Exogenous Catecholamines Research Articles

What an anesthesiologist should know about pediatric arrhythmias.

Identifying and treating pediatric arrhythmias is essential for pediatric anesthesiologists. Pediatric patients can present with narrow or wide complex tachycardias, though the former is more common. Patients with inherited channelopathies or cardiomyopathies are at increased risk. Since most pediatric patients present for anesthesia without a baseline electrocardiogram, the first identification of an arrhythmia may occur under general anesthesia. Supraventricular tachycardia, the most common pediatric tachyarrhythmia, represents a broad category of predominately narrow complex tachycardias. Stimulating events including intubation, vascular guidewire manipulation, and surgical stimulation can trigger episodes. Valsalva maneuvers are unreliable as treatment, making adenosine or other intravenous antiarrhythmics the preferred acute therapy. Reentrant tachycardias are the most common supraventricular tachycardia in pediatric patients, including atrioventricular reciprocating tachycardia (due to a distinct accessory pathway) and atrioventricular nodal reentrant tachycardia (due to an accessory pathway within the atrioventricular node). Patients with ventricular preexcitation, often referred to as Wolff-Parkinson-White syndrome, have a wide QRS with short PR interval, indicating antegrade conduction through the accessory pathway. These patients are at risk for sudden death if atrial fibrillation degenerates into ventricular fibrillation over a high-risk accessory pathway. Automatic tachycardias, such as atrial tachycardia and junctional ectopic tachycardia, are causes of supraventricular tachycardia in pediatric patients, the latter most typically noted after cardiac surgery. Patients with inherited arrhythmia syndromes, such as congenital long QT syndrome, are at risk of developing ventricular arrhythmias such as polymorphic ventricular tachycardia (Torsades de Pointes) which can be exacerbated by QT prolonging medications. Patients with catecholaminergic polymorphic ventricular tachycardia are at particular risk for developing bidirectional ventricular tachycardia or ventricular fibrillation during exogenous or endogenous catecholamine surges. Non-selective beta blockers are first line for most forms of long QT syndrome as well as catecholaminergic polymorphic ventricular tachycardia. Anesthesiologists should review the impact of medications on the QT interval and transmural dispersion of repolarization, to limit increasing the risk of Torsades de Pointes in patients with long QT syndrome. This review explores the key anesthetic considerations for these arrhythmias.

In a Canine Model of Septic Shock, Cardiomyopathy Occurs Independent of Catecholamine Surges and Cardiac Microvascular Ischemia.

High levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. Purpose-bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 μg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine-stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High-dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular-aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800-fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular-aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.

Apelin-13 administration allows for norepinephrine sparing in a rat model of cecal ligation and puncture-induced septic shock

