Biochemically normal adrenal pheochromocytoma following extensive central necrosis in a child with von Hippel-Lindau (VHL) gene mutation

Pheochromocytomas are rare in children. The diagnosis is usually established from a raised urinary or plasma catecholamine or their metabolites. We present a girl aged 11 years who manifested with a hypertensive crisis secondary to an adrenal tumour but with unexpectedly normal urinary metanephrine and catecholamine results. She improved spontaneously following the crisis and underwent surgery later. The histopathological study confirmed a pheochromocytoma with large central necrosis. Her genetic screening reported a pathogenic von Hippel-Lindau gene mutation. Surveillance scan postsurgery detected no other tumours. Following the catecholamine crisis, an acute infarct occurred, resulting in extensive tumour necrosis and subsequent rapid remission of symptoms and paradoxically normal biochemical markers. Although not unheard of in adults, we believe this is the first reported case of an extensive spontaneous necrosis resulting in a biochemically normal pheochromocytoma in a child.

Perioperative Supplemental Oxygen and Plasma Catecholamine Concentrations After Major Abdominal Surgery – a Substudy of a Randomized Clinical Trial

BackgroundIncreased sympathetic nerve activity due to perioperative stress is associated with higher plasma catecholamine concentrations that lead to an increase in heart rate and blood pressure. This fact plays a pivotal role in the development of perioperative myocardial ischemia. A previous study in healthy volunteers has shown that the administration of supplemental oxygen attenuated sympathetic nerve activity, which was associated with lower plasma catecholamine concentrations. However, in patients undergoing surgery evidence is still lacking. We therefore tested the hypothesis that perioperative supplemental oxygen attenuates sympathetic nerve activity estimated by plasma catecholamines in patients at risk for cardiovascular complications undergoing major abdominal surgery.MethodsWe randomly assigned 81 patients to receive either 80% versus 30% inspired oxygen concentration throughout surgery and for the first two postoperative hours. We assessed noradrenaline, adrenaline and dopamine plasma concentrations as surrogate parameters for sympathetic nerve activity before induction of anesthesia, two hours after surgery and on the third postoperative day.Results41 patients received 80% oxygen and 40 patients received 30% oxygen. There was no significant difference in postoperative noradrenaline (effect estimated:-41.5 ng.L-1, 95%CI -134.3, 51.2; p=0.38), adrenaline (effect estimated:11.2 ng.L-1, 95%CI -7.6, 30.1; p=0.24) and dopamine (effect estimated:-1.61 ng.L-1, 95%CI -7.2, 3.9; p=0.57) concentrations between both groups. ConclusionsWe found no significant difference in postoperative plasma catecholamine concentration between the 80% and 30% oxygen group in patients at risk for cardiovascular complications undergoing major abdominal surgery. Based on our results, it seems likely that supplemental oxygen did not influence sympathetic nerve activity in the perioperative setting.Trial RegistrationClinicalTrials.gov (NCT 03366857)European Clinical Trial Database (EudraCT 2017-003714-68)

Effect of ingesting a meal and orthostasis on the regulation of splanchnic and systemic hemodynamics and the responsiveness of cardiovascular α1-adrenoceptors

Background: Postprandial orthostasis activates mechanisms of cardiovascular homeostasis in order to maintain normal blood pressure (BP) and adequate blood flow to vital organs. The underlying mechanisms of cardiovascular homeostasis in postprandial orthostasis still require elucidation. Methods: Fourteen healthy volunteers were recruited to investigate the effect of an orthostatic challenge (600-head-up-tilt for 20 minutes) on splanchnic and systemic hemodynamics before and after ingesting an 800-kilocalorie composite meal. The splanchnic circulation was assessed by ultrasonography of the superior mesenteric and hepatic arteries and portal vein. Systemic hemodynamics were assessed non-invasively by continuous monitoring of BP, heart rate (HR), cardiac output (CO), and the pressor response to an intravenous infusion on increasing doses of phenylephrine, an α1-adrenoceptor agonist. Neurohumoral regulation was assessed by spectral analysis of HR and BP, plasma catecholamine and aldosterone levels and plasma renin activity. Results: Postprandial mesenteric hyperemia was associated with an increase in CO, a decrease in SVR and cardiac vagal tone, and reduction in baroreflex sensitivity with no change in sympathetic tone. Arterial α1-adrenoceptor responsiveness was preserved and reduced in hepatic sinusoids. Postprandial orthostasis was associated with a shift of 500 ml of blood from mesenteric to systemic circulation with preserved sympathetic-mediated vasoconstriction Conclusions: Meal ingestion provokes cardiovascular hyperdynamism, cardiac vagolysis, and resetting of the baroreflex without activation of the sympathetic nervous system. Meal ingestion also alters α1-adrenoceptor responsiveness in the hepatic sinusoids and participates in the redistribution of blood volume from the mesenteric to the systemic circulation in order to maintain a normal BP during orthostasis.

