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The activation of the α 1 -adrenoceptor-(α 1 -AR) by norepinephrine results in the G-protein (Gqα) mediated increase in the phosphoinositide-specific phospholipase C (PLC) activity. The byproducts of PLC hydrolytic activity, namely, 1,2-diacylglycerol and inositol-1,4,5-trisphosphate, are important downstream signal transducers for increased protein synthesis in the cardiomyocyte and the subsequent hypertrophic response. In this article, evidence was outlined to demonstrate the role of cardiomyocyte PLC isozymes in the catecholamine-induced increase in protein synthesis by using a blocker of α 1 -AR and an inhibitor of PLC. The discussion was focused on the α 1 -AR-Gqα-PLC-mediated hypertrophic signalling pathway from the viewpoint that it may compliment the other β 1 -AR-G s protein-adenylyl cyclase signal transduction mechanisms in the early stages of cardiac hypertrophy development, but may become more relevant at the late stage of cardiac hypertrophy. From the information provided here, it is suggested that some specific PLC isozymes may potentially serve as important targets for the attenuation of cardiac hypertrophy in the vulnerable patient population at-risk for heart failure.

Context.—: Myocarditis in adolescents has been diagnosed clinically following the administration of the second dose of an mRNA vaccine for coronavirus disease 2019 (COVID-19)., Objective.—: To examine the autopsy microscopic cardiac findings in adolescent deaths that occurred shortly following administration of the second Pfizer-BioNTech COVID-19 dose to determine if the myocarditis described in these instances has the typical histopathology of myocarditis., Design.—: Clinical and autopsy investigation of 2 teenage boys who died shortly following administration of the second Pfizer-BioNTech COVID-19 dose., Results.—: The microscopic examination revealed features resembling a catecholamine-induced injury, not typical myocarditis pathology., Conclusions.—: The myocardial injury seen in these postvaccine hearts is different from typical myocarditis and has an appearance most closely resembling a catecholamine-mediated stress (toxic) cardiomyopathy. Understanding that these instances are different from typical myocarditis and that cytokine storm has a known feedback loop with catecholamines may help guide screening and therapy.

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.)

Profound skeletal muscle wasting in the setting of total body hypermetabolism is a defining characteristic of massive burns, compromising the patient's recovery and necessitating a protracted period of rehabilitation. In recent years, the prolonged use of the non-selective beta-blocker, propranolol, has gained prominence as an effective tool to assist with suppressing epinephrine-dependent burn-induced hypermetabolism and by extension, blunting muscle catabolism. However, synthetic β-adrenergic agonists, such as clenbuterol, are widely associated with the promotion of muscle growth in both animals and humans. Moreover, experimental adrenodemedullation is known to result in muscle catabolism. Therefore, the blunting of muscle β-adrenergic signaling via the use of propranolol would be expected to negatively impair muscle protein homeostasis. This review explores these paradoxical observations and identifies the manner by which propranolol is thought to exert its anti-catabolic effects in burn patients. Moreover, we identify potential avenues by which the use of beta-blocker therapy in the treatment of massive burns could potentially be further refined to promote the recovery of muscle mass in these critically ill patients while continuing to ameliorate total body hypermetabolism., (Copyright © 2021 Elsevier Ltd and ISBI. 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.

Bcl-2 associated athanogene 5 (Bag5) is a novel endoplasmic reticulum (ER) regulator. However, its role in catecholamine-induced endothelial cells damage has not been fully understood. In our study, catecholamine was used to mimic hypertension-related endothelial cell damage. Then, western blots, enzyme-linked immunosorbent assay, immunofluorescence, quantitative polymerase chain reaction and pathway analysis were conducted to analyze the role of Bag5 in endothelial cell damage in response to catecholamine. Our results indicated that the endothelial cell viability was impaired by catecholamine. Interestingly, Bag5 overexpression significantly reversed endothelial cell viability. Mechanistically, Bag5 overexpression inhibited ER stress, attenuated oxidative stress and repressed inflammation in catecholamine-treated endothelial cells. These beneficial effects finally contributed to endothelial cell survival under catecholamine treatment. Pathway analysis demonstrated that Bag5 was under the control of the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway. Reactivation of the MAPK-ERK pathway could upregulate Bag5 expression and thus promote endothelial cell survival through inhibiting oxidative stress, ER stress, and inflammation. Altogether, our results illustrate that Bag5 overexpression sustains endothelial cell survival in response to catecholamine treatment. This finding identifies Bag5 downregulation and the inactivated MAPK-ERK pathway as potential mechanisms underlying catecholamine-induced endothelial cell damage., (© 2020 Wiley Periodicals LLC.)

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).