BackgroundInfusion of exogenous catecholamines (i.e., norepinephrine [NE] and dobutamine) is a recommended treatment for septic shock with myocardial dysfunction. However, sustained catecholamine infusion is linked to cardiac toxicity and impaired responsiveness. Several pre-clinical and clinical studies have investigated the use of alternative vasopressors in the treatment of septic shock, with limited benefits and generally no effect on mortality. Apelin-13 (APL-13) is an endogenous positive inotrope and vasoactive peptide and has been demonstrated cardioprotective with vasomodulator and sparing life effects in animal models of septic shock. A primary objective of this study was to evaluate the NE-sparing effect of APL-13 infusion in an experimental sepsis-induced hypotension.MethodsFor this goal, sepsis was induced by cecal ligation and puncture (CLP) in male rats and the arterial blood pressure (BP) monitored continuously via a carotid catheter. Monitoring, fluid resuscitation and experimental treatments were performed on conscious animals. Based on pilot assays, normal saline fluid resuscitation (2.5 mL/Kg/h) was initiated 3 h post-CLP and maintained up to the endpoint. Thus, titrated doses of NE, with or without fixed-doses of APL-13 or the apelin receptor antagonist F13A co-infusion were started when 20% decrease of systolic BP (SBP) from baseline was achieved, to restore SBP values ≥ 115 ± 1.5 mmHg (baseline average ± SEM).ResultsA reduction in mean NE dose was observed with APL-13 but not F13A co-infusion at pre-determined treatment time of 4.5 ± 0.5 h (17.37 ± 1.74 µg/Kg/h [APL-13] vs. 25.64 ± 2.61 µg/Kg/h [Control NE] vs. 28.60 ± 4.79 µg/Kg/min [F13A], P = 0.0491). A 60% decrease in NE infusion rate over time was observed with APL-13 co-infusion, (p = 0.008 vs NE alone), while F13A co-infusion increased the NE infusion rate over time by 218% (p = 0.003 vs NE + APL-13). Associated improvements in cardiac function are likely mediated by (i) enhanced left ventricular end-diastolic volume (0.18 ± 0.02 mL [Control NE] vs. 0.30 ± 0.03 mL [APL-13], P = 0.0051), stroke volume (0.11 ± 0.01 mL [Control NE] vs. 0.21 ± 0.01 mL [APL-13], P < 0.001) and cardiac output (67.57 ± 8.63 mL/min [Control NE] vs. 112.20 ± 8.53 mL/min [APL-13], P = 0.0036), and (ii) a reduced effective arterial elastance (920.6 ± 81.4 mmHg/mL/min [Control NE] vs. 497.633.44 mmHg/mL/min. [APL-13], P = 0.0002). APL-13 administration was also associated with a decrease in lactate levels compared to animals only receiving NE (7.08 ± 0.40 [Control NE] vs. 4.78 ± 0.60 [APL-13], P < 0.01).ConclusionAPL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.

Histological and functional assessment of a Takotsubo cardiomyopathy model established by immobilization stress.

Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, resembles acute heart failure syndrome but lacks disease-specific diagnosis and treatment strategies. TTC accounts for approximately 5-6% of all suspected cases of acute coronary syndrome in women. At present, animal models of TTC are often created by large amounts of exogenous catecholamines such as isoproterenol. However, isoproterenol injection cannot fully simulate the onset of stress-induced cardiomyopathy in humans since stress is not an instantaneous event. Rats were immobilized for 6h per day for 1-14 days. To examine whether the TTC model was successful, echocardiography was employed; Elisa detected serum sympathetic activation markers; and the Open-Field test (OFT) was used to analyze behavioral changes in rats after stress. Western blot and histology were used to assess sympathetic remodeling, inflammation levels, and fibrosis; qRT-PCR was used to explore the levels of fibrosis and myocardial hypertrophy. The electrical stability of ventricular was determined by electrophysiological testing. The rats showed severe stress behavior and local sympathetic remodeling of the heart after only 1 day of stress. After 3 days of stress, the induction of ventricular tachyarrhythmia increased prominently. The highest incidence of TTC in rats was at 5 days of immobilization stress. The pathological left ventricular remodeling caused by immobilization (IMO) stress includes inflammatory infiltration, fibrosis, and myocardial hypertrophy. Our study confirms the hypothesis that IMO stress can mimic Takotsubo cardiomyopathy, and the various effects on the heart depending on the duration of IMO stress. We observed the highest incidence of TTC occurred after 5 days of stress. Furthermore, there is a gradual occurrence of electrical and structural remodeling as the stress duration prolongs.

Measuring Laccase Activity and Melanin Production in Cryptococcus neoformans.

Melanin is a complex dark pigment synthetized by the phenoloxidase enzyme laccase in Cryptococcus neoformans. In vitro, this enzyme oxidizes exogenous catecholamines to produce melanin that may be secreted or incorporated into the fungal cell wall. This pigment has multiple roles in C. neoformans virulence during its interaction with different hosts and probably also in protecting fungal cells in the environment against predation and oxidative and radiation stresses, among others. However, it is important to note that laccase also has melanin-independent roles in C. neoformans interactions with host cells. In this chapter, we describe a quantitative laccase assay and a method for evaluating the kinetics of melanin production in C. neoformans colonies.

Running from a Bear: How We Teach Vasopressors, Adrenoreceptors, and Shock.

