The pathophysiology of sepsis-induced myocardial dysfunction still remains controversial. Macrophage migration inhibitory factor (MIF) has recently been identified as a cardiac-derived myocardial depressant factor in septic shock. Putative mechanisms by which MIF affects cardiac function are unknown. In an investigation of possible mechanisms of action, a rat model of endotoxin toxicity was designed using intraperitoneal (I/P) injection of lipopolysaccharides (LPS) with or without coinfusion of neutralizing anti-MIF or isotypic-matched antibodies. Echocardiographic evaluation revealed that MIF neutralization reversed endotoxin-induced myocardial dysfunction at 24 hours after injection. RNase protection assay (RPA) and Western blot established that MIF neutralization prevented LPS-induced mRNA expression and production of heart-derived inflammatory paracrine and autocrine cytokines such as IL-1s and IL-6. Moreover, MIF immunoneutralization increased heart Bcl-2/Bax protein ratio and suppressed endotoxin-induced release of mitochondrial cytochrome-c, as demonstrated by Western blotting. Inhibition of mitochondrial loss of cytochrome-c decreased in heart caspase-3 activity at 6 and 24 hours after injection. MIF neutralization also restored the LPS-induced deficient nuclear translocation of phospho-Akt and consequently the expression of the heart survival nuclear factor GATA-4. The restoration of the translocation/expression of survival factors by MIF inhibition resulted in lowered endotoxin-induced DNA fragmentation at 24 hours, a hallmark of downstream cardiomyocyte apoptosis. Our data indicate that early inactivation of MIF significantly reverses the imbalance of proapoptotic to prosurvival pathways and reduces acute inflammation of the heart thereby improving myocardial dysfunction induced by endotoxin.

Introduction: Neuropeptides arginine-vasopressin (AVP), apelin (APL), and stromal-derived factor-1α (SDF-1α) are involved in the dysfunction of the corticotropic axis observed in septic ICU patients. Study aims were: (i) to portray a distinctive stress-related neuro-corticotropic systemic profile of early sepsis, (ii) to propose a combination data score, for aiding ICU physicians in diagnosing sepsis on admission. Methods: This prospective one-center observational study was carried out in a medical intensive care unit (MICU), tertiary teaching hospital. Seventy-four out of 112 critically ill patients exhibiting systemic inflammatory response syndrome (SIRS) were divided into two groups: proven sepsis and non sepsis, based on post hoc analysis of microbiological criteria and final diagnosis, and compared to healthy volunteers (n = 14). A single blood sampling was performed on admission for measurements of AVP, copeptin, APL, SDF-1α, adrenocorticotropic hormone (ACTH), cortisol baseline and post-stimulation, and procalcitonin (PCT). Results: Blood baseline ACTH/cortisol ratio was lower and copeptin higher in septic vs. nonseptic patients. SDF-1α was further increased in septic patients vs. normal patients. Cortisol baseline, ACTH, PCT, APACHE II and sepsis scores, and shock on admission, were independent predictors of sepsis diagnosis upon admission. Using the three first aforementioned categorical bio-parameters, a probability score for predicting sepsis yielded an area under the Receiver Operating Curve (ROC) curves better than sepsis score or PCT alone (0.903 vs 0.727 and 0.726: P = 0.005 and P < 0.04, respectively). Conclusions: The stress response of early admitted ICU patients is different in septic vs. non-septic conditions. A proposed combination of variable score analyses will tentatively help in refining bedside diagnostic tools to efficiently diagnose sepsis after further validation.

Improving sepsis support is one of the three pillars of a 2017 resolution according to the World Health Organization (WHO). Septic shock is indeed a burden issue in the intensive care units. Hemodynamic stabilization is a cornerstone element in the bundle of supportive treatments recommended in the Surviving Sepsis Campaign (SSC) consecutive biannual reports. The “Pandera’s box” of septic shock hemodynamics is an eternal debate, however, with permanent contentious issues. Fluid resuscitation is a prerequisite intervention for sepsis rescue, but selection, modalities, dosage as well as duration are subject to discussion while too much fluid is associated with worsen outcome, vasopressors often need to be early introduced in addition, and catecholamines have long been recommended first in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has come out. Preservation of the macrocirculation through a “best” mean arterial pressure target is the actual priority but is still contentious. Microcirculation recruitment is a novel goal to be achieved but is claiming more knowledge and monitoring standardization. Protection of the cardio-renal axis, which is prevalently injured during septic shock, is also an unavoidable objective. Several promising alternative or additive drug supporting avenues are emerging, trending toward catecholamine’s sparing or even “decatecholaminization.” Topics to be specifically addressed in this review are: (1) mean arterial pressure targeting, (2) fluid resuscitation, and (3) hemodynamic drug support. Improving assessment and means for rescuing hemodynamics in early septic shock is still a work in progress. Indeed, the bigger the unresolved questions, the lower the quality of evidence.

Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and l-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased (∼35%) but aortic blood flow increased during endotoxin infusion (P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance (∼3- to 4-fold), whereas AVP or LC attenuated this drop (P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE (∼2-fold increase) but not AVP infusion (P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P (∼2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.