Intranasal orexin A modulates sympathetic vascular tone: a pilot study in healthy male humans.

Previous research suggests that the neuropeptide orexin A contributes to sympathetic blood pressure (BP) control inasmuch as hypothalamic injection of orexin A increases sympathetic vasomotor tone and arterial BP in rodents. In humans with narcolepsy, a disorder associated with loss of orexin-producing neurons, vasoconstrictive muscle sympathetic nerve activity (MSNA) is reduced. Since intranasally administered oligopeptides like orexin are known to modulate brain function, we investigated the effect of intranasal orexin A on vascular sympathetic baroreflex function in healthy humans. In a balanced, double-blind crossover study, orexin A (500 nmol) and placebo, respectively, were intranasally administered to 10 lean healthy males (age 25.8 ± 4.6 yr). MSNA was assessed microneurographically before and 30-45 min after either substance administration. Additionally, baroreflex was challenged via graded infusions of vasoactive drugs before and after substance administration. Baroreflex function was defined as the correlation of BP with MSNA and heart rate. Intranasal orexin A compared with placebo induced a significant increase in resting MSNA from pre-to postadministration [Δburst rate, orexin A vs. placebo: +5.8 ± 0.8 vs. +2.1 ± 0.6 bursts/min, P = 0.007; total activity 169 ± 11.5% vs. 115 ± 5.0%; P = 0.002]. BP, heart rate, and sympathovagal balance to the heart, as represented by heart rate variability (HRV), as well as baroreflex sensitivity during the vasoactive challenge were not altered. Intranasally administered orexin A acutely induced vasoconstrictory sympathoactivation in healthy male humans. This result suggests that orexin A mediates upward resetting of the vascular baroreflex set point at centers superordinate to the mere baroreflex feedback loop.NEW & NOTEWORTHY Our pilot study adds another important part to the complex network of neuroendocrine-sympathetic interaction. Our results demonstrate that intranasal orexin A elicits an excitatory effect on sympathetic vascular tone superordinate to mere baroreflex feedback regulation. This resetting of the baroreflex set point suggests an activation of hypothalamic core centers such as the paraventricular nucleus (PVN). The role of the orexinergic system in the development of neurogenic arterial hypertension warrants further investigations.

Intranasal oxytocin has sympathoexcitatory effects on vascular tone in healthy males.

Oxytocin appears to be involved in the neuroendocrine regulation of sympathetic blood pressure (BP) homeostasis. In animals, intracerebral administration of oxytocin induces BP-relevant sympathetic activation. In humans, central nervous effects of oxytocin on BP regulation remain unclear. Intranasal administration supposedly delivers oligopeptides such as oxytocin directly to the brain. We investigated the effects of intranasal oxytocin on sympathetic vascular baroreflex function in humans using microneurographic techniques. In a balanced, double-blind crossover design, oxytocin or placebo was administered intranasally to 12 lean, healthy males (age 25 ± 4 yr). Muscle sympathetic nerve activity (MSNA) was assessed microneurographically before (presubstance), 30-45 min (postsubstance I), and 105-120 min (postsubstance II) after oxytocin administration. Baroreflex was challenged via graded infusions of vasoactive drugs, and correlation of BP with MSNA and heart rate (HR) defined baroreflex function. Experiments were conducted in the afternoon after a 5-h fasting period. After oxytocin, resting MSNA (burst rate and total activity) showed significant net increases from pre to postsubstance II compared with placebo [Δincrease = +4.3 ± 1.2 (oxytocin) vs. +2.2 ± 1.4 bursts/min (placebo), ANOVA; P < 0.05; total activity = 184 ± 11.5% (oxytocin) vs. 121 ± 14.3% (placebo), ANOVA; P = 0.01). This was combined with a small but significant net increase in resting diastolic BP, whereas systolic and mean arterial BP or HR as well as baroreflex sensitivity at vasoactive drug challenge were not altered. Intranasally administered oxytocin induced vasoconstrictory sympathoactivation in healthy male humans. The concomitant increase of diastolic BP was most likely attributable to increased vascular tone. This suggests oxytocin-mediated upward resetting of the vascular baroreflex set point at centers superordinate to the mere baroreflex-feedback loop.

Intranasal application of the melanocortin 4 receptor agonist MSH/ACTH(4-10) in humans causes lipolysis in white adipose tissue.