Vasopressors are widely used in the management of shock among critically ill patients. The physiology of vasopressors and adrenoreceptors and their effects on end organs therefore represent important, high-yield topics for learners in the critical care environment. In this report, we describe our approach to teaching this core concept using the stereotypical human physiologic response when running from a bear, in the context of the relevant supporting literature. We use escaping from a threatening predator as a lens to describe the end-organ effects of activating adrenoreceptors together with the effects of endogenous and exogenous catecholamines and vasopressors. After reviewing this foundational physiology, we transition to the clinical environment, reviewing the pathophysiology of various shock states. We then consolidate our teaching by integrating the physiology of adrenoreceptors with the pathophysiology of shock to understand the appropriateness of each therapy to various shock phenotypes. We emphasize to learners the importance of generating a hypothesis about a patient's physiology, testing that hypothesis with an intervention, and then revising the hypothesis as needed, a critical component in the management of critically ill patients.

1261: LIBERATION FROM PROLONGED CATECHOLAMINE VASOPRESSOR EXPOSURE WITH 72-HOUR ANGIOTENSIN II INFUSION

Introduction: Angiotensin II produces vasoconstriction independent of adrenergic receptors and has been used in refractory shock. We report 2 patients in the recovery phase of shock that were successfully separated from prolonged exposure to catecholamines using 72-hours of angiotensin II infusion. Description: Case 1. A 46-year-old man with aortic valve dehiscence and recurrent endocarditis underwent redo mechanical aortic and mitral valve replacements. While recovering from multiple postoperative complications, he persistently required norepinephrine 0.06 mcg/kg/min, vasopressin 0.04 unit/min, droxidopa 300 mg q4h, and midodrine 15 mg q6h to maintain MAP > 55 mmHg for several weeks. Angiotensin II was trialed at 10 ng/kg/min and within 15 minutes the MAP was 86 mmHg and norepinephrine discontinued, with vasopressin stopped an hour later. Droxidopa and midodrine were also stopped, and over the next 72 hours angiotensin II was gradually tapered off in increments of 1-2 ng/kg/min every 6-12 hours. After a long hospital stay and eventual reintubation, the family decided to withdraw cares and the patient expired. Case 2. A 52-year-old man was admitted with urinary sepsis. After 4 weeks of complex treatment, he was recovering but persistently required norepinephrine 0.08 mcg/kg/min, vasopressin 0.04 unit/min, and midodrine 15 mg q8h to maintain MAP > 60 mmHg for 2 weeks. Angiotensin II was trialed at 20 ng/kg/min and within 30 minutes the MAP was 101 mmHg and norepinephrine discontinued, with vasopressin discontinued within 12 hours. Over the next 72 hours, midodrine was discontinued and angiotensin II was gradually tapered off. After an additional 8 weeks in the hospital, the patient discharged back to a skill nursing facility. Discussion: Prolonged stimulation of adrenergic receptors may lead to tachyphylaxis to catecholamines, believed to be due to adrenoreceptor desensitization and internalization. In such scenarios, alternative mechanisms of vasoconstriction may be necessary to achieve MAP targets. Angiotensin II engages the angiotensin type I receptor for venous and arterial constriction. We suspect in these two cases, augmenting MAP through the renin-angiotensin pathway provided a holiday from exogenous catecholamines and an opportunity for adrenoreceptors to externalize and re-sensitize.