Background: Cardiac surgery using cardiopulmonary bypass is a well-established procedure. However, up to 20% to 30% of patients require high dose vasopressor or inotropic support following surgery, enhancing the risk of organ dysfunction and impacting mortality. Nonalcoholic fatty liver disease (NAFLD) is a frequent finding in these patients and may be involved in the pathophysiology of vasoplegia and cardiac failure., Methods: Retrospective analysis of 463 patients undergoing elective cardiac surgery in 2014 at our institution. NAFLD was defined using the NAFLD fibrosis score and the vasoactive-inotropy score was used to determine postoperative vasopressor and inotropic dependency., Results: Patients with NAFLD more often presented with high vasopressor or inotropic support compared to patients without NAFLD, resulting in significant differences after 6 hours (n = 20 [27.0%] of 74 patients), 12 hours (n = 20 [27.0%] of 74 patients), and on the first postoperative day (n = 12 [16.4%] of 73 patients) of intensive care unit (ICU) treatment. Multivariate analysis revealed time of catecholamine application (P = .001), preoperative left ventricular ejection fraction (P = .001), type of surgery (P = .001), model of endstage liver disease on hospital admission (P = .002), pre-existing pulmonary hypertension (P = .004) and NAFLD-time interaction (P = .05) as independent predictors of high vasopressor and inotropic support. Patients with NAFLD had higher degrees of extrahepatic organ dysfunction, were more dependent on hemodialysis, spent more days in the ICU and within the hospital. Patients with NAFLD and high catecholamine support had the highest mortality rates among the study population., Conclusions: NAFLD is a common finding in elective cardiac surgery patients. Anesthesiologists and intensivists should be sensitive for the specific risk profile of this population., (© 2020 Wiley Periodicals, Inc.)

Innumerable physical stress factors including externally administered catecholamines, and pheochromocytomas and paragangliomas (PPGLs) have been reported to trigger Takotsubo syndrome (TS). A systematic search of PubMed/MEDLINE identified 156 patients with catecholamine-induced TS up to December 2017. Data were compared within the catecholamine-induced TS cohort, but some comparisons were also done to a previously published large all-TS cohort (n = 1750). The mean age was 46.4 ± 16.4 years (72.3% women). The clinical presentation was dramatic with high complication rates in (68.2%, n = 103; multiple complications 34.6%, n = 54). The most common TS ballooning pattern was apical or mid-apical (45.2%, n = 69), followed by basal pattern (28.8%, n = 45), global pattern (16.0%, n = 25), mid-ventricular (8.3%, n = 13), focal (0.6%, n = 1), and unidentified pattern (1.9%, n = 3). There was an increase in the prevalence of apical sparing ballooning pattern compared to all-TS population (37.7% vs 18.3%, P < .00001). Higher complication rates were observed in TS with global ballooning pattern compared to apical ballooning pattern (23/25, 92% vs 38/65, 58.5%; P = .0022). Higher complication rates were observed in patients with age < 50 years than patients >50 years (73/92, 79.3% vs 29/56, 51.8%, P = 0.0009). Recurrence occurred exclusively in patients with PPGL-induced TS (18/107 patients, 16.8%). PPGL-induced TS was characterized by more global ballooning's pattern (22/104, 21.2% vs 3/49, 6.1%, P = 0.02), and lower left ventricular ejection fraction (25.54 ± 11.3 vs 31.82 ± 9.93, P = 0.0072) compared to exogenous catecholamine-induced TS. In conclusion, catecholamine-induced TS was characterized by a dramatic clinical presentation with extensive left ventricular dysfunction, and high complication rate., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Pheochromocytoma crisis is a rare and possibly fatal emergency. Hypersecreted catecholamines may result in myocardial injury via its direct toxic effect on cardiomyocytes or mediating vasoconstriction which will reduce coronary blood flow in this special setting. Interestingly, several case studies have reported the occurrence of ST-segment elevation myocardial infarction in patients with pheochromocytoma crisis. However, no one found the angiographic evidence of occlusive thrombus in the infarct-related coronary artery. Additionally, pheochromocytoma can induce hypercoagulability and promote thrombosis, but spontaneous coronary thrombosis has never been reported in this condition. Here, we report an unusual case of pheochromocytoma crisis presenting with STEMI due to spontaneous coronary thrombosis., (Copyright © 2020 Chen, Zheng, Li, Peng and Chen.)

