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Autonomic function, postprandial hypotension and falls in older adults at one year after critical illness.
Ali Abdelhamid, Y, Weinel, LM, Hatzinikolas, S, Summers, M, Nguyen, TAN, Kar, P, Phillips, LK, Horowitz, M, Deane, AM, Jones, KL
Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine. 2020;(1):53-62
Abstract
OBJECTIVE Postprandial hypotension occurs frequently in older survivors of critical illness at 3 months after discharge. We aimed to determine whether postprandial hypotension and its predictors - gastric dysmotility and cardiovascular autonomic dysfunction - persist or resolve as older survivors of critical illness recover, and whether postprandial hypotension after intensive care unit (ICU) discharge is associated with adverse outcomes at 12 months. DESIGN Prospective observational study. SETTING Tertiary medical-surgical ICU. PARTICIPANTS Older adults (aged ≥ 65 years) who had been studied 3 months after ICU discharge and who returned for a follow-up study at 12 months after discharge. MAIN OUTCOME MEASURES On both occasions after fasting overnight, participants consumed a 300 mL drink containing 75 g glucose, radiolabelled with 20 MBq 99mTcphytate. Blood pressure, heart rate, blood glucose concentration and gastric emptying rate were measured concurrently before and after ingestion of the drink. Falls, quality of life, hospitalisation and mortality rates were also quantified. RESULTS Out of 35 older adults studied at 3 months, 22 returned for the follow-up study at 12 months. Postprandial hypotension was evident in 29% of participants (95% CI, 14-44%) at 3 months and 10% of participants (95% CI, 1-30%) at 12 months. Postprandial hypotension at 3 months was associated with a more than threefold increase in the risk of falls in the year after ICU discharge (relative risk, 3.7 [95% CI, 1.6-8.8]; P = 0.003). At 12 months, gastric emptying was normal (mean time taken for 50% of gastric contents to empty, 101.6 [SD, 33.3] min) and cardiovascular autonomic dysfunction prevalence was low (9% [95% CI, 1-29%]). CONCLUSIONS In older adults who were evaluated 3 and 12 months after ICU discharge, postprandial hypotension at 3 months was associated with an increased risk of subsequent falls, but the prevalence of postprandial hypotension decreased with time.
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The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases.
Goldstein, DS
Seminars in neurology. 2020;(5):502-514
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Abstract
The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.
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Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach.
Nesti, L, Pugliese, NR, Sciuto, P, Natali, A
Cardiovascular diabetology. 2020;(1):134
Abstract
The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.
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Autonomic testing: which value for each cardiovascular test? An observational study.
Bellavere, F, Ragazzi, E, Chilelli, NC, Lapolla, A, Bax, G
Acta diabetologica. 2019;(1):39-43
Abstract
AIMS: Cardiovascular autonomic testing is time consuming when adopting the entire Ewing battery of tests, hence, clinicians usually adopt an empirically reduced number of tests which may give controversial results. Our purpose was to examine the reliability of the cardiovascular tests most commonly used in autonomic diagnoses. METHODS We tested 334 subjects, from an original group of 3745, who had shown an altered deep breathing test to both Lying to standing and Valsalva manoeuvre, assuming a value of postural hypotension of more than 15 mmHg as a sign of almost true dysautonomia. RESULTS VM showed the highest sensitivity (85%) and, when coupled to LS, highest specificity (83%). CONCLUSIONS VM could be useful when screening for possible or early autonomic neuropathy, VM + LS is useful as a diagnostic tool for probable or advanced autonomic neuropathy, and VM + LS + PH is useful for certain diagnosis of definite or late stage autonomic neuropathy.
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Characteristics and natural history of autonomic involvement in hereditary ATTR amyloidosis: a systematic review.
Gonzalez-Duarte, A, Valdés-Ferrer, SI, Cantú-Brito, C
Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2019;(Suppl 1):1-9
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BACKGROUND Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in patients with hereditary ATTR amyloidosis. METHODS A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction. RESULTS Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment. CONCLUSION The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.