108 PHEOCHROMOCYTOMA-INDUCED CARDIOGENIC SHOCK: A MULTICENTRE ANALYSIS OF CLINICAL PROFILES, MANAGEMENT AND OUTCOMES

Abstract Aims There is still uncertainty on the management of patients with pheochromocytoma-induced CS (PICS), as only a few clinical cases have been reported. The aim of this study is to investigate the clinical presentation, management, and outcome of patients with PICS. Methods We collected retrospectively 18 patients without previously known pheochromocytoma with histologically proven PICS admitted to 8 European hospitals. Results Among the 18 patients with a mean age of 50 years, 50% were men. The main clinical features at presentation were pulmonary congestion (83%) and cyclic fluctuation of hypertension crises and hypotension (72%). On echocardiography, mean left ventricular ejection fraction (LVEF) was 25% with an atypical-Takotsubo pattern (basal/midventricular) in 50%. Laboratory exams showed increased inflammatory markers, in particular, the mean white blood count was 21.9*109/L. Inotropes/vasopressors were started in all patients and a temporary mechanical circulatory support (t-MCS) was required in 11 (61.1%) patients. All patients underwent surgical removal of the pheochromocytoma but 4 (22.2%) on t-MCS. Echocardiogram (16/17 patients) revealed a mean LVEF of 55% at discharge. Only one patient required heart transplantation (5.5%), and all patients were alive at a median follow-up of 679 days. Conclusions In patients with PICS, characteristically, an atypical Takotsubo pattern was observed in almost half of the cases. Although the use of exogenous catecholamine can be perceived as deleterious, we showed a fairly good mid-term prognosis with rapid improvement of LVEF in most, even if adrenalectomy often occurred on t-MCS.

L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β2-Adrenergic Receptor.

The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to 2-adrenergic receptor (2AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human 2AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible 2AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into 2AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 s MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF.

Hyperthermia as a trigger for Takotsubo syndrome in a rat model.

Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.

Transient ventricular bigeminy during emergence from general anesthesia in a pediatric patient with catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare genetic disease that is characterized by ventricular arrhythmias and sudden death, induced by exogenous and endogenous catecholamine. We performed general anesthesia for dental treatment of multiple teeth in a 7-year-old boy with CPVT. To avoid sympathetic tone, anesthesia was maintained by total intravenous anesthesia, but ventricular bigeminy was induced by stimulation on emergence form general anesthesia. Although bigeminy in the present case might have been less likely to induce a fatal arrhythmia, we should keep in mind that a small amount of sympathetic tone may induce arrhythmias in a patient with CPVT.

P045 Octopus Toes?

Abstract Background/Aims Takotsubo cardiomyopathy is a relatively rare condition. Its name derives from the distinctive apical ballooning seen on cardiac angiography, which resembles the shape of takotsubo, a Japanese octopus trap. The clinical presentation is similar to acute coronary syndrome (ACS). Ischaemic ECG changes and elevated serum cardiac biomarkers are seen despite normal coronary artery angiography. Methods: History A 72-year-old female presented with a five-day history of constant bilateral foot pain and toe discolouration, associated with reduced sensation. She had a past history of hypertension and Raynaud’s phenomenon. She had recently been admitted with an alcohol withdrawal seizure and had recent severe stressful life events. She denied chest pain or dyspnoea and was a non-smoker. Her medications were ramipril and thiamine. Examination: Both feet were warm to touch proximal to the toes, with tenderness and diminished sensation in the distal feet. The toes were dusky but pedal pulses were palpable with good biphasic Doppler signal. Blood pressure was 117/105 mmHg on admission, with normal nail folds and heart sound, and no splinter haemorrhages were seen. Results: Investigations Blood parameters were CRP 60 mg/L, eGFR 47 mL/min, troponin &amp;gt;25,000 ng/L, and negative RF, ANA, ANCA, MPO, PR3, C3, C4. ECG showed lateral ST-segment elevation but normal coronary vessels were seen on coronary angiography. Echocardiogram revealed hypokinetic apical region and mid-anterior wall, reduced ejection fraction 35-40 % with apical ballooning, consistent with Takotsubo cardiomyopathy. Urine catecholamines, normetadrenaline, metadrenaline and 3-methoxytyramine levels were normal when measured eight days after the initial presentation. Management Daily Iloprost was given for five days with aspirin, furosemide, spironolactone and ivabradine, but no significant improvement was observed in the ischaemic feet. Her foot pain gradually subsided but the toes remained necrotic. Over the next six months, her toes mummified and auto-amputated. She has had no further ischaemic events. Conclusion Takotsubo cardiomyopathy accounts for 1-2% of troponin positive suspected ACS. It is most common in older females. The cause is not clear, but the predominant hypothesis is that a catecholamine surge leads to microvascular spasm and myocardial stunning. Raised catecholamine levels at presentation have been documented in patients with takotsubo cardiomyopathy, and the syndrome has been described in patients exposed to exogenous catecholamines. Digital ischaemia has been described in phaeochromocytoma. We postulate that our patient’s background of Raynaud’s phenomenon predisposed her to digital ischaemia during a period of catecholamine excess, which led to takotsubo cardiomyopathy. To our knowledge, this phenomenon has not previously been described. Given the profound effect of the presumed catecholamine surge on cardiac function in takotsubo cardiomyopathy and the high prevalence of Raynaud's phenomenon in the general population, it is perhaps surprising that ischaemia in digits and other organs is not more commonly observed. Disclosure K. Yeap: None. C. Badu-Boateng: None. M. Lloyd: None.