Purpose: β-adrenoceptor antagonist (β-blocker) may have potential in the treatment of septic shock and sepsis. However, the relevant research findings are still controversial., Methods: We conducted a systematic review and meta-analysis to explore the efficacy of β-blocker in patients with septic shock and sepsis. The primary sources of the reviewed studies through August 2018, with restriction on the language of English, were Pubmed and Embase. Randomized controlled trials (RCT) were included to evaluate the efficacy of β-blocker in the treatment of septic shock and sepsis. Meta analysis was performed using a random effect model. Two researchers independently searched articles, extracted data, and assessed the quality of the included studies., Results: A total of 6 studies related to 5 original RCTs were qualified for inclusion in this systematic review and meta-analysis with a total of 363 patients with sepsis and/or septic shock. β-blocker was associated with a significantly decreased 28-day mortality compared to usual treatment group as the control (RR = 0.59, 95%CI: 0.48, 0.74; P < 0.00001). Heart rate in β-blocker was significantly lower than that in the standard care group (SMD = -2.01, 95%CI: -3.03, -0.98; P = 0001)., Conclusion: β-blocker of esmolol is safe and effective in improving 28-day mortality and controlling ventricular rate in patients with sepsis after fluid resuscitation, and has no significant adverse effect on tissue perfusion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Catecholamine-induced cardiomyopathy (CIC) and pheochromocytoma are both rare entities, and their exact incidence and prevalence are unknown. Pheochromocytoma has been implicated as one of the causes of CIC or Takotsubo syndrome (TTS) by means of case reports and retrospective reviews. However, the evaluation of any patient with TTS and pheochromocytoma is often faced with multiple challenges due to its rarity and atypical presentations, which subsequently leads to delay in diagnosis. Here, we present a case of a 51-year old female who had three distinct episodes of TTS and now presented in a hypertensive emergency with angina, palpitations, headache, nausea, and vomiting. She was treated for non-ST elevation myocardial infarction (NSTEMI) but coronary angiogram revealed patent coronary arteries. Due to the paroxysmal nature of her hypertensive emergencies and variable blood pressure response, pheochromocytoma was suspected. On further evaluation, she was found to have elevated metanephrines and a 6.3 cm left adrenal mass on CT scan. This case emphasizes the importance of considering or identifying pheochromocytoma as an underlying primary etiology for recurrent episodes of TTS and related concerns such as choice of anti-hypertensive agents., (Copyright© South Dakota State Medical Association.)

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.)

A 55-year-old female patient was presented with severe dyspnea due to sudden onset of heart failure (ejection fraction (EF) <10%). Echocardiogram showed a takotsubo pattern with an akinetic apical segment. Coronary angiography did not reveal any obstructive disease. She became hypotensive which was refractory to conventional pressor agents. Catecholamine-induced cardiomyopathy was suspected after the CT scan of the abdomen showed a 4 cm necrotic right adrenal mass consistent with pheochromocytoma (PHEO). Venous arterial extracorporeal membrane oxygenation and α blockers were initiated. There was a rapid improvement in cardiac function with EF normalising in 1 week. Subsequently, β-blockers were added and right adrenalectomy was done 3 weeks after the admission. She did extremely well after surgery with her blood pressure normalising without the need for antihypertensive therapy. Genetic evaluation revealed no pathogenic mutations implicated in the development of PHEO., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Vasodilatory shock is a life-threatening syndrome in critically ill patients and is characterized by severe hypotension and resultant tissue hypoperfusion. This shock state requires the use of vasopressor agents to restore adequate vascular tone. Norepinephrine is still recommended as first-line vasopressor in the management of critically ill patients suffering from severe vasodilation. In the recent time, catecholaminergic vasopressor drugs have been associated with possible side effects at higher dosages. This so-called catecholamine toxicity has focused on alternative noncatecholaminergic vasopressors or the use of moderate doses of multiple vasopressors with complementary mechanisms of action. Besides vasopressin and terlipressin, angiotensin II may be a promising drug for the management of vasodilatory shock. In addition, adjunctive drugs, such as hydrocortisone, methylene blue or ascorbic acid can be added to conventional vasopressor therapy. The objective of this review is to give an overview of the current available vasopressor agents used in vasodilatory shock. A thorough search of PubMed was conducted in order to identify the majority of studies related to the subject. Data on the outcome of several drugs and future perspective of possible management strategies for the therapy of vasodilatory shock are discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gaseous transmitters were assayed in rat blood during catecholamine-induced damage to the heart. Hypercatecholaminemia was modeled by single subcutaneous injection of 0.1% epinephrine hydrochloride in a dose of 2 mg/kg. The blood concentrations of NO, H 2 S, and CO were measured. The catecholamine-induced damage to the myocardium resulted in phasic changes in the blood levels of gaseous transmitters: CO concentration increased in 1 h, H 2 S increased in 24 h, and NO concentration increased in 72 h after injection.