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Diagnostic and therapeutical management of supine hypertension in autonomic failure: a review of the literature.
Vallelonga, F, Maule, S
Journal of hypertension. 2019;(6):1102-1111
Abstract
: Supine hypertension is defined as a blood pressure at least 140 mmHg systolic or at least 90 mmHg diastolic in the supine position; supine hypertension is present in over 50% of patients with autonomic failure and orthostatic hypotension, but it is often overlooked. It may be related to antihypotensive drugs, but its presence in untreated patients suggests a neurogenic origin. Supine hypertension is often asymptomatic although it is associated with multiple organ damage. There are no official guidelines on its treatment and long-term benefits have never been proved. The present review is focused on the management of supine hypertension, including nonpharmacological and pharmacological approach. All the tested drugs have been individually revised, focusing on their hypotensive effect and their ability to act on ancillary targets, such as morning orthostatic tolerance or sodium urine excretion. Moreover, the main pathogenic mechanisms and the correct approach to the diagnosis of supine hypertension have been resumed.
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Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis).
Gonzalez-Duarte, A
Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2019;(2):245-251
Abstract
PURPOSE Hereditary transthyretin amyloidosis (hATTR amyloidosis) is a progressive disease primarily characterized by adult-onset sensory, motor, and autonomic neuropathy. In this article, we discuss the pathophysiology and principal findings of autonomic neuropathy in hATTR amyloidosis, the most common methods of assessment and progression, and its relation as a predictive risk factor or a measure of progression in the natural history of the disease. METHODS A literature search was performed using the terms "autonomic neuropathy," "dysautonomia," and "autonomic symptoms" in patients with hereditary transthyretin amyloidosis and familial amyloid polyneuropathy. RESULTS Various scales to measure autonomic function have been employed, particularly within the major clinical trials, to assess novel therapies for the disease. Most of the evaluations were taken from diabetic clinical trials. Questionnaires include the COMPASS-31 and Norfolk QOL autonomic nerve function domain, whereas clinical evaluations comprise HRDB and the orthostatic tolerance test. Several treatment options are being employed although only diflunisal and tafamidis have reported improvement in the autonomic abnormalities. CONCLUSIONS Autonomic nerves are often affected before motor nerve impairment, and dysautonomia may support the diagnosis of hATTR amyloidosis when differentiating from other adult-onset progressive neuropathies and from other types of amyloidosis. Most of the progression of autonomic dysfunction is seen in early stages of the disease, commonly before motor impairment or affection of the overall quality of life. Unfortunately, there is no current single standardized approach to evaluate dysautonomia in hATTR amyloidosis.
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Neurological consequences of obesity.
O'Brien, PD, Hinder, LM, Callaghan, BC, Feldman, EL
The Lancet. Neurology. 2017;(6):465-477
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The high prevalence of obesity is associated with an enormous medical, social, and economic burden. The metabolic dysfunction, dyslipidaemia, and inflammation caused by obesity contribute to the development of a wide variety of disorders and effects on the nervous system. In the CNS, mild cognitive impairment can be attributed to obesity-induced alterations in hippocampal structure and function in some patients. Likewise, compromised hypothalamic function and subsequent defects in maintaining whole-body energy balance might be early events that contribute to weight gain and obesity development. In the peripheral nervous system, obesity-driven alterations in the autonomic nervous system prompt imbalances in sympathetic-parasympathetic activity, while alterations in the sensory-somatic nervous system underlie peripheral polyneuropathy, a common complication of diabetes. Pharmacotherapy and bariatric surgery are promising interventions for people with obesity that can improve neurological function. However, lifestyle interventions via dietary changes and exercise are the preferred approach to combat obesity and reduce its associated health risks.
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Intravenous magnesium sulfate for the management of severe hand, foot, and mouth disease with autonomic nervous system dysregulation in Vietnamese children: study protocol for a randomized controlled trial.
