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Background and Objectives : Metabolic disorders cause many skin issues, including acne vulgaris. This research investigated the function of glutathione peroxidase (GTPx) and biogenic amines as a potential novel pathophysiological link between metabolic syndrome (MetS) and acne vulgaris. Materials and Methods: The patients were distributed into two groups: metabolic precondition (MPG, n = 78) and control (CG, n = 81). To determine the extent of acne and metabolic preconditioning, patients were subjected to extensive clinical/paraclinical investigations. Additionally, catecholamine levels in urine and GTPx levels in blood were measured. Results: Mild acne was more common in the CG (32.1 vs. 6.4, p < 0.001), and severe acne was more common in the MPG (61.54 vs. 25.9, p < 0.001), with the average age being substantially higher in the MPG (23.81 vs. 21.05, p = 0.002). Significant variations were observed in the paraclinical levels for catecholamines ( p < 0.05). In the MPG, most severe acne patients were overweight (52.1%), insulin-resistant (48.8%), or obese (47.9%). Moderate acne was most often linked to obesity (56%), overweight (44%), and insulin resistance (20%). Patients with severe acne (48.83%) had a considerably greater incidence of insulin resistance syndrome ( p = 0.039) than those with moderate or severe acne (20%). The presence of two or three metabolic disorders considerably raised the risk of severe acne. Significant differences between groups were observed only in the subgroup of patients with severe acne, with lower values in the MPG ( p = 0.015). Significant differences between groups were observed regarding the subgroup of patients with severe acne, with lower DTPx values in the MPG. At the group level, only CG patients with severe acne had reduced GTPx levels. Significant differences in catecholamine values were seen between groups ( p < 0.05), independent of acne severity, except for adrenaline in mild acne patients ( p = 0.059). Conclusions: The complex connection between GTPx and catecholamines in MetS suggests a significant role of these factors in the pathogenesis of acne associated with this condition, opening new perspectives in the research and treatment of acne in the context of MetS.

Stress substantially increases the risk of developing painful temporomandibular disorders (TMDs) by influencing the release of endogenous catecholamines. Propranolol, an antagonist of β-adrenergic receptors, has shown potential in alleviating TMD-associated pain, particularly when the level of catecholamines is elevated. The aim of this study was to explore whether intra-articular propranolol administration is effective in diminishing temporomandibular joint (TMJ) pain during repeated stress situations. Additionally, we investigated the effect of repeated stress on the expression of genes encoding β-adrenoceptors in the trigeminal ganglion. In the present study, rats were exposed to a stress protocol induced by sound, then to the administration of formalin in the TMJ (to elicit a nociceptive response), followed immediately afterward by different doses of propranolol, after which the analgesic response to propranolol was evaluated. We also assessed the levels of beta-1 and beta-2 adrenergic receptor mRNAs (Adrb1 and Adrb2, respectively) using reverse transcription-quantitative PCR (RT-qPCR). Our findings revealed that propranolol administration reduces formalin-induced TMJ nociception more effectively in stressed rats than in non-stressed rats. Furthermore, repeated stress decreases the expression of the Adrb2 gene within the trigeminal ganglion. The findings of this study are noteworthy as they suggest that individuals with a chronic stress history might find potential benefits from β-blockers in TMD treatment., (© 2023 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

Phaeochromocytomas and paragangliomas (PPGLs) release catecholamines leading to catecholamine-induced hypertensive (CIH) crises, with blood pressure greater than or equal to 180/120 mm Hg. CIH crises can be complicated by tachyarrhythmias, hypotension, or life-threatening target organ damage while treatment remains undefined, often requiring co-management between endocrinologists and cardiologists. Furthermore, biochemical diagnosis of a PPGL as a cause of a CIH crisis can be difficult to identify or confounded by comorbid conditions, potentially resulting in misdiagnosis. Here, we combine relevant evidence, 60 years of collective clinical experience, insights derived from assessing over 2600 patients with PPGL, and supplementary outcomes from 100 patients (treated at the National Institutes of Health) with a CIH crisis to inform diagnosis and treatment of CIH crises. Recognising that disparities exist between availability, cost, and familiarity of various agents, flexible approaches are delineated allowing for customisation, given institutional availability and provider preference. A CIH crisis and its complications are readily treatable with available drugs, with effective intervention defining an avenue for mitigating consequent morbidity and mortality in patients with PPGL., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation., Methods and Analysis: This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg -1 min -1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test., Ethics and Dissemination: The trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal., Trial Registration Number: ClinicalTrials.govNCT04901169., Competing Interests: Competing interests: MB discloses that support was provided by La Jolla Pharmaceutical Company (now Innoviva, Waltham, MA, USA) for this trial as part of an investigator-initiated research proposal. This support consisted of study drug (AngII) at no cost for trial patients only, and $14 231 USD (direct plus indirect costs) to support an assistant research coordinator. La Jolla Pharmaceutical Company reviewed the protocol before trial initiation but suggested no changes. The authors have sole responsibility (independent of La Jolla Pharmaceutical/Innoviva) for conduct of the trial, analysis and interpretation of data, assignment of adverse events and dissemination of results. ML has received consulting fees from La Jolla Pharmaceutical Company, Alexion Pharmaceuticals and SphingoTec GmbH. All other authors have no competing interests to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In shock there is a significant mismatch between oxygen supply and consumption. In recent years the classification of forms of shock has been established based on pathophysiological and clinical aspects. The term distributive shock includes septic, anaphylactic and neurogenic shock. All these forms share a distinct vasoplegia with a relative volume deficiency. The adequate treatment of patients with distributive shock includes a rapid diagnosis and a consistent emergency treatment consisting of volume and catecholamine administration as well as additional specific emergency procedures when necessary., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Early initiation of a multimodal treatment strategy in the management of vasopressors during septic shock has been advocated to reduce delays in restoring adequate organ perfusion and to mitigate side effects associated with the administration of high-dose catecholamines. We provide a review that summarises the pathophysiology of vasodilation, the physiologic response to the vascular response, and the different drugs used in this situation, focusing on the need to combine early different vasopressors. Fluid loading being insufficient for counteracting vasoplegia, norepinephrine is usually the first-line vasopressor used to restore hemodynamics. Norepinephrine sparing is discussed in further detail through the concomitant use of adrenergic, vasopressinergic, and renin-angiotensin systems and the optimisation of endothelial reactivity with methylene blue. A blueprint for the construction of new studies is outlined to address the question of vasopressor selection and timing in septic shock., (Copyright © 2023 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Background: This study aimed to compare the serum angiotensin II and its receptor levels (AT1, AT2) in septic patients with catecholamine-responsive or resistant. The effect of hydrocortisone treatment on angiotensin II levels in the catecholamine-resistant septic patients was evaluated., Methods: This prospective observational study enrolled 40 patients diagnosed with septic shock based on sepsis-3 criteria. Patients were divided into two groups according to the noradrenalin infusion rate required to keep the mean arterial pressure above 65 mmHg: control group and hydrocortisone group (control group: below 0.5 µg/kg/min, hydrocortisone group: above 0.5 µg/kg/min). Serum angiotensin II, AT1, AT2 levels were measured at the time of diagnosis (A), one hour after hydrocortisone treatment (B), and three days later (C)., Results: In the catecholamine-resistant group, angiotensin II and AT1 levels were higher than the catecholamine-responder group in all periods. The sensitivity and specificity of AT-1 was observed to be high in all periods. AT2 levels decreased after hydrocortisone treatment in the catecholamine-resistant group and cut-off value was found 11%., Conclusions: It was concluded that angiotensin II and AT1 can be used as a biomarker of refractory septic shock and hydrocortisone may provide their blood pressure correcting effect by reducing AT2 level in these patients. AT2 can be a therapeutic target in the catecholamine-resistant septic shock patients.