Catecholamines are involved in the regulation of a wide variety of vital functions. The β-adrenergic receptor (β-AR) - adenylyl cyclase system has been identified early in embryogenesis before the heart has received adrenergic innervation. The structure of β-receptors in the immature myocardium is similar to that in adults; there are, however, significant quantitative developmental changes in the inotropic and chronotropic responsiveness. Information on the toxic effect of the β-AR agonists in the immature heart is surprisingly scarce, even though these agents are used in clinical practice both during pregnancy and in early postnatal development. Large doses of β-AR agonists induce malformations of the cardiovascular system; the type of change depends upon the time at which the β-AR agonist was administered during embryogenesis. During postnatal ontogeny, the cardiotoxicity of β-AR agonists increased from birth to adulthood. It seems likely that despite interspecies differences, developmental changes in the cardiac sensitivity to β-AR agonists may exist in all mammals, depending on the degree of maturation of the system involved in β-adrenergic signaling. All the existing data draw attention to the possible harmful consequences of the clinical use of β-AR agonists during early phases of cardiac development. Late effects of the early disturbances of the cardiac muscle cannot be excluded.

Importance: Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock-a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS)., Objectives: To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events., Data Sources: MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials., Study Selection: Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock., Data Extraction and Synthesis: Two reviewers abstracted data independently. A random-effects model was used to combine data., Main Outcomes and Measures: The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS., Results: Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], -0.06 [95% CI, -0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, -0.04 [95% CI, -0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, -0.07 [95% CI, -0.12 to -0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92, P for interaction = .77). There were no significant differences in the pooled risks for other outcomes., Conclusions and Relevance: In this systematic review and meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. Findings for secondary outcomes varied.

Background: Recent hypotheses have suggested the pathophysiological role of catecholamines in the evolution of the Takotsubo syndrome (TTS). The extent of cardiac and circulatory compromise dictates the use of some form of supportive therapy. This study was designed to investigate the clinical outcomes associated with catecholamine use in TTS patients., Methods: Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The study-patients were subsequently classified into two groups based on the need for catecholamine support during hospital stay (catecholamine group n = 93; 81%, non-catecholamine group = 21; 19%). The primary end-point of our study was all-cause mortality., Results: Patients receiving catecholamine support showed higher grades of circulatory and cardiac compromise (left ventricular ejection fraction (LVEF) 39.6% vs. 32.7%, p-value < 0.01) and the course of disease was often complicated by the occurrence of different TTS-associated complications. The in-hospital mortality (3.2% vs. 28.5%, p < 0.01), 30-day mortality (17.2% vs. 51.4%, p < 0.01) as well as long-term mortality (38.7% vs. 80.9%, p < 0.01) was significantly higher in the group of patients receiving catecholamine support. A multivariate Cox regression analysis attributed EF ≤ 35% (HR 3.6, 95% CI 1.6-8.1; p < 0.01) and use of positive inotropic agents (HR 2.2, 95% CI 1.0-4.8; p 0.04) as independent predictors of the adverse outcome., Conclusion: Rates of in-hospital events and short- as well as long-term mortality were significantly higher in TTS patients receiving catecholamine support as compared to the other study-patients. These results need further evaluation in pre-clinical and clinical trials to determine if external catecholamines contribute to an adverse clinical outcome already compromised by the initial insult.

The spectrum of sepsis and septic shock remains a highly prevalent disease state, carrying a high risk of morbidity and mortality. The sympathetic nervous system (SNS) plays an important role in this initial cascade, enabling the host to respond to invading pathogens; however, prolonged activation can become pathological. The potential for unregulated sympathetic tone to become of detriment in patients with sepsis has fueled interest in the role and impact of sympatholysis, the selective inhibition of sympathetic tone. The cornerstone of septic shock therapy for decades has been the supplementation of catecholamines and thus potential further perpetuation of this sympathetic dysregulation. Although the theory of sympatholysis circulates around cardiovascular effects and stroke volume optimization, the impact of augmenting the SNS may extend well beyond this, including the impacts on the immune system, inflammatory cascade, and even gene transcription. Presently, the most robust clinical evidence involves the use of the cardioselective β-blocker esmolol in patients with septic shock with persistent tachycardia secondary to catecholamine use. Evidence is isolated only to animal models with α-agonists. Future evidence stands to elucidate the balance of sympathetic and autonomic tone as well as the potential role of redirecting and maximizing sympathetic activity.

Catecholamines, in concert with fluid resuscitation, have long been recommended in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has emerged, trending toward decatecholaminization. Contextually, it is time to re-examine the "maintaining blood pressure" paradigm by identifying safer and life-saving alternatives. We put in perspective the emerging and growing knowledge on a promising alternative avenue: the apelinergic system. This target exhibits invaluable pleiotropic properties, including inodilator activity, cardio-renal protection, and control of fluid homeostasis. Taken together, its effects are expected to be greatly beneficial for patients in septic shock.

