Background—: Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Methods and Results—: Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A _1C , but neither body mass index nor the insulin resistance index (homeostasis model assessment–insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A _1C . Conclusion—: Worsening of intrinsic myocardial contraction in the transition from obesity to diabetes mellitus is likely related to worsening of cardiac mitochondrial function because impaired mitochondrial function and dynamics and contractile dysfunction are observed in diabetic patients but not in “metabolically healthy” obese patients at early stage in insulin resistance.

Objective: Rapid fluid loading is standard treatment for hypovolemia. Because volume expansion does not always improve hemodynamic status, predictive parameters of fluid responsiveness are needed. Passive leg raising is a reversible maneuver that mimics rapid volume expansion. Passive leg raising-induced changes in stroke volume and its surrogates are reliable predictive indices of volume expansion responsiveness for mechanically ventilated patients. We hypothesized that the hemodynamic response to passive leg raising indicates fluid responsiveness in nonintubated patients without mechanical ventilation. Design: Prospective study. Setting: Intensive care unit of a general hospital. Patients: We investigated consecutive nonintubated patients, without mechanical ventilation, considered for volume expansion. Interventions: We assessed hemodynamic status at baseline, after passive leg raising, and after volume expansion (500 mL 6% hydroxyethyl starch infusion over 30 mins). Measurements and Main Results: We measured stroke volume using transthoracic echocardiography, radial pulse pressure using an arterial catheter, and peak velocity of femoral artery flow using continuous Doppler. We calculated changes in stroke volume, pulse pressure, and velocity of femoral artery flow induced by passive leg raising (respectively, Δstroke volume, Δpulse pressure, and Δvelocity of femoral artery flow). Among 34 patients included in this study, 14 had a stroke volume increase of ≥15% after volume expansion (responders). All patients included in the study had severe sepsis (n = 28; 82%) or acute pancreatitis (n = 6; 18%). The Δstroke volume ≥10% predicted fluid responsiveness with sensitivity of 86% and specificity of 90%. The Δpulse pressure ≥9% predicted fluid responsiveness with sensitivity of 79% and specificity of 85%. The Δvelocity of femoral artery flow ≥8% predicted fluid responsiveness with sensitivity of 86% and specificity of 80%. Conclusions: Changes in stroke volume, radial pulse pressure, and peak velocity of femoral artery flow induced by passive leg raising are accurate and interchangeable indices for predicting fluid responsiveness in nonintubated patients with severe sepsis or acute pancreatitis.

Background: Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text: Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions: Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.

Objective: To investigate whether the collapsibility index of the inferior vena cava recorded during a deep standardized inspiration predicts fluid responsiveness in nonintubated patients. Design: Prospective, nonrandomized study. Setting: ICUs at a general and a university hospital. Patients: Nonintubated patients without mechanical ventilation (n = 90) presenting with sepsis-induced acute circulatory failure and considered for volume expansion. Interventions: We assessed hemodynamic status at baseline and after a volume expansion induced by a 30-minute infusion of 500-mL gelatin 4%. Measurements and Main Results: We measured stroke volume index and collapsibility index of the inferior vena cava under a deep standardized inspiration using transthoracic echocardiography. Vena cava pertinent diameters were measured 15–20 mm caudal to the hepatic vein junction and recorded by bidimensional imaging on a subcostal long-axis view. Standardized respiratory cycles consisted of a deep standardized inspiration followed by passive exhalation. The collapsibility index expressed in percentage equaled the ratio of the difference between end-expiratory and minimum-inspiratory diameter over the end-expiratory diameter. After volume expansion, a relevant (≥ 10%) stroke volume index increase was recorded in 56% patients. In receiver operating characteristic analysis, the area under curve for that collapsibility index was 0.89 (95% CI, 0.82–0.97). When such index is superior or equal to 48%, fluid responsiveness is predicted with a sensitivity of 84% and a specificity of 90%. Conclusions: The collapsibility index of the inferior vena cava during a deep standardized inspiration is a simple, noninvasive bedside predictor of fluid responsiveness in nonintubated patients with sepsis-related acute circulatory failure.

Anti-synthetase (AS) and dermato-pulmonary associated with anti-MDA-5 antibodies (aMDA-5) syndromes are near one of the other autoimmune inflammatory myopathies potentially responsible for severe acute interstitial lung disease. We undertook a 13-year retrospective multicenter study in 35 French ICUs in order to describe the clinical presentation and the outcome of patients admitted to the ICU for acute respiratory failure (ARF) revealing AS or aMDA-5 syndromes. From 2005 to 2017, 47 patients (23 males; median age 60 [1st–3rd quartiles 52–69] years, no comorbidity 85%) were admitted to the ICU for ARF revealing AS (n = 28, 60%) or aMDA-5 (n = 19, 40%) syndromes. Muscular, articular and cutaneous manifestations occurred in 11 patients (23%), 14 (30%) and 20 (43%) patients, respectively. Seventeen of them (36%) had no extra-pulmonary manifestations. C-reactive protein was increased (139 [40–208] mg/L), whereas procalcitonine was not (0.30 [0.12–0.56] ng/mL). Proportion of patients with creatine kinase ≥ 2N was 20% (n = 9/47). Forty-two patients (89%) had ARDS, which was severe in 86%, with a rate of 17% (n = 8/47) of extra-corporeal membrane oxygenation requirement. Proportion of patients who received corticosteroids, cyclophosphamide, rituximab, intravenous immunoglobulins and plasma exchange were 100%, 72%, 15%, 21% and 17%, respectively. ICU and hospital mortality rates were 45% (n = 21/47) and 51% (n = 24/47), respectively. Patients with aMDA-5 dermato-pulmonary syndrome had a higher hospital mortality than those with AS syndrome (n = 16/19, 84% vs. n = 8/28, 29%; p = 0.001). Intensivists should consider inflammatory myopathies as a cause of ARF of unknown origin. Extra-pulmonary manifestations are commonly lacking. Mortality is high, especially in aMDA-5 dermato-pulmonary syndrome.

Animal experiments are widely used in preclinical medical research with the goal of disease modeling and exploration of novel therapeutic approaches. In the context of sepsis and septic shock, the translation into clinical practice has been disappointing. Classical animal models of septic shock usually involve one-sex-one-age animal models, mostly in mice or rats, contrasting with the heterogeneous population of septic shock patients. Many other factors limit the reliability of preclinical models and may contribute to preclinical research failure in critical care, including the host specificity of several pathogens, the fact that laboratory animals are raised in pathogen-free facilities and that organ support techniques are either absent or minimal. Advanced animal models have been developed with the aim of improving the clinical translatability of experimental findings. So-called animal ICUs refer to the preclinical investigation of adult or even aged animals of either sex, using—in case of rats and mice—miniaturized equipment allowing for reproducing an ICU environment at a small animal scale and integrating chronic comorbidities to more closely reflect the clinical conditions studied. Strength and limitations of preclinical animal models designed to decipher the mechanisms involved in septic cardiomyopathy are discussed. This article reviews the current status and the challenges of setting up an animal ICU.