Qui, PT, Khanh, TH, Trieu, HT, Giang, PT, Bich, NN, Thoa, le PK, Nhan, le NT, Sabanathan, S, Van Doorn, R, Toan, ND, et al
Trials. 2016;:98
Abstract
BACKGROUND Over the last 15 years, hand, foot, and mouth disease (HFMD) has emerged as a major public health burden across the Asia-Pacific region. A small proportion of HFMD patients, typically those infected with enterovirus 71 (EV71), develop brainstem encephalitis with autonomic nervous system (ANS) dysregulation and may progress rapidly to cardiopulmonary failure and death. Although milrinone has been reported to control hypertension and support myocardial function in two small studies, in practice, a number of children still deteriorate despite this treatment. Magnesium sulfate (MgSO4) is a cheap, safe, and readily available medication that is effective in managing tetanus-associated ANS dysregulation and has shown promise when used empirically in EV71-confirmed severe HFMD cases. METHODS/DESIGN We describe the protocol for a randomized, placebo-controlled, double-blind trial of intravenous MgSO4 in Vietnamese children diagnosed clinically with HFMD plus ANS dysregulation with systemic hypertension. A loading dose of MgSO4 or identical placebo is given over 20 min followed by a maintenance infusion for 72 h according to response, aiming for Mg levels two to three times the normal level in the treatment arm. The primary endpoint is a composite of disease progression within 72 h defined as follows: development of pre-specified blood pressure criteria necessitating the addition of milrinone, the need for ventilation, shock, or death. Secondary endpoints comprise these parameters singly, plus other clinical endpoints including the following: requirement for other inotropic agents; duration of hospitalization; presence of neurological sequelae at discharge in survivors; and neurodevelopmental status assessed 6 months after discharge. The number and severity of adverse events observed in the two treatment arms will also be compared. Based on preliminary data from a case series, and allowing for some losses, 190 patients (95 in each arm) will allow detection of a 50 % reduction in disease progression with 90 % power at a two-sided 5 % significance level. DISCUSSION Given the large numbers of HFMD cases currently being seen in hospitals in Asia, if MgSO4 is shown to be effective in controlling ANS dysregulation and preventing severe HFMD complications, this finding would be important to pediatric care throughout the region. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 August 2013).
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New onset vasomotor symptoms but not musculoskeletal symptoms associate with clinical outcomes on extended adjuvant letrozole - Analyses from NCIC CTG MA.17.
Liedke, PE, Tu, D, Shepherd, L, Chavarri-Guerra, Y, Pritchard, KI, Stearns, V, Goss, PE
Breast (Edinburgh, Scotland). 2016;:99-104
Abstract
PURPOSE New onset symptoms on adjuvant aromatase inhibitors for hormone receptor positive early breast cancer may associate with clinical outcomes. We performed this exploratory analysis of the association of new onset musculoskeletal (MSK) and vasomotor (VM) symptoms with clinical outcomes in the NCIC CTG MA.17 trial 5 years of extended adjuvant endocrine therapy with letrozole after tamoxifen. METHODS Symptoms were collected at baseline, 1, 6, and every 12 months on study. Multivariate Cox Models adjusting for age, nodal status, duration of tamoxifen and prior chemotherapy were used to compare disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) based on data collected before, and after, the unblinding between women with VM or MSK symptoms and those without. RESULTS Data post-unblinding showed new VM symptoms on extended letrozole significantly improved DFS and DDFS when occurring 1 month (DFS HR 0.52, 95% CI, 0.28-0.96; p = 0.04; DDFS HR 0.49, 95% CI, 0.24-0.99; p = 0.046) and 6 months (DFS HR 0.43, 95% CI, 0.24-0.78; p = 0.006; DDFS HR 0.44, 95% CI, 0.22-0.85; p = 0.02) after treatment initiation. Those with new VM symptoms at 12 months also had a significantly better DFS (HR 0.47, 95% CI 0.26, 0.84; P = 0.01) and a trend in improved DDFS. Only a trend to improved OS was found for those with VM symptoms 6 month after treatment. No significant improvement was found for those with new MSK symptoms at any time point or for any endpoint. CONCLUSIONS New onset VM symptoms with extended letrozole may be useful in predicting treatment benefit.