OBJECTIVE: The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. In animals, intracerebroventricular infusion of melanocortin receptor 4 (MCR-4) agonists increases basal metabolic rate through activation of the sympathetic nervous system and subsequently reduces food intake. In humans, direct access of MCR-4 agonists to the central nervous system can be achieved by a transnasal route, which leads to weight loss with chronic administration. In the present study, we aimed at investigating the effects of intranasally administered MC4-R agonist MSH/ACTH(4-10) on lipolysis and sympathetic nervous system activity in healthy humans. DESIGN: Healthy normal weight, male volunteers (n=10) received either 10 mg MSH/ACTH(4-10) or placebo intranasally in a double-blinded randomized crossover design. Interstitial glycerol release was assessed by microdialysis in abdominal white adipose tissue (WAT) and in skeletal muscle (SM) of the forearm. Local blood flow, systemic blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) within the superficial peroneal nerve were recorded at rest and after nitroprusside infusion. RESULTS: At 45 min after MSH/ACTH(4-10) administration WAT glycerol concentrations increased by 53.4±19.3% compared with baseline conditions (P<0.05) and remained significantly higher throughout the experiment when compared with placebo (P<0.05) while local glycerol release in SM was not significantly affected. Resting MSNA was not altered by MSH/ACTH(4-10) administration; however, sympathoexcitation by intravenous nitroprusside was markedly elevated (MSH/ACTH(4-10) 569±69% increase to baseline; placebo: 315±64%; P<0.01). CONCLUSION: Intranasally administered MCR-4 agonist MSH/ACTH 4-10 increases both subcutaneous WAT lipolysis and MSNA, which suggests a direct central nervous peptide effect in humans on key factors of human energy metabolism.

Metabolic alterations in adipose tissue during the early phase of experimental endotoxemia in humans.

Adipose tissue plays an important role in energy homeostasis; however, there is only little knowledge about its metabolic activity during critical illness or sepsis. We assessed adipose tissue metabolic activity and local blood flow during experimental endotoxemia in otherwise healthy humans. In a prospective, placebo controlled and randomized experiment we measured changes in lactate, glycerol, and pyruvate concentrations in microdialysate samples of femoral adipose tissue after an intravenous bolus of lipopolysaccharide (LPS, 4 ng/kg). Intravenous endotoxin caused an early and constant increase in interstitial pyruvate, while formation of lactate in adipose tissue was not affected. In contrast, lactate levels in serum were elevated significantly after 90 min (p<0.05) and likewise, serum glycerol concentrations rose 90 min after LPS treatment (p<0.05) and 60 min earlier than in adipose tissue. Subcutaneous adipose tissue blood perfusion increased 2-fold while there was a strong decline in skin blood flow. Pyruvate accumulation in subcutaneous adipose tissue is an early marker of endotoxemia. While adipose tissue is a major source of serum glycerol and lactate in humans during physiological conditions, it contributes only little to increased serum lactate and glycerol levels during endotoxemia.

[Core curriculum Medical intensive care medicine of the German Society of Medical Intensive Care and Emergency Medicine (DGIIN)]. / Curriculum Internistische Intensivmedizin.

Medical intensive care medicine treats patients with severe, potentially life-threatening diseases covering the complete spectrum of internal medicine. The qualification in medical intensive care medicine requires a broad spectrum of knowledge and skills in medical intensive care medicine, but also in the general field of internal medicine. Both sides of the coin must be taken into account, the treatment with life-sustaining strategies of the acute illness of the patient and also the treatment of patient's underlying chronic diseases. The indispensable foundation of medical intensive care medicine as described in this curriculum includes basic knowledge and skills (level of competence I-III) as well as of behavior and attitudes. This curriculum is primarily dedicated to the internist in advanced training in medical intensive care medicine. However, this curriculum also intends to reach trainers in intensive care medicine and also the German physician chambers with their examiners, showing them which knowledge, skills as well as behavior and attitudes should be taught to trainees according to the education criteria of the German Society of Medical Intensive Care and Emergency Medicine (DGIIN).

[Glucocorticoids and hypertension]. / Glukokortikoide und Hypertonie.

