Reflex syncope : an integrative physiological approach

Síncope, a forma mais comum de perda temporária de consciência é responsável por até 5% das idas aos serviços de emergência e até 3% dos internamentos hospitalares. É um problema médico frequente, com múltiplos gatilhos, incapacitante, potencialmente perigoso e desafiante em termos diagnósticos e terapêuticos. Assim, é necessária uma anamnese detalhada para primeiro estabelecer a natureza da perda de consciência, mas, após o diagnóstico, as medidas terapêuticas existentes são pouco eficazes. Embora a fisiopatologia da síncope vasovagal ainda não tenha sido completamente esclarecida, alguns mecanismos subjacentes foram já desvendados. Em última análise, a síncope depende de uma falha transitória na perfusão cerebral pelo que qualquer factor que afecte a circulação sanguínea cerebral pode determinar a ocorrência de síncope. Assim, o objectivo do presente estudo é caracterizar o impacto hemodinâmico e autonómico nos mecanismos subjacentes à síncope reflexa, para melhorar o diagnóstico, o prognóstico e a qualidade de vida dos doentes e dos seus cuidadores. Para isso, desenhámos e implementámos novas ferramentas matemáticas e computacionais que permitem uma avaliação autonómica e hemodinâmica integrada, de forma a aprofundar a compreensão do seu envolvimento nos mecanismos de síncope reflexa. Além disso, refinando a precisão do diagnóstico, a sensibilidade e a especificidade do teste de mesa de inclinação (“tilt test”), estabelecemos uma ferramenta preditiva do episódio iminente de síncope. Isso permitiu-nos estabelecer alternativas de tratamento eficazes e personalizadas para os doentes refractários às opções convencionais, sob a forma de um programa de treino de ortostatismo (“tilt training”), contribuindo para o aumento da sua qualidade de vida e para a redução dos custos directos e indirectos da sua assistência médica. Assim, num estudo verdadeiramente multidisciplinar envolvendo doentes com síncope reflexa refractária à terapêutica, conseguimos demonstrar uma assincronia funcional das respostas reflexas autonómicas e hemodinâmicas, expressas por um desajuste temporal entre o débito cardíaco e as adaptações de resistência total periférica, uma resposta baroreflexa atrasada e um desequilíbrio incremental do tónus autonómico que, em conjunto, poderão resultar de uma disfunção do sistema nervoso autónomo que se traduz por uma reserva simpática diminuída. Igualmente, desenhámos, testámos e implementámos uma plataforma computacional e respectivo software associado - a plataforma FisioSinal –incluindo novas formas, mais dinâmicas, de avaliação integrada autonómica e hemodinâmica, que levaram ao desenvolvimento de algoritmos preditivos para a estratificação de doentes com síncope. Além disso, na aplicação dessas ferramentas, comprovámos a eficácia de um tratamento não invasivo, não disruptivo e integrado, focado na neuromodulação das variáveis autonómicas e cardiovasculares envolvidas nos mecanismos de síncope. Esta terapêutica complementar levou a um aumento substancial da qualidade de vida dos doentes e à abolição dos eventos sincopais na grande maioria dos doentes envolvidos. Em conclusão, o nosso trabalho contribuiu para preencher a lacuna entre a melhor informação científica disponível e sua aplicação na prática clínica, sustentando-se nos três pilares da medicina translacional: investigação básica, clínica e comunidade.Syncope, the most common form of transient loss of consciousness, accounts for up to 5% of emergency room visits and up to 3% of hospital admissions. It is a frequent medical problem with multiple triggers, potentially dangerous, incapacitating, and challenging to diagnose. Therefore, a detailed clinical history is needed first to establish the nature of the loss of consciousness. However, after diagnosis, the therapeutic measures available are still very poor. Although the exact pathophysiology of vasovagal syncope remains to be clarified, some underlying mechanisms have been unveiled, dependent not only on the cause of syncope but also on age and various other factors that affect clinical presentation. Ultimately, syncope depends on a failure of the circulation to perfuse the brain, so any factor affecting blood circulation may determine syncope occurrence. Thus, the purpose of the present study is to understand the impact of the hemodynamic and autonomic functions on reflex syncope mechanisms to improve patients diagnose, prognosis and general quality of life. Bearing that in mind, we designed and implemented new mathematical and computational tools for autonomic and hemodynamic evaluation, in order to deepen the understanding of their involvement in reflex syncope mechanisms. Furthermore, by refining the diagnostic accuracy, sensitivity and specificity of the head-up tilt-table test, we established a predictive tool for the impending syncopal episode. This allowed us to establish effective and personalised treatment alternatives to patient’s refractory to conventional options, contributing to their increase in the quality of life and a reduction of health care and associated costs. In accordance, in a truly multidisciplinary study involving reflex syncope patients, we were able to show an elemental functional asynchrony of hemodynamic and autonomic reflex responses, expressed through a temporal mismatch between cardiac output and total peripheral resistance adaptations, a deferred baroreflex response and an unbalanced, but incremental, autonomic tone, all contributing to autonomic dysfunction, translated into a decreased sympathetic reserve. Through the design, testing and implementation of a computational platform and the associated software - FisioSinal platform -, we developed novel and dynamic ways of autonomic and hemodynamic evaluation, whose data lead to the development of predictive algorithms for syncope patients’risk stratification. Furthermore, through the application of these tools, we showed the effectiveness of a non-invasive, non-disruptive and integrated treatment, focusing on neuromodulation of the autonomic and cardiovascular variables involved in the syncope mechanisms, leading to a substantial increase of quality of life and the abolishment of syncopal events in a vast majority of the enrolled patients. In conclusion, our work contributed to fill the gap between the best available scientific information and its application in the clinical practice by tackling the three pillars of translational medicine: bench-side, bedside and community