Acute kidney injury (AKI) is a common comorbidity, affecting approximately one in five hospitalized adults. The kidney is the site for the production, metabolism or excretion of most hormones, including the production of erythropoietin (EPO), the active form of vitamin D, renin, thrombopoietin, and the excretion of insulin, catecholamines, gastrin and many other hormones. Therefore, it is reasonable to say that AKI can have a considerable impact on the endocrine system. Although the effects of AKI on various parameters, including cardiovascular parameters, serum electrolytes and acid-base disorders, neuro-humoral mechanisms and neurological outcomes have been extensively studied, the endocrinological consequences of AKI are understudied. Thyroid dysfunction, mainly euthyroid sick syndrome, hypo/hyperglycemia, bone mineral disorders, changes in EPO and atrial natriuretic peptide (ANP) levels are commonly found in AKI. EPO, thyroxine and ANP administration have been evaluated as potential tools to prevent or treat AKI with varying success, while the effects of AKI on some key hormones, including cortisol and insulin, have never been studied. Aim of this narrative review is to illustrate what is known and what is not known about the endocrinological outcomes of AKI. Few clinical trials are ongoing: however, there is a clear need for large-scale randomized controlled trials investigating the endocrinological consequences of AKI., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Cytokine release syndrome (CRS) is a severe clinical syndrome marked by drastic elevation of inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). Despite the current empirical therapeutic strategies, prediction of CRS onset and identification of high-risk individuals are not satisfactory due to poor understanding of the mechanisms underlying CRS-related immune dysfunction and risk factors for CRS. Recent studies have suggested that conditions such as stress, obesity, diabetes, and hypertension may contribute to the development of CRS. Here, we discuss potential connections between these conditions and CRS pathogenesis, with a focus on stress hormone catecholamine-mediated effects, hoping that the design of CRS therapeutic approaches ensues from a renewed perspective., Competing Interests: Conflict of interest None declared by authors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Despite its widespread use, there is a paucity of data to guide the optimal use of arginine vasopressin (AVP) in critically ill patients with septic shock. Methods: This multicenter retrospective cohort study conducted in critically ill adults sought to evaluate the role of catecholamine requirements and timing on responsiveness to AVP. Responsiveness was defined as both a decrease in ≥ 50% of catecholamine requirements and no decrease in mean arterial pressure (MAP) at 4 hours post-AVP initiation. Primary outcomes of interest included the proportion of patients who started AVP within 4 hours after starting catecholamine therapy, as well as baseline norepinephrine (NE) equivalents (< 15, 15-39, or ≥ 40 mcg/min). Multivariate analyses and logistic regression were performed to identify other factors associated with AVP responsiveness. Results: There were 300 patients included in this study, with 74 patients being responders and 226 being non-responders. There was no significant difference in the number of patients who received AVP within 4 hours from catecholamine initiation between responders and non-responders (35% vs. 42%, P = 0.29). There were more patients in the non-responder group requiring ≥ 40 mcg/min of NE equivalents at AVP initiation (30% vs. 16%, P = 0.023). Stress dose steroid use was less common in responders (35% vs. 52%, P = 0.011), which was consistent with logistic regression analysis (OR 0.56, 95% 0.32-0.98, P = 0.044). Clinical outcomes between responders and non-responders were similar, apart from ICU (5.4% vs. 19.5%) and hospital (5.4% vs. 20.4%) mortality being lower in responders (P = 0.0032 and P = 0.0002, respectively). Conclusion: Shorter times to AVP initiation was not associated with responsiveness at 4 hours post-catecholamine initiation, although non-responders tended to require higher doses of NE equivalents at time of AVP initiation. Concomitant corticosteroids were associated with a lower likelihood of AVP responsiveness.

Given the heterogenous etiology of pediatric heart failure (pHF), evidence-based studies improving pHF are unlikely. A paradigm shift towards updated medicine-based evidence is therefore necessary. In view of the life expectancy of children, cardiac regeneration strategies are required. Therefore, age- and disease-related differences in myocardial (receptor) physiology require individualized precision medicine. First-line diuretic therapy, adopted from the treatment of adults with HF with no chance for recovery, should be questioned in the treatment of pHF with potential for recovery. Inadequate use of diuretics is a common reason for additional stimulation of the neurohumoral axis. Consecutive intravascular volume depletion led to an inadequate treatment with β-blocker and renin-angiotensin-aldosterone antagonists. Given the age-related catecholamine-driven cardiovascular (patho-) physiology, highly selective β1-blockers (bisoprolol) protect against β1-(noradrenaline)-related myocytic apoptosis and necrosis, but allow β2-receptor-mediated myocardial regeneration. Based on its high safety-efficacy profile with rarely seen adverse effects but easily monitorable efficacy by the surrogate of heart rate (reduction), bisoprolol is our first-line drug in infancy. Reduced heart rate economizes the heart and full body oxygen consumption and extends the diastolic filling and coronary perfusion time. Based on our many years of institutional experience, physicians should be encouraged to use β1-selected blockers in infants with dilated cardiomyopathy and hypoplastic left heart syndrome after stage-1 procedure, but also to treat ventricular septal defects with a significant left-to-right shunt. In summary, individualized pHF therapy is the prerequisite for a causal treatment to improve HF symptoms, but above all for the most functional regeneration possible., (© 2022. The Author(s).)

Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (https://clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://clinicaltrials.gov/ct2/show/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.

Introduction: Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure., Areas Covered: VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP., Expert Opinion: Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given.

Background: There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms underlying the effects of exercise on MD remain unclear. We conducted a preliminary study to clarify the effect of exercise therapy on MD, focusing on the dynamics of nitric oxide (NO) and catecholamine metabolites, which have been found to be associated with MD., Methods: Eleven outpatients with mild to moderate MD and 37 healthy controls (HC) were included in the study. The participants' clinical records and questionnaires were screened for their past medical history. For their exercise therapy, the participants were instructed to walk the equivalent of 17.5 kcal/kg/week for 8 weeks. Blood samples were collected from all participants at baseline, 4 weeks, and 8 weeks after the start of exercise therapy, and plasma metabolites of NO (NOx), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were analyzed. We also assessed the 17-item Hamilton Rating Scale for Depression (HRSD-17) in patients with MD. A mixed-effects regression model was used to compare the mean values by time (baseline, 4, and 8 weeks) for the three corresponding groups (NOx, MHPG, and HVA)., Results: HRSD-17 scores decreased significantly in the MD group after 8 weeks of exercise therapy. NOx and MHPG increased, but there was no significant change in HVA in the MD group after the exercise therapy. NOx decreased after exercise, and HVA increased significantly from baseline after 4 weeks of exercise but decreased after 8 weeks of exercise in the HC group., Conclusions: The effects of exercise on NOx, MHPG, and HVA may differ between MD and HC. The potential mechanisms for the benefits of walking exercise in MD patients will be the subject for future research., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Abstract: Sepsis and septic shock usually show a high mortality rate and frequently need of intensive care unit admissions. After fluid resuscitation, norepinephrine (NE) is the first-choice vasopressor in septic shock patients. However, high-NE doses are associated with increased rates of adverse effects and mortality. In this perspective, many authors have proposed the administration of non-adrenergic vasopressors (NAV). Selepressin is a selective vasopressin type 1A (V1A) receptor agonist and may be a valid option in this field, because it can decrease NE requirements and also limit the deleterious effects induced by high doses of catecholamines. Only few clinical data actually support selepressin administration in this setting. Here, we review the current literature on this topic analyzing some pathophysiological aspects, the rationale about the use of NAV, the possible use of selepressin differentiating animal, and human studies. Various issues remain unresolved and future trials should be focused on early interventions based on a multimodal activation of the vasopressive pathways using both alpha and V1A receptors pathways., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Germline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6-6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: To determine the association of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality., Design: Retrospective, observational study using segmented and multivariable logistic regression to evaluate the associations of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality., Setting: Multiple hospitals within the Cleveland Clinic Health System., Patients: Adult patients who met criteria for septic shock based on the U.S. Centers for Disease Control and Prevention Adult Sepsis Event definition., Interventions: All patients received continuous infusion vasopressin as an adjunct to catecholamine vasopressors., Measurements and Main Results: In total, 1,610 patients were included with a mean Acute Physiology and Chronic Health Evaluation III 109.0 ± 35.1 and Sequential Organ Failure Assessment 14.0 ± 3.5; 41% of patients survived the hospital admission. At the time of vasopressin initiation, patients had median (interquartile range) lactate concentration 3.9 mmol/L (2.3-7.2 mmol/L), norepinephrine-equivalent dose 25 µg/min (18-40 µg/min), and 5.3 hours (2.1-12.2 hr) elapsed since shock onset. The odds of in-hospital mortality increased 20.7% for every 10 µg/min increase in norepinephrine-equivalent dose up to 60 µg/min at the time of vasopressin initiation (adjusted odds ratio, 1.21 [95% CI, 1.09-1.34]), but no association was detected when the norepinephrine-equivalent dose exceeded 60 µg/min (adjusted odds ratio, 0.96 [95% CI, 0.84-1.10]). There was a significant interaction between timing of vasopressin initiation and lactate concentration (p = 0.02) for the association with in-hospital mortality. A linear association between increasing in-hospital mortality was detected for increasing lactate concentration at the time of vasopressin initiation, but no association was detected for time elapsed from shock onset., Conclusions: Higher norepinephrine-equivalent dose at vasopressin initiation and higher lactate concentration at vasopressin initiation were each associated higher in-hospital mortality in patients with septic shock who received vasopressin., Competing Interests: Dr. Bauer reports that he is a consultant for Wolters Kluwer, and he received funding from Wolters Kluwer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: The present study aims to investigate the underlying neurochemical mechanism of physical exercise on striatum synapsis and memory function in vascular dementia model., Methods: 32 Sprague-Dawley (SD) rats were randomly divided into 4 groups: control group (C group, n = 6), vascular dementia group (Vascular dementia group, n = 7), physical exercise and vascular dementia group (Exe-VD group, n = 6), physical exercise and black group (Exe group, n = 6). 4 weeks of voluntary wheel running were used as pre-exercise training. Vascular dementia model was established by bilateral common carotid arteries occlusion (BCCAo) for 1 week. Passive avoidance test (PAT) were used to test memory function. The level of striatum catecholamine in the microdialysate were detected by enzyme linked immunosorbent assy (ELISA). Golgi staining was used to analyze striatum neuronal spine density., Results: Behavioral data indicated that 4 weeks of physical exercise ameliorated memory impairment in vascular dementia model. Striatum catecholamine level significantly decreased in VD group when compared with C group ( P < .001). But this phenomenon can be rescue by physical exercise ( P < .001). In addition, compared with C group, neuronal spine density significantly decreased in VD group ( P < .01), but 4 weeks of physical exercise can rescue this phenomenon ( P < .05)., Conclusion: 4 weeks of physical exercise improves memory function by mitigate the decline of striatum catecholamine and spine density in VD model.