Background: The most plausible hypothesis for takotsubo cardiomyopathy (TCM) is a catecholamine surge. Direct administration of catecholamines or medications causing catecholamine surge is frequently used in clinical practice., Methods: A Medline/PubMed database search was conducted for case reports or series of drug-induced TCM. All reported cases of drug-induced TCM were systemically identified and analyzed., Results: We identified 157 cases of drug-induced TCM. Fifty-seven (36.3%) cases were related to the administration of exogenous catecholamines. In 50 (31.9%) other cases, there was potential adrenergic effect. This included drugs with adrenergic vasoconstriction properties (3.2%), hyperadrenergic state due to alcohol or opioid withdrawal (7.7%), inhibitors of catecholamine reuptake (14.7%), anaphylactic reaction that is accompanied by catecholamine release (3.2%), and psychological or somatic stress coinciding with the administration of a drug that was thought to be the culprit (3.2%). Overall, 68.2% of these drug-induced TCM cases were catecholamine related. In 14 (8.9%) cases, the likely etiology of cardiomyopathy was chemotherapy-induced coronary vasospasm., Conclusion: Our systematic review showed that over two-thirds of drug-induced TCM cases were due to direct or indirect catecholamine stimulation. The lowest effective dose and shortest duration of catecholamines should be utilized, and alternative therapies should be considered if feasible.

Objectives: The aim of this paper was to investigate whether ventricular arrhythmias in children with catecholaminergic polymorphic ventricular tachycardia (CPVT) show circadian patterns., Background: Circadian arrhythmic patterns have been established in long QT, Brugada, and early repolarization, but have not been investigated in CPVT., Methods: This is a multicenter, retrospective review of pediatric CPVT patients, age <21 years at diagnosis. Timing of ventricular tachycardia (VT ≥3 beats) was assessed during 24-h continuous monitoring (Holter, implantable loop recorder, implantable cardioverter defibrillator) and by eliminating sleep hours, in addition to sporadic exercise stress tests. Morning was defined as 6:00 am to 11:59 am, afternoon 12:00 pm to 5:59 pm, and evening 6:00 pm to 11:59 pm. Distribution of VT events was compared by time of day, day of week, age, and sex., Results: Eighty patients (53% male), 61% with an ICD, experienced 423 VT events during a median follow-up time of 6 years (interquartile range: 2 to 10 years). When compared to morning hours, VT was more likely to occur in the afternoon (odds ratio [OR]: 2.54; 95% confidence interval [CI]: 1.69 to 3.83) or evening hours (OR: 2.91; 95% CI: 1.82 to 4.67). The predominance of afternoon/evening events persisted regardless of age, gender, or day of the week. Among 50 patients who underwent exercise stress tests, VT was significantly more likely to occur in the afternoon (OR: 3.00; 95% CI: 1.39 to 6.48)., Conclusions: In pediatric CPVT patients, ventricular arrhythmias are more likely to occur in the afternoon and evening hours. Because children's activity levels peak in both the morning and afternoon, the lack of arrhythmias in the morning hours raises questions whether factors other than adrenergic stimulation influence arrhythmia induction in pediatric patients with CPVT., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We report a 54-year-old woman with scorpion bite. After 3 hours of admission, the patient developed sudden onset tachycardia with hypotension. Cardiac evaluation showed raised creatine kinase MB isoenzyme was elevated; ECG and two-dimensional echocardiography findings were suggestive of myocarditis. Subsequently, she developed transient ventricular tachycardia before developing abrupt onset, right hemiplegia, global aphasia and progressive worsening of sensorium 12 hours after the bite. MRI of brain revealed massive left middle cerebral artery (MCA) territory infarct. The magnetic resonance angiography showed non-visualisation of left internal carotid artery (ICA) and MCA. Coagulation parameters were normal. Sudden complete occlusion of left ICA was probably secondary to cardioembolic phenomenon leading to massive infarct. Despite aggressive medical and supportive measures, she clinically worsened rapidly to Glasgow Coma Scale of 3/15 over next 6 hours and succumbed to her illness the next day., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Catecholamine agents are commonly used to support circulation; however, they may cause unexpected hypotension in a special situation. Here we describe the first unexpected case of hypotension in response to catecholamine agents., Case Presentation: A 29-year-old Japanese man with schizophrenia was transferred to our emergency department. He was in shock and in coma. After fluid resuscitation, we induced catecholamine agents; however, his blood pressure decreased to 59/40 mmHg in response to catecholamine infusion. On the other hand, after we started vasopressin, his blood pressure markedly improved, and he finally became stable. On day 2, he admitted to ingesting a large amount of risperidone, and we diagnosed risperidone overdose. We believe that this unexpected hypotension in response to catecholamine infusion was caused by an α-adrenergic blockade effect of risperidone. Animal experiments proved that the simultaneous administration of adrenaline with an α-adrenergic blockade provoked a fall in blood pressure; this phenomenon is called "adrenaline reversal." In our case, catecholamine infusion under the α-adrenergic blockade effect of risperidone might have caused a fall in blood pressure in the same mechanism; we call this phenomenon "catecholamine reversal." In such a situation, because the mechanism of vasopressin is different from that of catecholamine, we recommend vasopressin for maintaining the blood pressure., Conclusions: We described the first clinical case of "catecholamine reversal" and highlighted that if unexpected hypotension occurs in response to catecholamine infusion, we should suspect the use of α-adrenergic antagonists. In such situations, we should consider the administration of vasopressin instead.