A randomised controlled feasibility trial to investigate the effects of a functional standing frame programme versus usual physiotherapy to improve function and quality of life and reduce neuromuscular impairment in people with severe sub-acute stroke

Background Task-related training can aid functional recovery post-stroke but has not been investigated in people with severe stroke. Orthostatic hypotension (OH) may limit rehabilitation, therefore, the effects of undertaking prolonged standing and sit to stand repetitions (functional standing frame programme) early after severe stroke during inpatient sub-acute rehabilitation is unknown. Methods A systematic review of non-pharmacological interventions to treat OH in people with neurological conditions was undertaken to inform a protocol for the management of OH during the functional standing frame programme. The feasibility of a blinded randomised controlled trial (RCT) investigating the effects of a functional standing frame programme compared to usual physiotherapy for people with severe stroke was conducted. Primary (Barthel Index, Edmans ADL Index for Stroke) and secondary outcomes (including lower limb joint range of movement, knee extensor strength, and quality of life) were assessed at baseline, post-intervention and 15-, 29- and 55-weeks post-randomisation. Semi-structured interviews were conducted with a subset of participants, relatives and physiotherapists to explore experiences of the intervention and trial procedures. Data were analysed using thematic analysis and descriptive analysis. Results The systematic review included randomised controlled trials (n=13), quasiexperimental (n=27), case control (n=1) and case report (n=2). A meta-analysis of seven studies concluded electrical stimulation, lower limb compression and resistance exercise training were favourable in treating or reducing OH. Forty-five participants (51-96 years; 42% male, mRS 4=80% 5=20%) were recruited; n=22 randomised to intervention, n=23 to control. Twenty-seven participants completed the trial: n=12 died (n=7 intervention), n=2 moved out of area, n=4 withdrawn. Adherence to the intervention was low: 38-51% of possible sessions being completed; average session duration 39.40 minutes (±18.8); standing duration 12.52 minutes (±8.8); and mean sit-to-stand repetitions 4.64 (±3.9 SD) per session. 91% of sessions were enjoyed. Adherence was affected by patient, physiotherapist and organisational factors. Conclusion A definitive RCT of a functional standing frame programme is feasible for people with severe stroke. However, intervention adherence need to be addressed before progressing to a definitive trial, which will investigate clinical and cost effectiveness.National Institute for Health Researc

Cardiovascular autonomic responses in pre- and post-ganglionic models of chronic autonomic failure