Introduction: Previous in vitro studies have shown that catecholamine inotropes are potent stimulators of bacterial growth and biofilm formation on catheter surfaces. This study aimed to investigate the effects of administering catecholamine inotropes during continuous renal replacement therapy (CRRT) on catheter-related infections in critically ill patients., Methods: This single-center retrospective cohort study included patients requiring CRRT in an intensive care unit from 2016 to 2017, who were divided into those who received and did not receive catecholamine inotropes for ≥24 h (catecholamine and control groups, respectively). The primary endpoint was catheter-related infection, including catheter-related colonization (CRCOL) and catheter-related bloodstream infection (CRBSI)., Findings: We included 235 patients with 297 dialysis catheters. The catecholamine group had higher proportions of cardiovascular disease (p = 0.002), shock (p < 0.001), mechanical ventilation (p < 0.001), and antibiotic use (p = 0.013). There was no significant between-group difference in the CRBSI incidence (5.742 vs. 3.143 events/1000 catheter-days; p = 0.205). However, the CRCOL incidence was significantly higher in the catecholamine group than in the control group (6.221 vs. 0.898 events/1000 catheter-days; p = 0.006). The prominent pathogenic bacteria were gram-negative bacteria. After adjusting for confounding factors in multivariate logistic models, catecholamine inotropes (OR: 3.575, 95% CI: 1.422-9.912, p = 0.008) and immunosuppression (OR: 2.980, 95% CI: 1.137-7.812, p = 0.026) were independently associated with a higher risk of catheter-related infections., Discussion: We observed a similar incidence of catheter-related infection with that in other CRRT patients. Using catecholamine inotropes in those patients increased CRCOL risk, which is consistent with previous in vitro studies. Our findings suggest that catecholamine inotropes is an independent risk factor for catheter-related infections in critically ill patients undergoing CRRT., (© 2021 International Society for Hemodialysis.)

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Vasodilatory shock is a serious medical condition that increases the morbidity and mortality of perioperative and critically ill patients. Norepinephrine is an established first-line therapy for this condition, but at high doses, it may lead to diminishing returns. Oftentimes, secondary noncatecholamine agents are required in those whose hypotension persists. Angiotensin II and vasopressin are both noncatecholamine agents available for the treatment of hypotension in vasodilatory shock. They have distinct modes of action and unique pharmacologic properties when compared to norepinephrine. Angiotensin II and vasopressin have shown promise in certain subsets of the population, such as those with acute kidney injury, high Acute Physiology and Chronic Health Evaluation II scores, or those receiving cardiac surgery. Any benefit from these drugs must be weighed against the risks, as overall mortality has not been shown to decrease mortality in the general population. The aims of this narrative review are to provide insight into the historical use of noncatecholamine vasopressors and to compare and contrast their unique modes of action, physiologic rationale for administration, efficacy, and safety profiles.

Introduction: Patients with hematological malignancies (HM) require intensive chemotherapy with curative intent, especially in case of AML that results in more frequent admissions to Intensive Care Units (ICU). Due to our knowledge, this study is the first multicenter retrospective analysis in Polish population., Methods: A total of 200 patients with HM hospitalized in 4 Polish hematological centers. Data concerning clinical indices and outcomes during admission and ICU stay were collected retrospectively., Results: The most common hematological malignancy was acute leukemia (55%). The main cause of ICU admission was respiratory failure (88.5%), often accompanied by sepsis (58.5%) and acute renal failure (51.5%). In patients with hematological malignancies, the following factors were associated with ICU mortality: prolonged ICU stay (odd ratio [OR] = 6.98, 95% confidence interval [CI]: 1.38-35.33, χ 2  = 5.61, p = 0.02), the presence of acute respiratory failure (odd ratio [OR] = 5.35, 95% confidence interval [CI]: 1.01-28.46, χ 2  = 3.93, p = 0.04), and the need for renal replacement therapy (odd ratio [OR] = 8.75, 95% confidence interval [CI]: 1.23-62.11, χ 2  = 4.78, p = 0.03). There were following associations with in-hospital mortality in patients with hematological malignancies: prolonged ICU stay (odd ratio [OR] = 10.12, 95% confidence interval [CI]: 1.85-55.37, χ 2  = 7.21, p = 0.008), the presence of acute respiratory failure (odd ratio [OR] =5.24, 95% confidence interval [CI]: 1.36-20.16, χ 2  = 5.87, p = 0.02), the need for catecholamine support (odd ratio [OR] =3.43, 95% confidence interval [CI]: 1.06-11.05, χ 2  = 4.32, p = 0.04), and renal replacement therapy (odd ratio [OR] =5.55, 95% confidence interval [CI]: 1.14-26.92, χ 2  = 4.59, p = 0.03)., Conclusions: We have demonstrated that ICU and in-hospital mortalities among patients with hematological malignancies are still poor, but easier access to the intensive care unit and close cooperation between hematologists and intensivists may improve outcomes. We have found that acute failure of key organs (acute respiratory failure, end-stage renal failure requires renal replacement therapy) and length of ICU stay (but probably no comorbidities and illness severity) may have impact on mortality (both ICU and in-hospital).