This 16-year-old boy presented with acute retrosternal pain possibly representing acute myocardial infarction. Cardiac enzymes were within reference ranges. There were marked increases in metanephrine to 3299 μg/24 h (reference, <400 μg/24 h), normetanephrine to 1309 μg/24 h (reference, 0-390 μg/24 h), and chromogranin A to 1605 ng/mL (reference, 0-150 μg/24 h). An incidental left adrenal mass was found during CTPA performed to exclude pulmonary embolism. I-MIBG scintigraphy was negative, and genetic screening detected SDHB (succinate dehydrogenase syndrome subunit B) gene mutation. Based on the gene mutation, F-DOPA PET/CT was performed, confirming a left-sided pheochromocytoma.

Pheochromocytoma is a rare tumor, usually benign, potentially lethal in case of crisis with acute release of catecholamines. The heart is a target and the clinical presentation can mimic various cardiac conditions, thus rendering diagnosis elusive. Cardiac magnetic resonance is a valuable non-invasive diagnostic tool for the evaluation of cardiomyopathies; it allows the identification of catecholamine-induced myocarditis pattern and, in some cases, it can detect the primary tumor. The definitive treatment of pheochromocytoma is surgical, while the acute crisis may require mechanical support to circulation. We here report a case of pheochromocytoma in a 25-year-old man complicated by catecholamine-induced myocarditis and heart failure.

We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes. Adamts2 silencing regulated the expression of the genes residing within the module and impaired isoproterenol-induced cellular hypertrophy. Our results provide a view of higher order interactions in heart failure with potential for diagnostic and therapeutic insights., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Secondary abdominal compartment syndrome is well known as a life-threatening complication in critically ill patients in an intensive care unit. Massive crystalloid fluid resuscitation has been identified as the most important risk factor. The time interval from hospital admittance to the development of manifest abdominal compartment syndrome is usually greater than 24 hours. In the absence of any direct abdominal trauma, we observed a rapidly evolving secondary abdominal compartment syndrome shortly after hospital admittance associated with massive transfusion of blood products and only moderate crystalloid resuscitation., Case Presentation: We report the case of an acute secondary abdominal compartment syndrome developing within 3 to 4 hours in a 74-year-old polytraumatized white woman. Although multiple fractures of her extremities and a B-type pelvic ring fracture were diagnosed by a full body computed tomography scan, no intra-abdominal injury could be detected. Hemorrhagic shock with a drop in her hemoglobin level to 5.7 g/dl was treated by massive transfusion of blood products and high doses of catecholamines. Shortly afterwards, her pulmonary gas exchange progressively deteriorated and mechanical ventilation became almost impossible with peak airway pressures of up to 60 cmH 2 O. Her abdomen appeared rigid and tense accompanied by a progressive hemodynamic decompensation necessitating mechanic cardiopulmonary resuscitation. Although preoperative computed tomography scans showed no signs of intra-abdominal fluid, a decompressive laparotomy under cardiopulmonary resuscitation conditions was performed and 2 liters of ascites-like fluid disgorged. Her hemodynamics and pulmonary ventilation improved immediately., Conclusions: This case report describes for the first time acute secondary abdominal compartment syndrome in a trauma patient, evolving in a very short time period. We hypothesize that the massive transfusion of blood products along with high doses of catecholamines triggered the acute development of abdominal compartment syndrome. Trauma teams need to consider a rapidly developing secondary abdominal compartment syndrome to be a potential cause of hemodynamic decompensation not only in the later phase of treatment but also in the emergency phase of treatment.

