Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine.
BackgroundEarly revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility.Methods and findingsIn vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced.ConclusionsThe inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.
The early metabolic signatures associated with the progression of septic shock and with responsiveness to therapy can be useful for developing target therapy. The Sequential Organ Failure Assessment (SOFA) score is used for stratifying risk and predicting mortality. This study aimed to verify whether different responses to therapy, assessed as changes in SOFA score at admission (T1, acute phase) and 48 h later (T2, post-resuscitation), are associated with different metabolite patterns. We examined the plasma metabolome of 21 septic shock patients (pts) enrolled in the Shockomics clinical trial (NCT02141607). Patients for which SOFAT2 was >8 and Δ = SOFAT1 − SOFAT2 < 5, were classified as not responsive to therapy (NR, 7 pts), the remaining 14 as responsive (R). We combined untargeted and targeted mass spectrometry-based metabolomics strategies to cover the plasma metabolites repertoire as far as possible. Metabolite concentration changes from T1 to T2 (Δ = T2 − T1) were used to build classification models. Our results support the emerging evidence that lipidome alterations play an important role in individual patients’ responses to infection. Furthermore, alanine indicates a possible alteration in the glucose-alanine cycle in the liver, providing a different picture of liver functionality from bilirubin. Understanding these metabolic disturbances is important for developing any effective tailored therapy for these patients.
PurposeRodent models of sepsis are frequently used to investigate pathophysiological mechanisms and to evaluate putative therapeutic strategies. However, preclinical efficacy in these models has failed to translate to the clinical setting. We thus questioned the representativeness of such models and herein report a detailed comparison of the metabolic and cardiovascular phenotypes of long-term faecal peritonitis in fluid-resuscitated rats and mice with similar mortality profiles.MethodsWe conducted prospective laboratory-controlled studies in adult male Wistar rats and C57 black mice. Animals were made septic by intraperitoneal injection of faecal slurry. Rats received continuous intravenous fluid resuscitation, whereas mice received intermittent fluid boluses subcutaneously. Sham-treated animals served as controls. Survival was assessed over 72 h. In separate studies, whole body metabolism (O2 consumption, CO2 production) was measured over 24 h with echocardiography performed at early (6 h) and established (24 h) phases of sepsis. Blood gas analysis was performed at 6 h (rats) and 24 h (rats, mice).ResultsSimilar survival curves were seen in both rodent models with approximately 75% mortality at 72 h. In mice, sepsis caused severity-dependent falls in core temperature and global metabolism. Oxygen consumption in severely septic mice fell by 38% within 2 h, and 80% at 22 h compared with baseline values. This was only partially restored by external warming. By contrast, septic rats maintained core temperature; only severely affected animals showed a pre-mortem decline in oxygen consumption. Significant myocardial dysfunction was seen in mice during early and established sepsis, whereas peak velocity and other hemodynamic variables in rats were similar at 6 h and significantly worse by 24 h in severely septic animals only.ConclusionsMarkedly differing metabolic and cardiovascular profiles were seen in long-term fluid-resuscitated rat and mouse models of bacterial sepsis despite similar mortality. The mouse model, in particular, does not represent the human condition. We urge caution in applying findings in murine models to septic patients, both with regard to our understanding of pathophysiology and the failure to translate preclinical efficacy into successful clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-425X-1-6) contains supplementary material, which is available to authorized users.
There is increasing evidence that levosimendan exerts beneficial effects in the treatment of sepsis-induced myocardial and pulmonary dysfunction. Future large-scale multicenter clinical trials are now needed to clarify whether levosimendan improves the overall outcome of patients with sepsis and septic shock.
BackgroundThe ShockOmics study (ClinicalTrials.gov identifier NCT02141607) is a multicenter prospective observational trial aimed at identifying new biomarkers of acute heart failure in circulatory shock, by means of a multiscale analysis of blood samples and hemodynamic data from subjects with circulatory shock.Methods and DesignNinety septic shock and cardiogenic shock patients will be recruited in three intensive care units (ICU) (Hôpital Erasme, Université Libre de Bruxelles, Belgium; Hospital Universitari Mutua Terrassa, Spain; Hôpitaux Universitaires de Genève, Switzerland). Hemodynamic signals will be recorded every day for up to seven days from shock diagnosis (time T0). Clinical data and blood samples will be collected for analysis at: i) T1 < 16 h from T0; ii) T2 = 48 h after T0; iii) T3 = day 7 or before discharge or before discontinuation of therapy in case of fatal outcome; iv) T4 = day 100.The inclusion criteria are: shock, Sequential Organ Failure Assessment (SOFA) score > 5 and lactate levels ≥ 2 mmol/L. The exclusion criteria are: expected death within 24 h since ICU admission; > 4 units of red blood cells or >1 fresh frozen plasma transfused; active hematological malignancy; metastatic cancer; chronic immunodepression; pre-existing end stage renal disease requiring renal replacement therapy; recent cardiac surgery; Child-Pugh C cirrhosis; terminal illness. Enrollment will be preceded by the signature of the Informed Consent by the patient or his/her relatives and by the physician in charge.Three non-shock control groups will be included in the study: a) healthy blood donors (n = 5); b) septic patients (n = 10); c) acute myocardial infarction or patients with prolonged acute arrhythmia (n = 10).The hemodynamic data will be downloaded from the ICU monitors by means of dedicated software. The blood samples will be utilized for transcriptomics, proteomics and metabolomics (“-omics”) analyses.DiscussionShockOmics will provide new insights into the pathophysiological mechanisms underlying shock as well as new biomarkers for the timely diagnosis of cardiac dysfunction in shock and quantitative indices for assisting the therapeutic management of shock patients.
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