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy. Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS. Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours. Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios ( r  = 0.39; P  < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo ( P  < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P  = 0.012) ( P  = 0.048 for the interaction). Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Introduction: Beta-adrenoreceptor antagonist (beta-blocker) poisoning is a common overdose which can lead to significant morbidity and mortality. Objective: To evaluate the effects of treatments for beta-adrenoreceptor antagonist poisoning. Methods: Searches were conducted across MEDLINE (1946-26 November 2019, Ovid); Embase (1974-26 November 2019, Ovid); and the Cochrane Central Register of Controlled Trials (CENTRAL, to 26 November 2019) utilising a combination of subject headings and free text. The search strategy identified 15, 553 citations. Two reviewers screened titles and abstracts prior to selecting 141 articles (Kappa on articles included = 0.982, 95% CI 0.980-0.985). Primary outcomes included mortality and improvement in haemodynamic parameters (e.g., heart rate, blood pressure or a composite measure able to quantitate a haemodynamic response). Results: The risk of bias was high for all interventions. Gastric decontamination: Fifteen case reports described the administration of activated charcoal and five detailed the use of gastric lavage. As there was concurrent utilisation of multiple interventions, it was difficult to draw definitive conclusions regarding the relative contribution of these interventions to mortality or survival. Catecholamines, inotropes and vasopressors: The use of catecholamines in treating beta-blocker toxicity was reported in 16 case reports, 3 case series and 2 animal studies. These agents most likely provided a survival benefit and improved haemodynamics. Atropine: Multiple intravenous boluses of atropine were associated with improvement in heart rate and blood pressure in one case report. Calcium: Intravenous calcium was associated with an improvement in haemodynamics in three out of six case reports but in association with multiple other therapies as well as in two animal studies. High-dose insulin euglycaemic therapy: The use of this therapy was associated with mortality benefit in 10 case series. Two case reports showed clear haemodynamic improvement in a timeframe consistent with insulin administration (bolus then continuous infusion). Maintenance dosing ranged from 1 to 10 units/kg/h of insulin. However, it is unclear whether high-dose insulin euglycaemic therapy improved haemodynamic response above catecholamines and other inotropic agents in humans. Hypoglycaemia and hypokalemia were commonly observed adverse effects. Glucagon: Glucagon was associated with minor improvements in haemodynamics through an increase in heart rate in two cases series, nine case reports and five animal studies. Methylthioninium chloride (methylene blue): Four case reports reported an association with improvement in haemodynamics following administration of methylene blue but in the setting of co-ingestion with amlodipine. Intravenous lipid emulsion therapy: There was variable response to intravenous lipid emulsion therapy reported in 10 case series, 5 animal studies and 21 case reports. Lignocaine: There were four case reports showing variable response to lignocaine in arrhythmias secondary to beta-blocker toxicity. Other treatments: Fructose diphosphate, levosimendan and amrinone did not provide a mortality or significant haemodynamic benefit in three animal studies and nine case reports. . Veno-arterial extracorporeal membrane oxygenation: Veno-arterial extracorporeal membrane oxygenation was associated with improved survival in patients with severe cardiogenic shock or cardiac arrest in an observational study and four cases series. Dialysis: The evidence of four case reports suggest haemodialysis may assist in the management of massive overdose of specific water-soluble beta-blockers (e.g., atenolol) by improving elimination; however, a survival or haemodynamic benefit was not established. Pacing: One case series and a single case report showed the utility of temporary overdrive cardiac pacing to prevent arrhythmias in sotalol toxicity. Conclusions: Catecholamines, vasopressors, high-dose insulin euglycaemic therapy and veno-arterial extracorporeal membrane oxygenation were associated with reduced mortality. However, it must be acknowledged that multiple treatments were often given simultaneously. Haemodynamic improvements in blood pressure and cardiac output were seen with the use of catecholamines, vasopressin and high-dose insulin euglycaemic therapy. Evidence for treatment recommendations is almost entirely drawn from very low- to low-quality studies and subject to bias. However, it is reasonable to have a graduated response to cardiovascular instability beginning with intravenous fluids, commencement of a single or a combination of catecholamine inotropes and vasopressors depending upon the type of haemodynamic compromise (bradycardia, left ventricular dysfunction, vasodilation). High-dose insulin euglycaemic therapy can be introduced as an adjunctive inotrope and lastly, more invasive methods such as veno-arterial extracorporeal membrane oxygenation should be considered in cases unresponsive to other therapies.

Background: We aimed to robustly categorize glycemic control in our medical intensive care unit (ICU) as either acceptable or suboptimal based on time-weighted daily blood glucose averages of <180 mg/dL or >180 mg/dL; identify clinical risk factors for suboptimal control; and compare clinical outcomes between the 2 glycemic control categories., Methods: This was a retrospective cohort study in an academic tertiary and quaternary medical ICU., Results: Out of total of 974 unit stays over a 2-year period, 920 had complete data sets available for analysis. Of unit stays 63% (575) were classified as having acceptable glycemic control and the remaining 37% were classified (345) as having suboptimal glycemic control. Adjusting for covariables, the odds of suboptimal glycemic control were highest for patients with diabetes mellitus (odds ratio [OR] 5.08, 95% confidence interval [CI] 3.72-6.93), corticosteroid use during the ICU stay (OR 4.50, 95% CI 3.21-6.32), and catecholamine infusions (OR 1.42, 95% CI 1.04-1.93). Adjusting for acuity, acceptable glycemic control was associated with decreased odds of hospital mortality but not ICU mortality (OR 0.65, 95% CI 0.48-0.88 and OR 0.81, 95% CI 0.55-1.17, respectively). Suboptimal glycemic control was associated with increased odds of longer-than-predicted ICU and hospital stays (OR 1.76, 95% CI 1.30-2.38 and OR 1.50, 95% CI 1.12-2.01, respectively)., Conclusions: In our high-acuity medically critically ill patient population, achieving time-weighted average daily blood glucose levels <180 mg/dL reliably while in the ICU significantly decreased the odds of subsequent hospital mortality. Suboptimal glycemic control during the ICU stay, on the other hand, significantly increased the odds of longer-than-predicted ICU and hospital stay., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The management of hemodynamic instability in the context of sepsis or septic shock is at the forefront in emergency care as well as in the intensive care unit. Cardiovascular instability has a dramatic impact on the rate of organ complications and mortality from sepsis. According to the guideline for the treatment of sepsis, mean arterial pressure should not fall below 65 mm Hg. Crystalloid balanced fluid and catecholamines are the cornerstones of therapy management for septic cardiovascular instability. In this article, the most important points of what, when and how much regarding circulation therapy are presented and critically discussed.