Background: Morbidity and mortality following initial survival of cardiac arrest remain high despite great efforts to improve resuscitation techniques and post-resuscitation care, in part due to the ischemia-reperfusion injury secondary to the restoration of the blood circulation. Patients resuscitated from cardiac arrest display evidence of endothelial injury and coagulopathy (hypocoagulability, hyperfibrinolysis), which in associated with poor outcome. Recent randomized controlled trials have revealed that treatment with infusion of prostacyclin reduces endothelial damage after major surgery and AMI. Thus, a study is pertinent to investigate if prostacyclin infusion as a therapeutic intervention reduces endothelial damage without compromising, or even improving, the hemostatic competence in resuscitated cardiac arrest patients. Post-cardiac arrest patients frequently have a need for vasopressor therapy (catecholamines) to achieve the guideline-supported blood pressure goals. To evaluate a possible catecholamine interaction with the primary endpoints of this study, included patients will be randomized into two different blood pressure goals within guideline-recommended targets., Methods/design: A randomized, placebo-controlled, double-blind investigator-initiated pilot trial in 40 out-of-hospital-cardiac-arrest (OHCA) patients will be conducted. Patients will be randomly assigned to either the active treatment group (48 hours of active study drug (iloprost, 1 ng/kg/min) or to the control group [placebo (saline) infusion]. Target mean blood pressure levels will be allocated 1:1 to 65 mmHg or approximately 75 mmHg, which gives four different permutations, namely: (i) iloprost/65 mHg, (ii) iloprost/75 mmHg, (iii) placebo/65 mmHg, and (iv) placebo/75 mmHg. All randomized patients will be treated in accordance with state-of-the art therapy including targeted temperature management. The primary endpoint of this study is change in biomarkers indicative of endothelial activation and damage, [soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), nucleosomes] and sympathoadrenal over activation (epinephrine/norepinephrine) from baseline to 48 hours post-randomization. The secondary endpoints of this trial will include: (1) the hemostatic profile [change in functional hemostatic blood test (thrombelastography (TEG) and whole blood platelet aggregometry (multiplate)) blood cell and endothelial cell-derived microparticles]; (2) feasibility of blood pressure target intervention (target 90 %); (3) interaction of primary endpoints and blood pressure target; (4) levels of neuron-specific enolase at 48 hours post-inclusion according to blood pressure targets., Discussion: The ENDO-RCA study is a pilot study trial that investigates safety and efficacy of low-dose infusion of prostacyclin administration as compared to standard therapy in post-cardiac arrest syndrome patients., Trial Registration: Trial registration at ClinicalTrials.gov (identifier NCT02685618 ) on 18 February 2016.

Purpose of Review: The aim of this review was to examine the main determinants of cardiac dysfunction in critically ill patients, as well as how a reduction in cardiac performance influences other organ function., Recent Findings: Cardiac dysfunction is a frequent complication in critically ill patients and contributes to organ hypoperfusion and poor outcome. Pathophysiological determinants may include a primary ischaemia/reperfusion injury of the heart, effects of systemic inflammatory and adrenergic responses of the body to a variety of acute insults, as well as cardiovascular effects of commonly applied intensive respiratory or haemodynamic treatments. A strict connection exists between cardiac and other organ function, mediated by haemodynamic, humoral, and immune mechanisms. Heart, lungs, kidneys, and other splanchnic organs such as gut and liver influence each other function in a bidirectional way: this organ crosstalk must be regarded as a key aspect in multiorgan dysfunction., Summary: The heart should never be regarded as an isolated organ. When dealing with cardiac dysfunction, clinicians must consider the underlying pathophysiology, potential myocardial depressant effects of intensive treatments, and the complex interaction with other organ function.

Cardiomyopathy as the initial presentation of phaeochromocytoma (PCA) is uncommon. Diagnostic work-up and perioperative management may be challenging within this context. We report three cases of PCA presenting with cardiomyopathy to illustrate the pitfalls in diagnosis and management. None of the patients had typical adrenergic symptoms and all three were established on beta-blockers prior to diagnosis. Their fractionated plasma catecholamine levels were elevated and the diagnosis of PCA was confirmed with various imaging modalities and post adrenalectomy. Interpretation of fractionated catecholamine levels in the context of established cardiomyopathy is difficult as cardiac failure of any aetiology generates an adrenergic response. Hence screening all patients with idiopathic cardiomyopathy is likely to generate a high false-positive rate. However, a high index of suspicion should prompt further diagnostic work-up in patients with idiopathic cardiomyopathy for occult PCAs. Peer-reviewed guidelines are required to guide the investigation and management of suspected catecholamine-induced cardiomyopathy., (© 2016 Royal College of Physicians.)