Multiple System Atrophy (MSA) and Pure Autonomic Failure (PAF) are contrasting models of Chronic Autonomic failure. PAF primarily involves the post-ganglionic autonomic nervous system, whilst in MSA the pre-ganglionic structures are impaired. My central hypothesis is that this underlying neuropathological difference between MSA and PAF will lead to differing cardiovascular responses. I will assess the cardiovascular effects of known pressor and vasomotor stimuli (mental arithmetic, cold pressor test, isometric exercise, water ingestion, inhaled CO2 and inspiratory gasp) in MSA and PAF. Neurohormonal aspects will be explored by comparing the cardiovascular effects of the α2-adrenoceptor agonist clonidine with serum noradrenaline levels in these groups, as well as comparing supine antidiuretic hormone (ADH) levels after head up tilt and correlating these with supine blood pressure (BP). As well as contrasting the cardiovascular responses, I will use the water ingestion studies to examine effects on orthostatic hypotension, a common complication of both MSA and PAF. To measure cardiovascular responses during these studies I have used the Portapres II device to obtain continuous, non-invasive, beat-to-beat measurements of BP and heart rate (HR). Subsequent Model flow analysis using Beatscope software has then been used to calculate further cardiovascular indices, including cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR). In addition, intermittent BP and HR measurements have been obtained with an automated sphygmomanometer (Dinamap). Finally, peripheral vasomotor responses have been recorded by means of the Laser Doppler perfusion meter

Cardiovascular autonomic responses in pre- and post-ganglionic models of chronic autonomic failure

Multiple System Atrophy (MSA) and Pure Autonomic Failure (PAF) are contrasting models of Chronic Autonomic failure. PAF primarily involves the post-ganglionic autonomic nervous system, whilst in MSA the pre-ganglionic structures are impaired. My central hypothesis is that this underlying neuropathological difference between MSA and PAF will lead to differing cardiovascular responses. I will assess the cardiovascular effects of known pressor and vasomotor stimuli (mental arithmetic, cold pressor test, isometric exercise, water ingestion, inhaled CO2 and inspiratory gasp) in MSA and PAF. Neurohormonal aspects will be explored by comparing the cardiovascular effects of the α2-adrenoceptor agonist clonidine with serum noradrenaline levels in these groups, as well as comparing supine antidiuretic hormone (ADH) levels after head up tilt and correlating these with supine blood pressure (BP). As well as contrasting the cardiovascular responses, I will use the water ingestion studies to examine effects on orthostatic hypotension, a common complication of both MSA and PAF. To measure cardiovascular responses during these studies I have used the Portapres II device to obtain continuous, non-invasive, beat-to-beat measurements of BP and heart rate (HR). Subsequent Model flow analysis using Beatscope software has then been used to calculate further cardiovascular indices, including cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR). In addition, intermittent BP and HR measurements have been obtained with an automated sphygmomanometer (Dinamap). Finally, peripheral vasomotor responses have been recorded by means of the Laser Doppler perfusion meter

The psychophysiology of dysautonomia

Modern theories of emotion emphasise the role of homeostatic requirements in motivating and shaping behaviour and link emotions with motor and autonomic responses to define physiological, behavioural and neurobiological phenomena initiated by the emotional valence and relevance of a stimulus. Intermittent dysautonomia is a transient but recurrent dysregulation of autonomic nervous system function, such as orthostatic intolerance (postural tachycardia syndrome, vasovagal syncope) or thermoregulatory dysfunction (essential hyperhidrosis). The sympathetic and parasympathetic nervous systems often work antagonistically and with organ specificity, producing definable patterns of activity, yet despite the coupling of emotion with autonomic function, the evidence for robust emotionspecific patterns remains elusive. Although psychiatric patients may report symptoms akin to intermittent dysautonomia, such as sweating, faintness or palpitations, autonomic diagnostic criteria are rarely met. However, comorbid psychological symptoms, such as subclinical anxiety and depression, are often reported in intermittent dysautonomia. Recent neuroimaging techniques have elucidated the interrelationship of autonomic and neurobiological pathophysiology and the perturbation of autonomic neuroanatomy by peripheral autonomic function and dysfunction. This thesis will investigate the complex interplay between brain and body in intermittent dysautonomia and healthy controls in order to improve our understanding of the common cognitive-affective symptomatology in vasovagal syncope (VVS), the postural tachycardia syndrome (PoTS) and essential hyperhidrosis (EH) that can complicate diagnosis and treatment. Moreover, organic conditions that provide such an overrepresentation of comorbid psychological symptoms may provide insight into cognitive-affective processes beyond autonomic medicine

Vibration and bone – an option for long-term space missions?

