Circulatory shock is defined as an imbalance between tissue oxygen supply and demand, and mostly results from a loss of blood volume, cardiac pump failure, and/or reduction of vasomotor tone. The clinical hallmarks of circulatory shock are arterial hypotension and lactate acidosis. Since the degree and duration of hypotension are major determinants of outcome, vasopressor administration represents a cornerstone therapy to treat these patients. Current guidelines recommend the use of catecholamines as the drug of first choice. However, apart from their hemodynamic effects, which depend on the different receptor profile, receptor affinity, receptor density, and the relative potency of the individual molecule, catecholamines have numerous other biological effects as a result of the ubiquitous presence of their receptors. In shock states, catecholamines aggravate hypermetabolism by promoting hyperglycemia and hyperlactatemia, and further increase oxygen demands, which can contribute to further organ damage. In the mitochondria, catecholamines may promote mitochondrial uncoupling, and aggravate oxidative stress, thereby contributing to the progression of mitochondrial dysfunction. Immunological side effects have also gained specific attention. Although both pro- and anti-inflammatory effects have been described, current evidence strongly indicates an immunosuppressive effect, thereby making patients potentially vulnerable to secondary infections. Catecholamines may not only decrease splanchnic perfusion due to their vasoconstrictor properties, but can also directly impair gastrointestinal motility. This article reviews the non-hemodynamic effects of different catecholamines, both under physiologic and pathophysiologic conditions, with a special focus on energy metabolism, mitochondrial function, immune response, and the gastrointestinal system.

BackgroundBoth the hydrogen sulfide/cystathionine-γ-lyase (H2S/CSE) and oxytocin/oxytocin receptor (OT/OTR) systems have been reported to be cardioprotective. H2S can stimulate OT release, thereby affecting blood volume and pressure regulation. Systemic hyper-inflammation after blunt chest trauma is enhanced in cigarette smoke (CS)-exposed CSE−/− mice compared to wildtype (WT). CS increases myometrial OTR expression, but to this point, no data are available on the effects CS exposure on the cardiac OT/OTR system. Since a contusion of the thorax (Txt) can cause myocardial injury, the aim of this post hoc study was to investigate the effects of CSE−/− and exogenous administration of GYY4137 (a slow release H2S releasing compound) on OTR expression in the heart, after acute on chronic disease, of CS exposed mice undergoing Txt.MethodsThis study is a post hoc analysis of material obtained in wild type (WT) homozygous CSE−/− mice after 2-3 weeks of CS exposure and subsequent anesthesia, blast wave-induced TxT, and surgical instrumentation for mechanical ventilation (MV) and hemodynamic monitoring. CSE−/− animals received a 50 μg/g GYY4137-bolus after TxT. After 4h of MV, animals were exsanguinated and organs were harvested. The heart was cut transversally, formalin-fixed, and paraffin-embedded. Immunohistochemistry for OTR, arginine-vasopressin-receptor (AVPR), and vascular endothelial growth factor (VEGF) was performed with naïve animals as native controls.ResultsCSE−/− was associated with hypertension and lower blood glucose levels, partially and significantly restored by GYY4137 treatment, respectively. Myocardial OTR expression was reduced upon injury, and this was aggravated in CSE−/−. Exogenous H2S administration restored myocardial protein expression to WT levels.ConclusionsThis study suggests that cardiac CSE regulates cardiac OTR expression, and this effect might play a role in the regulation of cardiovascular function.

Chronic CS exposure per se had the strongest impact on inflammatory responses. The degree of inflammation was similar upon an additional TxT; however, mice presented with organ dysfunction and increased mortality rates. Hence, in mice the degree of inflammation may be dissociated from the severity of organ dysfunction or injury.

OBJECTIVEAcute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings.METHODSAnesthetized, mechanically ventilated, and instrumented pigs with human-like coagulation underwent subdural injection of 20 mL of autologous blood and subsequent observation for 54 hours. Continuous bilateral multimodal brain monitoring (intracranial pressure [ICP], cerebral perfusion pressure [CPP], partial pressure of oxygen in brain tissue [PbtO2], and brain temperature) was combined with intermittent neurological assessment (veterinary modified Glasgow Coma Scale [MGCS]), microdialysis, and measurement of plasma protein S100β, GFAP, neuron-specific enolase [NSE], nitrite+nitrate, and isoprostanes. Fluid resuscitation and continuous intravenous norepinephrine were targeted to maintain CPP at pre-ASDH levels. Immediately postmortem, the brains were taken for macroscopic and histological evaluation, immunohistochemical analysis for nitrotyrosine formation, albumin extravasation, NADPH oxidase 2 (NOX2) and GFAP expression, and quantification of tissue mitochondrial respiration.RESULTSNine of 11 pigs survived the complete observation period. While ICP significantly increased after ASDH induction, CPP, PbtO2, and the MGCS score remained unaffected. Blood S100β levels significantly fell over time, whereas GFAP, NSE, nitrite+nitrate, and isoprostane concentrations were unaltered. Immunohistochemistry showed nitrotyrosine formation, albumin extravasation, NOX2 expression, fibrillary astrogliosis, and microglial activation.CONCLUSIONSThe authors describe a clinically relevant, long-term, resuscitated porcine model of ASDH-induced brain injury. Despite the morphological injury, maintaining CPP and PbtO2 prevented serious neurological dysfunction. This model is suitable for studying therapeutic interventions during hemorrhage-induced acute brain injury with standard brain-targeted intensive care.

BackgroundReversible, depressed cardiac function is frequently encountered during septic shock and commonly called septic cardiomyopathy. Previous studies demonstrated reduced ejection fraction and left ventricular dilatation in both humans and animal models. However, the majority of the studies in humans excluded pre-existing cardiac disease and animal studies were performed on healthy specimen and/or without vasopressor support during sepsis. In order to more closely mimic the actual patients’ conditions on intensive care units and to assess the influence of both cardiac comorbidity and vasopressor support on septic cardiomyopathy, we evaluated the left ventricular function in a porcine model of resuscitated septic shock with pre-existing atherosclerosis.MethodsHypercholesterolaemic, atherosclerotic pigs due to homozygous low-density lipoprotein receptor mutation and high-fat diet were anaesthetised and surgically instrumented. Faecal peritonitis was induced by inoculation of autologous faeces into the peritoneal cavity in n = 8 animals; n = 5 pigs underwent sham procedure. Sepsis resuscitation included administration of fluids and noradrenaline. Left ventricular function was analysed via pressure-conductance catheters before, 12 and 24 h after the induction of sepsis.ResultsThe main findings were impaired ventricular dilatation (no significant change in the left ventricular end-diastolic volume) and unchanged ejection fraction in septic pigs with pre-existing atherosclerosis. The relaxation time constant τ decreased while dp/dtmax increased. Cardiac nitrotyrosine formation increased while expression of the endogenous hydrogen sulphide (H2S)-producing enzyme cystathionine γ-lyase (CSE) decreased.ConclusionsThe data of the present study are in conflict with previously published data from healthy animal models, most likely as a result of ongoing resuscitation including noradrenaline treatment or intrinsic pathophysiologic processes of the pre-existing atherosclerosis. Moreover, increased nitrotyrosine formation and decreased expression of CSE suggest the implication of augmented oxidative/nitrosative stress and/or reduced bioavailability of nitric oxide as well as diminished endogenous H2S release in the pathophysiology of septic cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0089-y) contains supplementary material, which is available to authorized users.