Hypertensive, hypervolumic, and hemodilution therapy (triple-H therapy) is administered to patients with symptomatic cerebral vasospasm after intracranial aneurysm clipping. This therapy can sometimes result in cardiac dysfunction because of pharmacologically induced hyperadrenergic state. The diagnosis may be missed if blood pressure alone is monitored to guide triple-H therapy. In this report, we describe one such patient who developed cardiac failure after triple-H therapy. This was diagnosed by using a bioreactance noninvasive cardiac output monitoring. Continuous cardiac output monitoring by this technique facilitated treatment of cardiac failure with milrinone and dobutamine. At discharge, the patient had no neurologic deficits., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1(-/-)) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1(-/-) mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1(-/-) mice. UCP1(-/-) mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1(-/-) mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1(-/-) BAT transplanted to either UCP1(-/-) or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1(-/-) mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1(-/-) mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Small bowel damage is frequent but underdiagnosed among critically ill patients with shock. High catecholamine doses may have a deleterious effect on mesenteric blood flow. Plasma intestinal fatty acid-binding protein (I-FABP) concentration is a marker of enterocyte damage, whereas plasma citrulline concentration is a marker of functional enterocyte mass. We hypothesized that high doses of catecholamines in critically ill patients may be associated with enterocyte damage. This study aimed to determine the link between catecholamine use and dose with enterocyte damage. This is a prospective observational study performed in a large regional university teaching hospital. Critically ill patients requiring epinephrine and/or norepinephrine at admission to a medical intensive care unit (ICU) were included, as well as controls not receiving catecholamines. We evaluated at admission plasma I-FABP and citrulline concentrations, abdominal perfusion pressure (APP), and variables relating to prognosis and treatment. Patients were categorized according to the quartiles of catecholamine dose at ICU admission. Sixty critically ill patients receiving catecholamines and 27 not receiving catecholamines were included. Plasma I-FABP was higher among patients receiving catecholamine than in controls. Among patients receiving catecholamines, a dose of 0.48 γ kg min or more at ICU admission was associated with a higher I-FABP concentration. A Sepsis-related Organ Failure Assessment score higher than 11 and plasma I-FABP more than 524 pg mL at ICU admission were independently associated with 28-day mortality (odds ratio, 4.0 [1.24-12.95] and odds ratio, 4.90 [1.44-16.6], respectively). Catecholamine use is associated with I-FABP elevation in critically ill patients. Critically ill patients receiving more than 0.48 γ kg min of epinephrine and/or norepinephrine at ICU admission have high I-FABP concentrations. This suggests that enterocyte damage reflects the severity of shock, and an adverse effect of catecholamines per se is possible.

Objective: We performed a multicenter study of preterm infants, who were about to undergo patent ductus arteriosus ligation, to determine whether echocardiographic indices of impaired myocardial performance were associated with subsequent development of catecholamine-resistant hypotension following ligation., Study Design: A standardized treatment approach for hypotension was followed at each center. Infants were considered to have catecholamine-resistant hypotension if their dopamine infusion was > 15 μg kg(-1)min(-1). Echocardiograms and cortisol measurements were obtained between 6 and 14 h after the ligation (prior to the presence of catecholamine-resistant hypotension)., Result: Forty-five infants were enrolled, 10 received catecholamines (6 were catecholamine-responsive and 4 developed catecholamine-resistant hypotension). Catecholamine-resistant hypotension was not associated with decreased preload, shortening fraction or ventricular output. Infants with catecholamine-resistant hypotension had significantly lower levels of systemic vascular resistance and postoperative cortisol concentration., Conclusion: We speculate that low cortisol levels and impaired vascular tone may have a more important role than impaired cardiac performance in post-ligation catecholamine-resistant hypotension.

Placental insufficiency is associated with fetal hypoglycemia, hypoxemia, and elevated plasma norepinephrine (NE) that become increasingly pronounced throughout the third trimester and contribute to intrauterine growth restriction (IUGR). This study evaluated the effect of fetal adrenal demedullation (AD) on growth and pancreatic endocrine cell mass. Placental insufficiency-induced IUGR was created by exposing pregnant ewes to elevated ambient temperatures during mid-gestation. Treatment groups consisted of control and IUGR fetuses with either surgical sham or AD at 98 days gestational age (dGA; term = 147 dGA), a time-point that precedes IUGR. Samples were collected at 134 dGA. IUGR-sham fetuses were hypoxemic, hypoglycemic, and hypoinsulinemic, and values were similar in IUGR-AD fetuses. Plasma NE concentrations were ~5-fold greater in IUGR-sham compared to control-sham, control-AD, and IUGR-AD fetuses. IUGR-sham and IUGR-AD fetuses weighed less than controls. Compared to IUGR-sham fetuses, IUGR-AD fetuses weighed more and asymmetrical organ growth was absent. Pancreatic β-cell mass and α-cell mass were lower in both IUGR-sham and IUGR-AD fetuses compared to controls, however, pancreatic endocrine cell mass relative to fetal mass was lower in IUGR-AD fetuses. These findings indicate that NE, independently of hypoxemia, hypoglycemia and hypoinsulinemia, influence growth and asymmetry of growth but not pancreatic endocrine cell mass in IUGR fetuses.

Background: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock., Methods/design: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs., Discussion: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015., Trial Registration: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013).