Background: Supplemental oxygen is frequently administered to patients with acute respiratory distress syndrome (ARDS), including ARDS secondary to viral illness such as coronavirus disease 19 (COVID-19). An up-to-date understanding of how best to target this therapy (e.g. arterial partial pressure of oxygen (PaO 2 ) or peripheral oxygen saturation (SpO 2 ) aim) in these patients is urgently required., Objectives: To address how oxygen therapy should be targeted in adults with ARDS (particularly ARDS secondary to COVID-19 or other respiratory viruses) and requiring mechanical ventilation in an intensive care unit, and the impact oxygen therapy has on mortality, days ventilated, days of catecholamine use, requirement for renal replacement therapy, and quality of life., Search Methods: We searched the Cochrane COVID-19 Study Register, CENTRAL, MEDLINE, and Embase from inception to 15 May 2020 for ongoing or completed randomized controlled trials (RCTs)., Selection Criteria: Two review authors independently assessed all records in accordance with standard Cochrane methodology for study selection. We included RCTs comparing supplemental oxygen administration (i.e. different target PaO 2 or SpO 2 ranges) in adults with ARDS and receiving mechanical ventilation in an intensive care setting. We excluded studies exploring oxygen administration in patients with different underlying diagnoses or those receiving non-invasive ventilation, high-flow nasal oxygen, or oxygen via facemask., Data Collection and Analysis: One review author performed data extraction, which a second review author checked. We assessed risk of bias in included studies using the Cochrane 'Risk of bias' tool. We used the GRADE approach to judge the certainty of the evidence for the following outcomes; mortality at longest follow-up, days ventilated, days of catecholamine use, and requirement for renal replacement therapy., Main Results: We identified one completed RCT evaluating oxygen targets in patients with ARDS receiving mechanical ventilation in an intensive care setting. The study randomized 205 mechanically ventilated patients with ARDS to either conservative (PaO 2 55 to 70 mmHg, or SpO 2 88% to 92%) or liberal (PaO 2 90 to 105 mmHg, or SpO 2 ≥ 96%) oxygen therapy for seven days. Overall risk of bias was high (due to lack of blinding, small numbers of participants, and the trial stopping prematurely), and we assessed the certainty of the evidence as very low. The available data suggested that mortality at 90 days may be higher in those participants receiving a lower oxygen target (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.03 to 3.27). There was no evidence of a difference between the lower and higher target groups in mean number of days ventilated (14.0, 95% CI 10.0 to 18.0 versus 14.5, 95% CI 11.8 to 17.1); number of days of catecholamine use (8.0, 95% CI 5.5 to 10.5 versus 7.2, 95% CI 5.9 to 8.4); or participants receiving renal replacement therapy (13.7%, 95% CI 5.8% to 21.6% versus 12.0%, 95% CI 5.0% to 19.1%). Quality of life was not reported., Authors' Conclusions: We are very uncertain as to whether a higher or lower oxygen target is more beneficial in patients with ARDS and receiving mechanical ventilation in an intensive care setting. We identified only one RCT with a total of 205 participants exploring this question, and rated the risk of bias as high and the certainty of the findings as very low. Further well-conducted studies are urgently needed to increase the certainty of the findings reported here. This review should be updated when more evidence is available., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Impact of prior cardiovascular antihypertensive medication during the initial phase of septic shock in terms of catecholamine requirements and mortality has been poorly investigated and remains unclear., Objectives: To investigate the association between chronic prescription of cardiovascular antihypertensive medication prior to intensive care unit (ICU) admission, catecholamine requirement, and mortality in patients with septic shock., Methods: We included all consecutive patients diagnosed with septic shock within the first 24 h of ICU admission, defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors despite adequate fluid filling. Prior cardiovascular antihypertensive medication was defined as the chronic use of betablockers (BB), calcium channel blockers (CCB), angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blockers (ARB). ICU mortality was investigated using multivariate competitive risk analysis., Results: Among 735 patients admitted for septic shock between 2008 and 2016, 46.9% received prior cardiovascular antihypertensive medication. Prior cardiovascular antihypertensive therapy was not associated with increased norepinephrine requirements during the first 24 h (median = 0.28 μg/kg/min in patients previously treated vs. 0.26 μg/kg/min). Prior cardiovascular antihypertensive medication was not associated with a higher risk of ICU mortality after adjustment (cause-specific hazard = 1.28, 95% confidence interval [0.98-1.66], P = 0.06). Subgroups analyses for BB, CCB, and ACEi/ARB using propensity score analyses retrieved similar results., Conclusion: In patients admitted with septic shock, prior cardiovascular antihypertensive medication seems to have limited impact on initial hemodynamic failure and catecholamine requirement.

Vasodilatory shock is common following cardiac surgery, caused by an inflammatory response to cardiopulmonary bypass (CPB). Some cases are refractory to volume resuscitation, high-dose catecholamines, arginine vasopressin, and established adjunctive therapies. Angiotensin II (ANG-2), an endogenous hormone in the renin-angiotensin-aldosterone system (RAAS), has several direct and indirect vasoconstrictive properties that make it a promising potential treatment. This case describes the successful use of ANG-2 in an anephric patient who suffered from severe refractory shock following CPB, offering a unique potential mechanism of benefit in a broader population of patients with baseline impaired RAAS.

Background: Concomitant vasoactive drugs are often required to maintain adequate perfusion pressure in patients with acute myocardial infarction (AMI) and cardiogenic shock (CS) receiving hemodynamic support with an axial flow pump (Impella CP)., Objective: To compare the effect of equipotent dosages of epinephrine, dopamine, norepinephrine, and phenylephrine on cardiac work and end-organ perfusion in a porcine model of profound ischemic CS supported with an Impella CP., Methods: CS was induced in 10 pigs by stepwise intracoronary injection of polyvinyl microspheres. Hemodynamic support with Impella CP was initiated followed by blinded crossover to vasoactive treatment with norepinephrine (0.10 μg/kg/min), epinephrine (0.10 μg/kg/min), or dopamine (10 μg/kg/min) for 30 min each. At the end of the study, phenylephrine (10 μg/kg/min) was administered for 20 min. The primary outcome was cardiac workload, a product of pressure-volume area (PVA) and heart rate (HR), measured using the conductance catheter technique. End-organ perfusion was assessed by measuring venous oxygen saturation from the pulmonary artery (SvO 2 ), jugular bulb, and renal vein. Treatment effects were evaluated using multilevel mixed-effects linear regression., Results: All catecholamines significantly increased LV stroke work and cardiac work, dopamine to the greatest extend by 341.8 × 10 3 (mmHg × mL)/min [95% CI (174.1, 509.5), p < 0.0001], and SvO 2 significantly improved during all catecholamines. Phenylephrine, a vasoconstrictor, caused a significant increase in cardiac work by 437.8 × 10 3 (mmHg × mL)/min [95% CI (297.9, 577.6), p < 0.0001] due to increase in potential energy (p = 0.001), but no significant change in LV stroke work. Also, phenylephrine tended to decrease SvO 2 (p = 0.063) and increased arterial lactate levels (p = 0.002)., Conclusion: Catecholamines increased end-organ perfusion at the expense of increased cardiac work, most by dopamine. However, phenylephrine increased cardiac work with no increase in end-organ perfusion.

