack of evidence of benefit from AEDand the possible adverse effects of the drugs, the use of pro-phylactic AEDs for SAH should be reconsidered and not rou-tinely started in the Emergency Department.

e UNDERSTANDING THE INFLAMMATORY CYTO-KINE RESPONSE IN PNEUMONIA AND SEPSIS. KellumJA, Lan K, Fink MP, et al. Arch Intern Med 2007;167:1655–63.

This multi-center cohort study examined 1886 patients ad-mitted to hospitals for pneumonia to determine whether specificcytokine patterns are associated with severe sepsis and death.All patients enrolled in the study had clinical and radiologicalevidence of pneumonia. Blood was drawn for cytokine assaysupon admission, then daily for the first week, then weeklywhile patients remained in the hospital. Cytokines examinedincluded tumor necrosis factor (TNF), interleukin 6 (IL-6)(pro-inflammatory), and interleukin 10 (IL-10) (anti-inflamma-tory.) The authors looked at the differences in cytokine levelsbetween patients who never developed severe sepsis, those whodeveloped severe sepsis and survived, and those who developedsevere sepsis and died. On day 1 of the study, mean cytokineconcentrations were elevated. However, normal concentrationsof IL-6, TNF, and IL-10 were seen in 17%, 64%, and 63% ofpatients, respectively. There were significant differences in thelevels of all three cytokines between the three groups of pa-tients. The mean cytokine levels of IL-6, TNF, and IL-10 weregreater on day 1 in patients with severe sepsis when comparedto patients who did not have severe sepsis (p value � 0.001 forall cytokines). Similarly, in those patients who did not havesevere sepsis on day 1 but later developed severe sepsis, meancytokine levels were higher than in those who never developedsevere sepsis (p value � 0.001 for all cytokines). In those

patients who did develop severe sepsis, mean cytokine levelswere higher in those who died than in those who survived (pvalue 0.01 for IL-6, 0.01 for IL-12, and 0.22 for TNF). How-ever, 4 of 149 cases of severe sepsis had no cytokine elevation,and some patients who never developed severe sepsis hadcytokine elevation. Cytokine levels remained elevated longerthan clinical signs of illness, with � 50% of patients havingtwo criteria for the systemic inflammatory response syndromeby day 2, despite more than 50% of patients still havingelevated IL-6 levels on day 7. Although systemic cytokinelevels were higher in patients with poorer outcomes, the dif-ference between groups of patients was not dramatic. Further-more, many patients with elevated cytokine levels had goodoutcomes, suggesting that cytokine activation is not necessarilyharmful. Interestingly, cytokine activation persisted muchlonger than the standard course of anti-cytokine treatmentsused in previous trials. The authors concluded that the cytokineresponse to infection and severe sepsis is longer in duration andmore variable than described in previous studies, however,there is a significant pattern of increased risk of severe sepsisand death in patients with markedly elevated cytokine levels.

[Jessica Brooks, MD,

Denver Health Medical Center, Denver, CO]

Editor’s Comment: This study reinforces the concept thatunderstanding the magnitude of the complicated inflammatorycascade seen in sepsis is not amenable to measurement of anyone specific marker. Although both inflammatory and anti-inflammatory cytokine activation seems to play a role in infec-tion and sepsis, the exact significance of their absolute levelsremains unclear. This study is limited by the very specific entrycriteria and thus cannot necessarily be generalized to all pa-tients with sepsis or infection. Further studies of patients withsepsis may bring to light more information regarding the utilityof measuring cytokine levels or using cytokine-based therapies.Until then, routine measurement of cytokine levels in the Emer-gency Department does not seem to be useful.

e ENOXAPARIN DOSING AND ASSOCIATED RISKOF IN-HOSPITAL BLEEDING AND DEATH IN PA-TIENTS WITH NON-ST SEGMENT ELEVATIONACUTE CORONARY SYNDROMES. LaPointe NM, ChenAY, Alexander KP, et al. Arch Intern Med 2007;167:1539–44.

This study sought to determine the extent that enoxaparin isdosed at current recommendations for non-ST elevation acutecoronary syndrome (ACS). A patient cohort that received enox-aparin for non-ST elevation ACS was obtained using a data setfrom the CRUSADE (Can Rapid Risk Stratification of UnstableAngina Patient Suppress Adverse Outcomes with Early Imple-mentation of the American College of Cardiology/AmericanHeart Association Guidelines) National Quality ImprovementInitiative. The authors also evaluated the outcomes in thosepatients who received excess dosing of enoxaparin (� 10 mgabove recommended daily dose) and lower-than-recommendedenoxaparin dosing (� 10 mg below recommended daily dose).Of 10,687 patients who received enoxaparin, 2002 (18.7%)received an excessive dose and 3116 (29.2%) received a lower-

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