Severe arterial hypertension is a hallmark of Cushing syndrome which occurs in 80% of the patients. Additionally, persistent cortisol excess induces obesity, hyperinsulinemia with disturbed glucose tolerance and dyslipidemia which all contribute to the development of hypertension and its deleterious sequelae. Cortisol effects are mediated through diversely distributed intracellular glucocorticoid and mineralocorticoid receptors which are protected by the 11-beta-hydroxysteroiddehydrogenase type 2 in cells of some organs (i.e. kidney) but not in other. A highly complex clinical picture evolves in case of hypercortisolism due to the ubiquitous distribution of steroid receptors with different affinity and binding capacities for glucocorticoids. The present review focuses on the cortisol induced changes in blood pressure regulation which contribute to the development of hypertension.

[Transient loss of consciousness : Algorithm for the (differential) diagnosis of syncope at emergency department]. / Passagere Bewusstlosigkeit : Algorithmus für die Notaufnahme zur (Differenzial-)Diagnostik von Synkopen.

Transient loss of consciousness (TLoC) is a common complaint leading to presentation at the emergency department. This comprises a heterogeneous group of disorders including cerebral events, metabolic disturbances, intoxication, psychogenic patterns or any form of syncope. While many causes are benign and self-limited not requiring extensive in-hospital evaluation, others are potentially severe. The optimal evaluation of patients with TLoC/syncope follows a risk-adapted diagnostic algorithm in order to exclude life-threatening conditions and to identify those with high risk for further deterioration like structural heart diseases requiring further diagnostic evaluation. Low-risk patients can be discharged without further extensive diagnostic work up. This article presents an algorithm for structured, evidence-based care of the syncope patient in accordance with the recently launched "2018 ESC guidelines for the diagnosis and management of syncope" in order to ensure that patients requiring hospitalization are managed appropriately and those with benign causes are discharged safely. The English version of this algorithm is available at the end of the article under "Supplementary Material".

[Point-of-care ultrasonography of the abdomen in emergency and intensive care medicine]. / Point-of-care-Sonographie des Abdomens in der Notfall- und Intensivmedizin.

Point-of-care ultrasound is a fundamental part of diagnostic and therapeutic management in emergency and intensive care medicine. The availability of high-resolution mobile ultrasound systems allows high-quality imaging at the bedside of the patient. Point-of-care ultrasound is not a comprehensive differential diagnostic abdominal ultrasound examination. Rather, the aim of the method is to integrate easily detectable sonographic findings into the clinical context. From this, the necessary diagnostic or therapeutic procedures are derived. This article shows opportunities and limitations of this method. The structure of the article is given by the leading clinical symptoms. The focus is on the ultrasound examination and the characteristic sonographic findings with illustrative ultrasound images. This is followed by a short differential diagnostic interpretation. Further diagnostic or therapeutic management is also briefly addressed.

[Successful lipid rescue therapy in a case of severe amitriptyline/quetiapine intoxication]. / Erfolgreiche "Lipidrescuetherapie" bei Amitriptylin-Quetiapin-Mischintoxikation in mehrfach letaler Dosis.

A 25-year-old patient was admitted urgently due to mixed amitriptyline/quetiapine intoxication at a potentially lethal dose. Alongside severe anticholinergic toxidrome, she presented with antiadrenergic and quinidin-like cardiotoxic findings, including ventricular tachycardia. In the present case, arrhythmia and circulatory shock responded neither to alkalization and elevated sodium levels after infusion of sodium bicarbonate, nor to any other established therapies. Following the lipid rescue paradigm, bolus infusion of a 20% lipid emulsion led to rapid stabilization and continued reversal of all intoxication features.

[Mother and son between omnipotence and coma]. / Mutter und Sohn zwischen Allmacht und Koma.

An academic and his mother, both with Chinese roots, present to the emergency department due to acute confusion. After short latency nausea, complex-focal seizures and finally coma with preserved protective reflexes occur. The cardiorespiratory stable patients are observed in an intensive care unit. The extended emergency diagnostic work-up revealed no cause for the underlying symptoms. Following medical request, the apartment of the patient is inspected by the police, where a meal with self-picked mushrooms is found. Special laboratory exams lead to the diagnosis of pantherina syndrome.

Acute effects of aldosterone on the autonomic nervous system and the baroreflex function in healthy humans.