Beneficial effect of regular moderate physical exercise (PE) and negative effect of severe exercise and/or overtraining as an activator of the sympathetic nervous system (SNS) have been shown in numerous aspects of human health, including reduced risk of cardiovascular disease, neurological disease, depression, and some types of cancer. Moderate-to-vigorous PE stimulates the SNS activation, releasing catecholamines (CATs) adrenaline, noradrenaline, dopamine that play an important regulatory and modulatory actions by affecting metabolic processes and the immune system. Summary of the dispersed literature in this area and explanation of the biological mechanisms operating between PE-CATs and the immune system would lead to a better understanding of the beneficial and negative effects of PE on health. This overview aimed to: demonstrate representative literature findings on the exercise released CATs levels, major functions performed by these hormones, their interactions with the immune system and their effects on carbohydrate and lipid metabolism. Also, mechanisms of cytotoxic free radicals and reactive oxygen species (ROS) generation during CATs oxidation, and molecular mechanisms of CATs response to exercise are discussed to demonstrate positive and negative on human health effects. Owing to the large body of the subject literature, we present a representative cross-section of the published studies in this area. The results show a significant role of CATs in carbohydrate and lipid metabolism, immunity and as generators of ROS, depending on PE intensity and duration. Further investigation of the PE-CATs relationship should validate CATs levels to optimize safe intensity and duration of exercise and individualize their prescription, considering CATs to be applied as markers for a dose of exercise. Also, a better understanding of the biological mechanisms is also needed.

The Canadian Critical Care Society performed a meta- analysis to assess the benefits and risks of the application of vasopressin and vasopressin- analogues in distributive shock. Their results were formulated as a Guideline in 2019. In the meta- analysis mainly included were studies with patients suffering from sepsis causing the distributive shock. The recommendations of the Surviving Sepsis Campaign 2016 concerning catecholamine therapy clearly prefer norepinephrin as the first- choice vasopressor, the use of vasopressin as an additionally administered drug is rated more tentative. Also the Canadian guideline now, implicating recently published studies, argues for the use of vasopressin or vasopressin- analogues in addition to an existing norepinephrine therapy, even though the level of evidence remains still low and there's no simple therapeutic algorithm formulated. This is based on a lowered incidence of newly- diagnosed atrial fibrillation and decreased mortality rate while administration remains safe.

Background: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study., Methods: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes., Results: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P <  0.0001), lower ANG II levels (P <  0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P <  0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses., Conclusions: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction., Trial Registration: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Background: Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis. In recent years, it has been postulated that the rate of multidrug-resistant organisms (MDROs) is increasing, especially in nosocomial SBP patients. Aim of the present work was to investigate this hypothesis and its possible clinical consequences., Materials and Methods: One hundred and three culture-positive patients between 2007 and 2014 were compared with 81 patients between 2015 and 2017, to study the change of microbiological profiles and their clinical consequences. The cirrhosis patients with bacterascites requiring treatment were included as well., Results: The most prevalent Gram-negative bacteria isolated from ascites were Enterobacterales (31.6%) and in Gram-positive pathogens Staphylococci (22.8%). There was a significant increase in MDROs (22.3% ICU 40.7%, P = .048), accompanied by an increased incidence of sepsis (from 21.4% to 37.0%, P = .021), hepatorenal syndrome (from 40.8% to 58.0%, P = .007) and the need of catecholamine therapy (from 21.4% to 38.8%, P = .036). Nosocomial origin correlated with higher MDRO proportion, more complications and lower antimicrobial susceptibility rates in 12 commonly used antibiotics. MDROs were confirmed as an isolated predictor for inpatient mortality and complications in multivariable logistic regression., Conclusions: The feeling in clinical practice that MDROs have increased in the last 11 years could be confirmed in our study in Munich, Germany. Nosocomial SBP correlated with significantly higher MDRO rates (nearly 50%) and complication rates. In our opinion, an antibiotic combination with comprehensive effect should be taken into account in nosocomial SBP patients in this region., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Initial treatment (ventilator settings, rescue therapy, supportive measures), and prevention of critical events improve survival in ARDS patients, but little data exists on its effect on health-related quality of life (HRQOL) and return to work (RtW) in survivors. We analyzed the association of the intensity of treatment at ARDS onset and the incidence of critical events on HRQOL and RtW a year after ICU discharge. Methods: In a prospective multi-centre cohort study, the intensity of treatment and the incidence of critical events were determined at 61 ICUs in Germany. At 3, 6, and 12 months, 396 survivors reported their HRQOL (Short-Form 12) and RtW. The parameters of the intensity of acute management (lung protective ventilation, prone position, hemodynamic stabilization, neuromuscular blocking agents), and critical events (hypoxemia, hypoglycemia, hypotension) were associated with HRQOL and RtW. Results: Patients ventilated at ARDS onset with a low tidal volume (VT≤7 ml/kg) had higher arterial carbon dioxide levels (PaCO 2 =57.5±17 mmHg) compared to patients ventilated with VT>7ml/kg (45.7±12, p=0.001). In a multivariate adjusted dichotomized analysis, a better mental 3-month SF-12 was observed in the higher VT-group (mean 43.1±12) compared to the lower VT-group (39.5±9, p=0.042), while a dichotomized analysis for driving pressures (≤14 mbar vs >14 mbar) did not show any difference neither in PaCO 2 levels nor in HRQOL parameters. A decrease in the mental (6-month: 40.0±11 vs 44.8±13, p=0.038) and physical SF-12 (12-month: 38.3±11 vs 43.0±13, p=0.015) was reported from patients with hypoglycemia (blood glucose <70 mg/dl) compared to those without hypoglycemic episodes. More frequent vasopressor use with mean arterial pressure ≥65 mmHg was associated with an impaired physical SF-12 (6-month: 38.8±10) compared to less vasopressor use (43.0±11, p=0.019). Conclusions: In acute management of ARDS, a lower VT strategy associated with hypercapnia, as well as the frequent usage of catecholamines and the management of blood glucose may influence short-term HRQOL of survivors. The awareness of these findings is of clinical importance for the acute and post-ICU care., Competing Interests: This study is part of the DACAPO study which was funded by a research grant from the German Federal Ministry of Education and Research (01GY1340). Grant holders were TB (University Hospital Regensburg, principal investigator) and CA (University of Regensburg, co-principal investigator). SuB, FDS, MB and SeB were funded by this grant for parts of or the entire study period. All other authors received payments from the grant to support patient recruitment. TB, CK, MQ, SK, CP, SvB, BE, TK, CAr, PM, and SWC are members of the German ARDS Network. TB: received honoraria for lectures from Xenios, Germany. MQ: received honoraria for lectures from Maquet and Xenios, Germany. All other authors declare: no relationships/conditions/circumstances that present a potential conflict of interest., (Copyright © 2020 Bein et al.)

