Execution of sepsis trials needs an overhaul, experts say

Khamsi, Roxanne

doi:10.1038/nm0712-998b

Cited by 9 publications

(9 citation statements)

References 3 publications

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“… 14 Our study also goes beyond previous investigations by evaluating a longer term end point (90 days); this endpoint was investigated because patients with sepsis continue to face an increased risk of mortality even after ICU and hospital discharge. 32 …”

Section: Discussionmentioning

confidence: 99%

Primary bacteraemia is associated with a higher mortality risk compared with pulmonary and intra-abdominal infections in patients with sepsis: a prospective observational cohort study

et al. 2015

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ObjectiveTo investigate whether common infection foci (pulmonary, intra-abdominal and primary bacteraemia) are associated with variations in mortality risk in patients with sepsis.DesignProspective, observational cohort study.SettingThree surgical intensive care units (ICUs) at a university medical centre.ParticipantsA total of 327 adult Caucasian patients with sepsis originating from pulmonary, intra-abdominal and primary bacteraemia participated in this study.Primary and secondary outcome measuresThe patients were followed for 90 days and mortality risk was recorded as the primary outcome variable. To monitor organ failure, sepsis-related organ failure assessment (Sequential Organ Failure Assessment, SOFA) scores were evaluated at the onset of sepsis and throughout the observational period as secondary outcome variables.ResultsA total of 327 critically ill patients with sepsis were enrolled in this study. Kaplan-Meier survival analysis showed that the 90-day mortality risk was significantly higher among patients with primary bacteraemia than among those with pulmonary and intra-abdominal foci (58%, 35% and 32%, respectively; p=0.0208). To exclude the effects of several baseline variables, we performed multivariate Cox regression analysis. Primary bacteraemia remained a significant covariate for mortality in the multivariate analysis (HR 2.10; 95% CI 1.14 to 3.86; p=0.0166). During their stay in the ICU, the patients with primary bacteraemia presented significantly higher SOFA scores than those of the patients with pulmonary and intra-abdominal infection foci (8.5±4.7, 7.3±3.4 and 5.8±3.5, respectively). Patients with primary bacteraemia presented higher SOFA-renal score compared with the patients with other infection foci (1.6±1.4, 0.8±1.1 and 0.7±1.0, respectively); the patients with primary bacteraemia required significantly more renal replacement therapy than the patients in the other groups (29%, 11% and 12%, respectively).ConclusionsThese results indicate that patients with sepsis with primary bacteraemia present a higher mortality risk compared with patients with sepsis of pulmonary or intra-abdominal origins. These results should be assessed in patients with sepsis in larger, independent cohorts.

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Section: Discussionmentioning

confidence: 99%

Primary bacteraemia is associated with a higher mortality risk compared with pulmonary and intra-abdominal infections in patients with sepsis: a prospective observational cohort study

et al. 2015

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“…A strong research drive and extensive media coverage have served to bring sepsis into public prominence in recent years. A significant factor in the lack of effective treatments for septic shock, in addition to the limitations of related clinical trials ( 28 ), is the problem of research translatability; numerous interventions that have proved beneficial in rodent models have failed to translate into improved outcome in humans ( 38 ). Patient and pathogen heterogeneity, and the confounding effects of clinical intervention, complicate the process of developing a relevant model in which to investigate disease mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Quantification of microcirculatory blood flow: a sensitive and clinically relevant prognostic marker in murine models of sepsis

Sand

Starr

Wilder

et al. 2015

Journal of Applied Physiology

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Sepsis and sepsis-associated multiorgan failure represent the major cause of mortality in intensive care units worldwide. Cardiovascular dysfunction, a key component of sepsis pathogenesis, has received much research interest, although research translatability remains severely limited. There is a critical need for more comprehensive preclinical sepsis models, with more clinically relevant end points, such as microvascular perfusion. The purpose of this study was to compare microcirculatory blood flow measurements, using a novel application of laser speckle contrast imaging technology, with more traditional hemodynamic end points, as part of a multiparameter monitoring system in preclinical models of sepsis. Our aim, in measuring mesenteric blood flow, was to increase the prognostic sensitivity of preclinical studies. In two commonly used sepsis models (cecal ligation and puncture, and lipopolysaccharide), we demonstrate that blood pressure and cardiac output are compromised postsepsis, but subsequently stabilize over the 24-h recording period. In contrast, mesenteric blood flow continuously declines in a time-dependent manner and in parallel with the development of metabolic acidosis and organ dysfunction. Importantly, these microcirculatory perturbations are reversed by fluid resuscitation, a mainstay intervention associated with improved outcome in patients. These data suggest that global hemodynamics are maintained at the expense of the microcirculation and are, therefore, not sufficiently predictive of outcome. We demonstrate that microcirculatory blood flow is a more sensitive biomarker of sepsis syndrome progression and believe that incorporation of this biomarker into preclinical models will facilitate sophisticated proof-of-concept studies for novel sepsis interventions, providing more robust data on which to base future clinical trials.

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“…Human SE transitions from systemic inflammation to a diffuse disturbance in the blood-brain barrier (BBB) associated with a period of neurological dysfunction 4 . Several recent studies have suggested roles for vascular factors in SE-related injury of the brain vascular endothelium, changes in BBB permeability and microcirculatory distress 10 , 11 , 12 , but the contributions of various cell types, cellular receptors and signaling events remain unclear 13 , 14 , 15 . For example, although leukocyte adhesion to activated endothelial cells has been identified as an early event in sepsis-related central nervous system dysfunction 16 , the triggers of this event and the mechanism by which leukocyte adhesion may lead to the development of encephalopathy remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, P2RX 7 activation was shown to amplify lipopolysaccharide (LPS)-induced hyporeactivity in the endothelium-intact mouse aorta 21 . Because brain endothelial activation during sepsis significantly impacts microcirculation and BBB integrity 13 , 14 , 15 , we hypothesized that P2RX 7 plays a critical role in sepsis-induced neurovascular damage. P2RX 7 is an ATP-gated purinoceptor channel that mediates Ca 2+ influx and subsequent downstream intracellular signaling events 22 , 23 .…”

Section: Introductionmentioning

confidence: 99%

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

et al. 2015

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Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE.

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Execution of sepsis trials needs an overhaul, experts say

Cited by 9 publications

References 3 publications

Primary bacteraemia is associated with a higher mortality risk compared with pulmonary and intra-abdominal infections in patients with sepsis: a prospective observational cohort study

Primary bacteraemia is associated with a higher mortality risk compared with pulmonary and intra-abdominal infections in patients with sepsis: a prospective observational cohort study

Quantification of microcirculatory blood flow: a sensitive and clinically relevant prognostic marker in murine models of sepsis

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

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