Cryptococcus neoformans melanization incorporates multiple catecholamines to produce polytypic melanin

Melanin is a major virulence factor in pathogenic fungi that enhances the ability of fungal cells to resist immune clearance. Cryptococcus neoformans is an important human pathogenic fungus that synthesizes melanin from exogenous tissue catecholamine precursors during infection, but the type of melanin made in cryptococcal meningoencephalitis is unknown. We analyzed the efficacy of various catecholamines found in brain tissue in supporting melanization using animal brain tissue and synthetic catecholamine mixtures reflecting brain tissue proportions. Solid-state NMR spectra of the melanin pigment produced from such mixtures yielded more melanin than expected if only the preferred constituent dopamine had been incorporated, suggesting uptake of additional catecholamines. Probing the biosynthesis of melanin using radiolabeled catecholamines revealed that C. neoformans melanization simultaneously incorporated more than one catecholamine, implying that the pigment was polytypic in nature. Nonetheless, melanin derived from individual or mixed catecholamines had comparable ability to protect C. neoformans against ultraviolet light and oxidants. Our results indicate that melanin produced during infection differs depending on the catecholamine composition of tissue and that melanin pigment synthesized in vivo is likely to accrue from the polymerization of a mixture of precursors. From a practical standpoint, our results strongly suggest that using dopamine as a polymerization precursor is capable of producing melanin pigment comparable to that produced during infection. On a more fundamental level, our findings uncover additional structural complexity for natural cryptococcal melanin by demonstrating that pigment produced during human infection is likely to be composed of polymerized moieties derived from chemically different precursors.

Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients

Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

Adrenoceptors Modulate Cholinergic Synaptic Transmission at the Neuromuscular Junction.

Adrenoceptor activators and blockers are widely used clinically for the treatment of cardiovascular and pulmonary disorders. More recently, adrenergic agents have also been used to treat neurodegenerative diseases. Recent studies indicate a location of sympathetic varicosities in close proximity to neuromuscular junctions. The pressing question is whether there could be any effects of endo- or exogenous catecholamines on cholinergic neuromuscular transmission. It was shown that the pharmacological stimulation of adrenoceptors, as well as sympathectomy, can affect both acetylcholine release from motor nerve terminals and the functioning of postsynaptic acetylcholine receptors. In this review, we discuss the recent data regarding the effects of adrenergic drugs on neurotransmission at the neuromuscular junction. The elucidation of the molecular mechanisms by which the clinically relevant adrenomimetics and adrenoblockers regulate quantal acetylcholine release from the presynaptic nerve terminals and postsynaptic sensitivity may help in the design of highly effective and well-tolerated sympathomimetics for treating a number of neurodegenerative diseases accompanied by synaptic defects.

Relationship Between Serum Norepinephrine Levels at ICU Admission and the Risk of ICU-Acquired Delirium: Secondary Analysis of the Melatonin Evaluation of Lowered Inflammation of ICU Trial.