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Purpose: There is no consensus for the optimum duration of preoperative administration of phenoxybenzamine (PXB) before adrenalectomy for pheochromocytoma. The aim of this study is to investigate whether perioperative hemodynamics and postoperative outcomes are related to the duration of PXB administration., Methods: In total, 102 patients managed preoperatively with single α -receptor blocker phenoxybenzamine were enrolled from 469 consecutive patients diagnosed histologically with pheochromocytoma. The patients received surgical treatment in the Department of Urology, Peking University First Hospital, between January 2001 and July 2018. All patients were divided into three groups: Group A (<14 d), Group B (14-30 d), and Group C (>30 d). Patient and tumor characteristics, intraoperative hemodynamics, and postoperative outcomes were recorded and compared among the three groups., Results: These patients included 47 men and 55 women, with an average age of 43 years at the time of surgery. Clinical characteristics, except the status of preoperative biochemical tests (24 hr urine fractioned catecholamine or plasma-fractioned catecholamine) ( p =0.020), preoperative hemodynamics, and medicine management and surgical approaches, in the three groups were comparable. Multivariate analyses demonstrated that the size of the tumor ( p =0.034) was an independent risk factor for intraoperative hemodynamic instability. Among the three groups, we found no significant difference in intraoperative hemodynamics and postoperative outcomes., Conclusion: The data from the current study indicated that the preoperative management of pheochromocytoma with single α -receptor blocker PXB for more than 2 weeks, after the final dose adjustment, could not further reduce the risk of intraoperative hemodynamic instability or postoperative complications. Thus, our study supports that 14 days would be enough for the duration of preoperative management of pheochromocytoma with single α -receptor blocker PXB in final dose., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2019 Jie Tian et al.)

Acute kidney injury (AKI) is common in the setting of shock. Hemodynamic instability is a risk factor for the development of AKI, and pathophysiological mechanisms include loss of renal perfusion pressure and impaired microcirculation. Although restoration of mean arterial pressure (MAP) may mitigate the risk of AKI to some extent, evidence on this is conflicting. Also debatable is the optimal blood pressure needed to minimize the risk of kidney injury. A MAP of 65 mm Hg traditionally has been considered adequate to maintain renal perfusion pressure, and studies have failed to consistently show improved outcomes at higher levels of MAP. Therapeutic options to support renal perfusion consist of catecholamines, vasopressin, and angiotensin II. Although catecholamines are the most studied, they are associated with adverse events at higher doses, including AKI. Vasopressin and angiotensin II are noncatecholamine options to support blood pressure and may improve microcirculatory hemodynamics through unique mechanisms, including differential vasoconstriction of efferent and afferent arterioles within the nephron. Future areas of study include methods by which clinicians can measure renal blood flow in a macrocirculatory and microcirculatory way, a personalized approach to blood pressure management in septic shock using patient-specific measures of perfusion adequacy, and novel agents that may improve the microcirculation within the kidneys without causing adverse microcirculatory effects in other organs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Primary graft dysfunction (PGD) remains the leading cause of early mortality post-heart transplantation. Despite improvements in mechanical circulatory support and critical care measures, the rate of PGD remains significant. A recent consensus statement by the International Society of Heart and Lung Transplantation (ISHLT) has formulated a definition for PGD. Five years on, we look at current concepts and future directions of PGD in the current era of transplantation.

In addition to cutaneous, gastrointestinal, hemodynamic, and respiratory symptoms, allergic reactions can induce an acute coronary syndrome in normal or atheromatous coronary arteries and can cause coronary stent thrombosis. Here, we report a case of coronary stent thrombosis due to allergic acute coronary syndrome during anaphylaxis induced by sugammadex in a female patient undergoing general anesthesia. She was emergently treated with percutaneous transluminal coronary balloon angioplasty with catecholamine, vasodilator, and intraaortic balloon support. Knowledge of perioperative allergy-triggered acute coronary syndrome is crucial for prompt and appropriate treatment.

Background: Sinus tachycardia coupled with high-dose catecholamine is common after cardiopulmonary bypass (CPB). The present study assessed the hemodynamic efficacy and safety of combination therapy using low-dose β 1 -selective adrenergic blocker (landiolol) and inotropes., Methods: This was a retrospective, single center, self-comparison study at post-anesthesia care unit within a tertiary care center. The study included adults who underwent cardiac surgery with CPB and received landiolol between April 2007 and November 2011. We assessed hemodynamic data prior to and 1 h after initiation of landiolol therapy., Results: We evaluated 11 patients who were administered 2.6 ± 1.3 μg/kg/min (mean ± SD) landiolol with sinus tachycardia and received catecholamine therapy after on-pump cardiovascular surgery. Landiolol administration led to a significant reduction in heart rate (HR; 112.4 ± 5.8 vs 126.0 ± 7.6 beats/min, p < 0.001), and a significant increase in stroke volume index (SVI) assessed by pulmonary artery catheterization (22.4 ± 5.4 vs. 18.9 ± 4.2 mL/m 2 , p = 0.04). Only one patient showed no HR reduction, whereas seven patients showed decreased HR and increased SVI (64, 95% confidence interval: 30-98%). Moreover, all five patients who received high-dose catecholamine support showed improved hemodynamics. In terms of safety, no patients required cessation of landiolol therapy., Conclusions: Low-dose landiolol therapy may safely decrease HR and improve hemodynamics among patients with sinus tachycardia receiving catecholamine treatment after cardiovascular surgery., Trial Registration: This study is retrospective. Registration number: 11. Duration of registration: April 2007~November 2011.

Catecholamines are used to increase cardiac output and blood pressure, aiming ultimately at restoring/improving tissue perfusion. While intuitive in its concept, this approach nevertheless implies to be effective that regional organ perfusion would increase in parallel to cardiac output or perfusion pressure and that the catecholamine does not have negative effects on the microcirculation. Inotropic agents may be considered in some conditions, but it requires prior optimization of cardiac preload. Alternative approaches would be either to minimize exposure to vasopressors, tolerating hypotension and trying to prioritize perfusion but this may be valid as long as perfusion of the organ is preserved, or to combine moderate doses of vasopressors to vasodilatory agents, especially if these are predominantly acting on the microcirculation. In this review, we will discuss the pros and cons of the use of catecholamines and alternative agents for improving tissue perfusion in septic shock.