Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study

Reinhart, Konrad; Menges, T.; Gårdlund, Bengt; Zwaveling, JH; Smithes, Mark; Vincent, Jean‐Louis; Tellado, Jose M.; Salgado-Remigio, Antonio; Zimlichman, Reuven; Withington, Stuart; Tschaikowsky, K.; Brase, Rainer; Damas, Pierre; Küpper, H.; Kempeni, Joachim; Eiselstein, Juergen; Kaul, Martin

doi:10.1097/00003246-200104000-00015

Cited by 222 publications

(101 citation statements)

References 21 publications

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“…However, inflammatory cytokines are also necessary to control the initial infection. It is therefore not surprising that although therapies directed against TNF-␣ (2) and IL-1␤ (27) have improved survival in murine endotoxemia models, blocking TNF-␣ and IL-1␤ has failed to improve survival in patients with sepsis (8,29). In addition, mice that are resistant to endotoxin have been shown to have increased mortality with true sepsis (16).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

Ashare¹,

Powers²,

Butler³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 99%

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

Ashare¹,

Powers²,

Butler³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…These results have since been confirmed in multiple studies, including a study which examined all patients admitted to an intensive care unit and documented that levels of IL-6 correlated with mortality (8). In one clinical study of the treatment of sepsis, patients were stratified to receive immunomodulating therapy on the basis of their plasma levels of IL-6 (26). In septic patients with hypothermia, plasma levels of IL-6 were elevated (2).…”

mentioning

confidence: 87%

Role of Interleukin-6 in Mortality from and Physiologic Response to Sepsis

et al. 2005

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Previous studies have suggested that interleukin-6 (IL-6) serves as both a marker and a mediator for the severity of sepsis. We tested whether interleukin 6 knockout (IL-6KO) mice were more susceptible to sepsis mortality induced by cecal ligation and puncture. IL-6KO and wild-type (WT) mice were subjected to increasing degrees of sepsis severity. Physiologic support was given with fluids and appropriate antibiotics. Plasma IL-6 levels were determined 6 h after the onset of sepsis, and a complete hematologic profile was performed on day 2. As expected, increasing sepsis severity resulted in greater and more rapid mortality. However, the mortality was nearly identical in the IL-6KO and WT mice. All WT septic mice had high plasma levels of IL-6 6 h after the onset of sepsis, while IL-6KO were near or below the lower limit of detection. Among the WT mice, mortality was significantly higher in mice with plasma IL-6 >3,000 pg/ml. Both IL-6KO and WT mice destined to die in the early stages of sepsis had substantial and nearly identical weight gain in the first 24 h. However, at later stages the WT mice had significantly greater weight loss than the KO mice. The KO mice failed to develop the characteristic hypothermia within the first 24 h of severe sepsis routinely observed in the WT mice. These data demonstrate that IL-6 serves as a marker of disease severity in sepsis and does modulate some physiologic responses, but complete lack of IL-6 does not does not alter mortality due to sepsis.

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“…Although the inflammatory response has important protective effects, an anti-inflammatory intervention likely only works if there is excessive inflammation. Initial attempts to target the most severely inflamed patients using a general marker of inflammation failed to improve outcomes [91]. Future RCTs that use specific predictive biomarkers [87] and pharmacogenomic biomarkers of response to drug(s) that are the target for the intervention, should be used to select patients for inclusion in many future trials.…”

Section: Biomarker-guided Trialsmentioning

confidence: 99%

The intensive care medicine research agenda on septic shock

et al. 2017

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Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study

Abstract: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

Cited by 222 publications

References 21 publications

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

Role of Interleukin-6 in Mortality from and Physiologic Response to Sepsis

The intensive care medicine research agenda on septic shock

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