A secondary analysis of the data of 81 patients enrolled in our previous randomized clinical trial. ICU of an academic hospital. ICU patients in whom the serum levels of catecholamines were measured at ICU admission. None. We evaluated the association between the serum levels of catecholamines measured at ICU admission and the risk of ICU-acquired delirium separately in patients who had received exogenous catecholamines at ICU admission (Ex[+] group) and those who had not received exogenous catecholamines (Ex[-] group). The serum levels of norepinephrine measured at ICU admission were significantly associated with the risk of ICU-acquired delirium in the Ex(-) group (odds ratio, 2.58; 95% CI, 1.02-6.52; p = 0.046), but not in the Ex(+) group (odds ratio, 1.02; 95% CI, 0.88-1.18; p = 0.823). Furthermore, there was a statistically significant interaction effect between the serum levels of norepinephrine and the use/nonuse of exogenous catecholamines at ICU admission in relation to the risk of occurrence of ICU-acquired delirium (p interaction = 0.017). The serum levels of norepinephrine measured at admission were associated with the risk of occurrence of ICU-acquired delirium in patients who had not received exogenous catecholamines at ICU admission, whereas no such association was observed in those who had received exogenous catecholamines previously. Thus, the association between the serum levels of catecholamines measured at admission and the risk of ICU-acquired delirium differed between patients who had/had not received exogenous catecholamines at ICU admission.

Junctional Ectopic Tachycardia: Recognition and Modern Management Strategies.

Junctional ectopic tachycardia is a common dysrhythmia after congenital heart surgery that is associated with increased perioperative morbidity and mortality. Risk factors for development of junctional ectopic tachycardia include young age (neonatal and infant age groups); hypomagnesemia; higher-complexity surgical procedure, especially near the atrioventricular node or His bundle; and use of exogenous catecholamines such as dopamine and epinephrine. Critical care nurses play a vital role in early recognition of dysrhythmias after congenital heart surgery, assessment of hemodynamics affecting cardiac output, and monitoring the effects of antiarrhythmic therapy. This article reviews the underlying mechanisms of junctional ectopic tachycardia, incidence and risk factors, and treatment options. Currently, amiodarone is the pharmacological treatment of choice, with dexmedetomidine increasingly used because of its anti-arrhythmic properties and sedative effect.

Beta-blockers in sepsis

Catecholamines are an integral component of the host stress response and usually increase appropriately at times of need. Unfortunately, in severe and prolonged critical illness, they can contribute to significant harm with unwanted biological effects on cardiac function, inflammatory, immune, metabolic, and coagulation pathways1. A good example is Takotsubo (‘stress’) cardiomyopathy where heart failure ensues after an emotional stress resulting in extremely high levels of circulating catecholamines, considerably above that seen in a significant myocardial infarction2.Unwittingly, we are likely contributing to catecholamine toxicity in our management of the critically ill septic patient through use of exogenous catecholamine therapies which carry the same detrimental effects as endogenous catecholamines1,3. Catecholamines are currently recommended first-line agents for septic shock, and are used in an attempt to overcome the vascular hyporeactivity and myocardial depression associated with sepsis. Use of higher doses of catecholamines is however associated with worse outcomes4. This is usually ascribed to the patient's underlying illness severity and an iatrogenic contribution is not considered – but perhaps should be.Beta-blockers have multiple actions, on cardiac function and beyond. They reduce cardiac work through negative inotropic and chronotropic effects. Importantly, through slowing an excessive heart rate, both systolic and diastolic ventricular function are improved. They also act on adrenergic receptor responsiveness, enhancing the activity of catecholamines and allowing reductions in dose to achieve the same haemodynamic effect. Outside the heart, they improve vascular tone, enhance metabolic efficiency, and have anti-inflammatory effects and anti-thrombotic activity.The first use of beta-blockade in sepsis goes back nearly 50 years with successful use in some patients in refractory shock. In the last decade an increasing number of observational studies and a few single-centre randomised controlled trials have shown both safety and improved outcomes5. These reflect findings in animal models of sepsis where various mechanisms were demonstrated including protective effects on the heart, anti-inflammatory actions and preservation of the gut barrier5.Clearly, the patient needs to be adequately fluid-resuscitated and stabilised before commencing beta-blockers. Ideally, the use of a short-acting agent such as esmolol or landiolol allows easy titration, or cessation, of the infusion should hypotension or excess bradycardia occur with the unwanted effects wearing off within minutes. The largest study to date by Morelli et al., randomised 154 septic shock patients to receive either placebo or esmolol to reduce heart rate to 80-95 bpm. This was successfully achieved with no increase in complication rates compared to placebo. Importantly, there were also benefits in terms of earlier recovery of renal function, cessation of norepinephrine infusion, lower troponin levels (indicative of less cardiac damage), and improved survival rates. These encouraging findings need to be repeated in multicentre settings and two studies (one UK-based “STRESS-L”, one in 4 European countries) are currently ongoing.