Aldosterone has been reported to impair the baroreflex response in animal models. The present study aimed to investigate the acute effects of aldosterone on the autonomic nervous system and the baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. Nine healthy subjects were examined in a double-blind, placebo-controlled, cross-over study design, receiving either i.v. aldosterone (100 microg) or placebo on the experimental day. Heart rate variability (HRV) was measured at rest, whereas blood pressure, heart rate and MSNA (assessed by microneurography from the peroneal nerve) were monitored both at rest and during baroreflex tests. Baroreceptor stimulation and deactivation was induced by i.v. infusion of incremental doses of phenylephrine and sodium nitroprusside. HRV indices at rest were specifically changed by aldosterone with a significant increase in standard deviation of RR intervals and total power, and a trend towards increased time domain parameters indicating parasympathetic predominance in heart rate regulation. Basal MSNA, blood pressure and heart rate remained unaffected by aldosterone administration. Sodium nitroprusside decreased diastolic blood pressure and increased MSNA as well as heart rate in both the aldosterone and placebo experiments. However, the tachycardic response to arterial baroreceptor deactivation was more pronounced in the aldosterone experiments. By contrast, baroreflex control of MSNA and heart rate during phenylephrine infusion was not affected by aldosterone. Thus, our study demonstrates that, in healthy humans, aldosterone tends to increase cardiac vagal activity and enhances the heart rate response to nitroprusside whereas MSNA remains unaffected.

[Syncope--algorithms for emergency medicine]. / Synkope--Algorithmen in der Notfallmedizin.

Syncope is a common symptom in the emergency department. While most causes are benign and self-limiting not requiring extensive in-hospital evaluation, others are potentially severe. The optimal evaluation of patients with syncope follows a risk-adapted diagnostic algorithm in order to exclude life-threatening conditions and to identify those with high risk for further deterioration, such as structural heart diseases requiring further diagnostic evaluation. Low risk patients can be discharged without further extensive diagnostic work-up. This article presents an algorithm for the diagnostics of syncope in accordance with current guidelines.

[Endocrine emergencies during pregnancy]. / Endokrine Notfälle in der Schwangerschaft.

Endocrine emergencies during pregnancy can become life-threatening for both mother and fetus. In addition to some pregnancy-linked endocrine disorders, several pre-existing forms of endocrinopathy, such as Grave's disease, type 1 diabetes and adrenal insufficiency might deteriorate acutely during pregnancy. Early diagnosis and management are challenging because the classical symptoms are often modified by pregnancy. Laboratory tests are subject to altered physiological ranges and pharmacological options are limited while therapeutic goals are stricter than in the non-pregnant patient. This article focuses on endocrine emergencies complicating pregnancy.

[Cancer-to-cancer metastasis: amelanotic melanoma into renal cell carcinoma]. / Karzinom-in-Karzinom-Metastasierung eines amelanotischen Melanoms in ein Nierenzellkarzinom.

HISTORY AND PHYSICAL FINDINGS: A 54-year old man was admitted because of motor aphasia, behavioral changes and weight loss and suffered from a widely disseminated cancer with unknown primary origin (CUP) syndrome. DIAGNOSIS: The autopsy revealed that he was affected by two malignant neoplasms simultaneously: an amelanotic malignant melanoma metastasizing into a localized renal cell carcinoma. CONCLUSION: Cancer-to-cancer metastasis is an exceedingly rare, but well documented phenomenon. This is the third reported case of a malignant melanoma as donor tumor spreading into a renal cell carcinoma. Well-vascularized and slowly growing renal tumors are typical recipients for cancer-to-cancer metastases. The amelanotic character of the melanoma exerted a special diagnostic challenge. Clinical and autopsy findings as well as the immunophenotypical features of the metastatic amelanotic melanoma (HMB-45, Melan-A/MART-1, S100) and the renal cell carcinoma are described with a review of the relevant literature.

[Diabetes and hypertension]. / Diabetes und Hypertonie.

Diabetes mellitus and arterial hypertension are major cardiovascular risk factors with high co-morbidity. Microalbuminuria is an independent risk marker, and routine monitoring of urinary albumin is mandatory in patients with diabetes and hypertension. The therapeutic goal of antihypertensive treatment is < 130/80 mm Hg, however in the presence of nephropathy < 125/75 mm Hg should be achieved. Therapy is based on lifestyle-interventions including 1) weight reduction, 2) regular moderate physical activity, 3) modification of diet with restriction of salt- and alcohol consumption as well as 4) cessation of smoking. Renin- and ACE-inhibitors as well as AT1-receptor antagonists are drugs of first choice, delaying the progression of diabetic nephropathy most effectively.