Bone is lost during sojourns in microgravity. In order to prevent fractures in future manned inter-planetary missions, efforts are currently being made to develop effective countermeasures. Bones adapt to mechanical stimuli, and biomechanical analysis suggests that muscle forces play an important role. Thus, resistance training is advocated as a first option for a countermeasure modality. In addition, vibration has certain characteristics (well controllable, rapid stretch-shortening and large number of contractions) that could be of interest. Studies in the past decade have shown that conventional resistive exercise may be sufficient to maintain bone when performed on a daily basis, but not when performed only every other day. Whole body vibration without additional load seems to be ineffective, but it shows good potential, and probably will have a genuine effect upon bone when combined with additional loads in the order of twice the body weight. There is now accumulating evidence to suggest that effective exercises exist to counteract microgravity-related bone loss. At least for bed rest, forceful muscle contractions seem to be a prerequisite. They may be fortified, but probably not replaced, by vibration exposure

A clinical study of patients with concurrent dizziness and neck pain

Dizziness is a relatively common complaint with a heterogeneous group of patients with several plausible causes. There has long been a controversy regarding the role of the cervical spine in dizziness and balance issues, even though there are well-established physiological connections between the vestibular, visual and cervical proprioceptive systems In addition, previous studies have shown that concurrent dizziness and neck pain exist in both patients with primary dizziness and patients with primary neck pain, resulting in a common clinical issue. However, there is little knowledge about the prevalence of patients with concurrent dizziness and neck pain and how neck pain influences patients with dizziness and balance. This project was a cross-sectional study of patients referred for either dizziness or neck pain to one of two outpatient clinics − an ear, nose and throat clinic or a spine clinic − both at Haukeland University Hospital in Bergen. The overall object of this thesis was to examine to what extent and how neck pain influences dizziness in terms of physical and dizziness characteristics, dizziness severity, postural control and quality of life. Our findings are presented in four papers. Paper I was a systematic review of the clinical characteristics of patients with cervicogenic dizziness. Only eight out of 2161 articles met our inclusion criteria. We found that reduced postural control measured with posturography was the most common clinical finding in patients with cervicogenic dizziness compared with other populations. Paper II examined differences in dizziness disability and quality of life in patients with and without neck pain, referred for dizziness to the ear, nose and throat clinic. Additionally, we examined whether neck pain was associated with a nonvestibular or vestibular diagnosis. We found that patients with additional neck pain reported higher dizziness disability and lower quality of life. In addition, there was no association between neck pain and the presence or absence of a vestibular disorder. Paper III explored the relationship between the pressure pain threshold in the neck and postural control in patients referred to both clinics. The patients were divided according 9 to their referred clinic and thus their primary complaint. In the patients referred for dizziness as the main complaint, we found a small, inverse relationship between pressure pain thresholds and sway area with eyes closed, after adjusting for age, sex and generalized pain. The same inverse relationship was found between pressure pain thresholds in the neck and the Romberg ratio on a bare platform after adjusting for age, sex and generalized pain. Neither of these relationships were present in the neck pain group. In Paper IV, we explored clinical symptoms and physical findings in patients with concurrent neck pain and dizziness from both centers and examined whether they differed from patients with dizziness alone. Both neck pain groups were associated with certain dizziness characteristics and increased physical impairment. The neck pain group, having dizziness as their primary complaint, had the highest symptom severity score. The overall findings of this thesis indicate that neck pain may affect postural control, dizziness symptoms, physical impairments and quality of life. As the relationship between dizziness and neck pain is a controversial topic, these finding may be helpful and should be considered when examining patients with concurrent complaints, regardless of diagnosis

Physiological responses to prolonged bed rest in humans: A compendium of research, 1981-1988

Clinical observations and results form more basic studies that help to elucidate the physiological mechanisms of the adaptation of humans to prolonged bed rest. If the authors' abstract or summary was appropriate, it was included. In some cases a more detailed synopsis was provided under the subheadings of purpose, methods, results, and conclusions

Adaptation to prolonged bedrest in man: A compendium of research

A compilation of major studies that describe the clinical observations and elucidate the physiological mechanisms of the adaptive process of man undergoing prolonged bed rest is presented. Additional studies are included that provide background information in the form of reviews or summaries of the process. Wherever possible a detailed annotation is provided under the subheadings: (1) purpose, (2) procedure and methods, (3) results, and (4) conclusions. Additional references are provided in a selected bibliography

Aerospace Medicine and Biology: A continuing bibliography with indexes (supplement 238)

This bibliography lists 583 reports, articles and other documents introduced into the NASA scientific and technical information system in October 1982