Effects of pretreatment with cardiostimulants and beta-blockers on isoprenaline-induced takotsubo-like cardiac dysfunction in rats

BackgroundTakotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that is not caused by coronary artery occlusion. Exogenous as well as endogenous excess catecholamines can induce TS. The aim of this study was to explore the effects of pharmacological cardio-simulative and cardio-depressing drugs on the development of isoprenaline-induced takotsubo-like cardiac dysfunction, a rat model of TS. MethodsWe randomized 295 rats into twelve groups. The animals were randomized to pre-treatment with either a low or high dose of metoprolol, propranolol, ICI 118551 (beta2-receptor antagonists), milrinone (phosphodiesterase inhibitor), levosimendan or saline (control) before induction of TS with isoprenaline. In one additional group, high dose of milrinone was administered alone. We measured invasively blood pressure and heart rate over a period of 90 min. Cardiac function and morphology were evaluated with high-resolution echocardiography. ResultsMilrinone alone induced apical ballooning similar to isoprenaline. Pretreatment with propranolol and metoprolol but not with ICI 118551 attenuated takotsubo-like akinesia in a dose-dependent manner. Pretreatment with metoprolol decreased mortality. Pretreatment with levosimendan resulted in higher incidence of apical ballooning while pretreatment with milrinone did not change the degree of akinesia. ConclusionThe phosphodiesterase inhibitor milrinone induces takotsubo-like dysfunction in the absence of exogenous catecholamines. This finding challenges the concept that high levels of circulating catecholamines or excessive stimulation of adrenergic receptors are necessary for the development of takotsubo syndrome. Our study provides experimental evidence for the concept of avoidance of inotropes and that selective beta1-blockade may be beneficial in the treatment of TS-patients.

The effects of endogenous and exogenous catecholamines on hypoxic cardiac performance in red-bellied piranhas.

Catecholamines protect the fish heart during hypoxia. However, the humoral adrenergic stress response may only be invoked in extremis. We investigated the hypothesis that endogenous (e.g., neuronal) myocardial catecholamines may also impact cardiac performance during hypoxia in a hypoxia-tolerant tropical fish, the red-bellied piranha (Pygocentrus nattereri). First, we measured endogenous tissue catecholamines and in vitro catecholamine release from piranha myocardium using ultraperformance liquid chromatography. Ventricle homogenates contained detectable levels of both adrenaline (7.27 ng/g) and noradrenaline (14.48 ng/g), but only noradrenaline was released from ventricular tissue incubated in Ringer's solution. Noradrenaline released in this assay was not affected by hypoxia but was promoted by the catecholamine releasing agent tyramine. Our second series of experiments explored cardiac contractile performance in vitro using tyramine, exogenous noradrenaline or adrenaline, and propranolol (a β-adrenoceptor antagonist). In ventricular strip preparations, β-adrenergic blockade with propranolol had no effects on twitch force or contraction kinetics in either normoxia or hypoxia, confirming that spontaneous endogenous catecholamine release did not impact cardiac performance. However, in the absence of propranolol, tyramine mimicked the positive inotropic effect of noradrenaline (10 µM) during hypoxia, although adrenaline was capable of generating larger effects. Our results suggest that, although it is not spontaneously released, inducible endogenous noradrenaline release may have a significant β-adrenoceptor-dependent impact on hypoxic performance in the fish heart.