Left ventricular depression and pulmonary edema in rats after short-term normobaric hypoxia: effects of adrenergic blockade and reduced fluid load

Acute normobaric hypoxia may induce pulmonary injury with edema (PE) and inflammation. Hypoxia is accompanied by sympathetic activation. As both acute hypoxia and high plasma catecholamine levels may elicit PE, we had originally expected that adrenergic blockade may attenuate the severity of hypoxic pulmonary injury. In particular, we investigated whether administration of drugs with reduced fluid load would be beneficial with respect to both cardiocirculatory and pulmonary functions in acute hypoxia. Rats were exposed to normobaric hypoxia (10% O2) over 1.5 or 6 h and received 0.9% NaCl or adrenergic blockers either as infusion (1 ml/h, increased fluid load) or injection (0.5 ml, reduced fluid load). Control animals were kept in normoxia and received infusions or injections of 0.9% NaCl. After 6 h of hypoxia, LV inotropic function was maintained with NaCl injection but decreased significantly with NaCl infusion. Adrenergic blockade induced a similar LV depression when fluid load was low, but did not further deteriorate LV depression after 6 h of infusion. Reduced fluid load also attenuated pulmonary injury after 6 h of hypoxia. This might be due to an effective fluid drainage into the pleural space. Adrenergic blockade could not prevent PE. In general, increased fluid load and impaired LV inotropic function promote the development of PE in acute hypoxia. The main physiologic conclusion from this study is that fluid reduction under hypoxic conditions has a protective effect on cardiopulmonary function. Consequently, appropriate fluid management has particular importance to subjects in hypoxic conditions.

The Effects of Acute Glucoprivation on Adrenomedullary Function in SHR and WKY Rats

We have shown previously, acute intraperitoneal administration of 2-deoxy-d-glucose (2DG) into Sprague-Dawley rats led to activation of the adrenal medulla chromaffin cells, indicated with increased protein kinase activity and increased tyrosine hydroxylase (TH) phosphorylation, as well as increased plasma adrenaline and glucose levels. Here we have used spontaneous hypertensive (SHR) and Wistar Kyoto (WKY) rats to investigate whether hypertension alters basal adrenal chromaffin cell function, or the response of these cells to acute 2DG treatment. At basal level, we found no differences in adrenal medulla TH protein, TH phosphorylation, TH activity or catecholamine levels between SHR and WKY despite a significant difference in the level of systolic blood pressure; nor were there differences in plasma catecholamine levels or blood glucose (BG). Furthermore, the vehicle animals evoked no significant changes in any parameter measured in SHR, but evoked significant increases in pSer19TH, plasma adrenaline and BG in WKY. Single episode of glucoprivation evoked increases in PKA and CDK/MAPK, pSer40TH, pSer31TH, TH activity, and plasma adrenaline and BG in SHR, and in addition evoked increases in PKC, CAMKII, and pSer19TH in WKY. These findings are significant which indicates hypertension does not impact catecholamine function in the adrenal gland. It also appears that hypertension does not alter the adrenal response to glucoprivation. The findings are also significant as WKY showed greater adrenal activation of protein kinases and TH phosphorylation in response to saline and 2DG when compared to SHR and possible reasons for these findings are further discussed.

No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.

MON-907 Silent Presentation of Urinary Bladder Paraganglioma: A Case Report

Background: Paraganglioma is a rare extraadrenal, neuroendocrine tumor of the sympathetic or parasympathetic ganglia (1). Bladder paraganglioma accounts for 1% of all paragangliomas and 0.05% of all bladder tumors (1,2). Characteristic presentation of this tumor includes hypertensive crisis and postmicturition syncope (3). Clinical Case: 35 year old Middle Eastern man with no pertinent past medical history presented with gross hematuria associated with dysuria, purulent penile discharge, urinary frequency, suprapubic pain, and bilateral flank pain for eight months for which he was given a course of an unknown antibiotic in his home country. Social history revealed smoking half a pack of cigarettes/day for 7 years. Has no family history of cancer. On physical exam he had normal blood pressure with mild tenderness to palpation in suprapubic region. U/A was remarkable for hematuria. Patient was treated for UTI with a course ciprofloxacin without resolution of symptoms. Culture returned negative. CT abdomen/pelvis yielded an approximately 1.9 cm enhancing mural nodule involving the anterior aspect of the bladder. Free metanephrine, nor-metanephrine, plasma catecholamine, and urine vanillylmandelic acid were within normal limits. Cystoscopy and transurethral resection of the tumor (TURBT) was completed; a 5-6mm tumor was visualized and resected. Surgical pathology demonstrated tumor growth into the lamina propria and muscularis propria. Neoplastic cells in the sample were diffusely positive for synaptophysin and chromogranin. S100 protein immunostain highlighted sustentacular cells. The diagnosis of paraganglioma was made based on surgical pathology. Post TURP MRI yielded an approximately 1.7 x 0.9 cm transmural hypervascular enhancing mass lesion involving the anterior aspect of the bladder. Given transmural extension of the tumor, an open partial cystectomy was performed. The tumor was resected successfully with resolution of symptoms. Conclusion: This is an exceedingly rare example of a hormonally silent paraganglioma, mimicking the presentation of a UTI. This case may present the unique consideration of tobacco specific carcinogens as a potential risk factor for the development of bladder paraganglioma. References 1. Benn, DE, Robinson, BG, & Clifton-Bligh, RJ. (2015). “Clinical Manifestations of Paraganglioma Syndromes Types 1-5”. Endocrine-Related Cancer, vol. 22, T91-T103. 2. Loveys, FW, Pushpanathan, C, & Jackman, S. Urinary Bladder Paraganglioma: AIRP Best Cases in Radiologic-Pathologic Correlation”. RadioGraphics, vol 35, no. 5, 1433-1438. 3. Priyadarshi, V, & Pal DK (2015). “Paraganglioma of Urinary Bladder”. Urology Annals, vol 7, no. 3, 402-404.