Use of a physiological reflex to standardize vagal nerve stimulation intensity improves data reproducibility in a memory extinction assay.

BACKGROUND: Modulating brainstem activity, via electrical vagus nerve stimulation (VNS), influences cognitive functions, including memory. However, controlling for changes in stimulus efficacy during chronic studies, and response variability between subjects, is problematic. OBJECTIVE/HYPOTHESIS: We hypothesized that recruitment of an autonomic reflex, the Hering-Breuer reflex, would provide robust confirmation of VNS efficacy. We compared this to measurement of electrode resistance over time. We also examined whether VNS modulates contextual memory extinction. METHODS: Electrodes for VNS and diaphragm electromyography recording were implanted into anesthetized Sprague Dawley rats. When conscious, we measured the electrode resistance as well as the minimum VNS current required to evoke the Hering-Breuer reflex, before, and after, an inhibitory avoidance assay - a two chamber, dark/light model, where the dark compartment was paired with an aversive foot shock. The extinction of this contextual memory was assessed in sham and VNS treated rats, with VNS administered for 30 s at 1.5 times the Hering-Breuer reflex threshold during extinction memory formation. RESULTS: Assessment of VNS-evoked Hering-Breuer reflex successfully identified defective electrodes. VNS accelerated extinction memory and decreased multiple physiological metrics of fear expression. We observed an inverse relationship between memory extinction and respiratory rate during the behavioural assay. Additionally, no current - response relationship between VNS and extinction memory formation was established. CONCLUSION: These data demonstrate that reliable, experimental VNS studies can be produced by verifying reflex initiation as a consequence of stimulation. Further, studies could be standardised by indexing stimulator efficacy to initiation of autonomic reflexes.

Compassion satisfaction and compassion fatigue in Australian emergency nurses: A descriptive cross-sectional study.

INTRODUCTION: Emergency nurses are at risk of compassion fatigue. Compassion fatigue caused by exposure to suffering may compromise the individual's personal wellbeing and reduce work efficiency. METHODS: A quantitative cross-sectional survey with open responses was conducted using the Professional Quality of Life: Compassion Satisfaction and Compassion Fatigue (ProQOL) scale and open-ended questions. Responses from a convenience sample of 86 nurses from two hospital emergency departments in Victoria, Australia, were analysed. RESULTS: The median score for Compassion Satisfaction was 78% with all nurses reporting average to high scores. Most had average levels of Compassion Fatigue: Burnout median score was 53% and Secondary Traumatic Stress median score 49%. No statistically significant correlation was found between scales nor with influencing demographic characteristics. A qualification in emergency nursing was predictive of Compassion Satisfaction. Six descriptive job-associated factors contributed to nurses' stress: human resources, the organisation, job-specific components, patient mix and professional and personal components. CONCLUSION/S: Average to high levels of Compassion Satisfaction and low to average levels of Compassion Fatigue were found in emergency nurses. Issues contributing to stress were work and role related. An understanding of these stressors may help nurses and nurse managers to ameliorate emergency nurses' levels of stress and help limit staff burnout.

Enhancing respiratory sinus arrhythmia increases cardiac output in rats with left ventricular dysfunction.

KEY POINTS: Respiratory sinus arrhythmia is physiological pacing of the heart that disappears in cardiovascular disease and is associated with poor cardiac prognosis. In heart failure, cardiac pacing has little, if any, variation in rate at rest. We proposed that reinstatement of respiratory sinus arrhythmia would improve cardiac function in rats with heart failure. Heart failure rats were paced daily for 2 weeks with either respiratory sinus arrhythmia or paced monotonically at a matched heart rate; cardiac function was measured using non-invasive echocardiography. Cardiac output and stroke volume were increased in rats paced with respiratory sinus arrhythmia compared to monotonic pacing, via improvement in systolic function that persisted beyond the pacing treatment period. We propose that respiratory sinus arrhythmia pacing reverse-remodels the heart in heart failure and is worth considering as a new form of cardiac pacemaking. ABSTRACT: Natural pacing of the heart results in heart rate variability, an indicator of good health and cardiac function. A contributor to heart rate variability is respiratory sinus arrhythmia or RSA - an intrinsic respiratory modulated pacing of heart rate. The loss of RSA is associated with poor cardiac prognosis and sudden cardiac death. We tested if reinstatement of respiratory-modulated heart rate (RMH) would improve cardiac performance in heart failure. Heart failure was induced in Wistar rats by ligation of the left anterior descending coronary artery. Rats were unpaced, monotonically paced and RMH paced; the latter had the same average heart rate as the monotonically paced animals. Cardiac function was assessed non-invasively using echocardiography before and after 2 weeks of daily pacing at a time when pacing was turned off. RMH increased cardiac output by 20 ± 8% compared to monotonic pacing (-3 ± 5%; P < 0.05). This improvement in cardiac output was associated with an increase in stroke volume compared to monotonic pacing (P = 0.03) and improvement in circumferential strain (P = 0.02). Improvements in ejection fraction (P = 0.08) and surrogate measures of left ventricle compliance did not reach significance. Increases in contractility (P < 0.05) and coronary blood flow (P < 0.05) were seen in vitro during variable pacing to mimic RMH. Thus, in rats with left ventricular dysfunction, chronic RMH pacing improved cardiac function through improvements in systolic function. As these improvements were made with pacing switched off, we propose the novel idea that RMH pacing causes reverse-remodelling.

Cardiorespiratory interactions in humans and animals: rhythms for life.

The cardiorespiratory system exhibits oscillations from a range of sources. One of the most studied oscillations is heart rate variability, which is thought to be beneficial and can serve as an index of a healthy cardiovascular system. Heart rate variability is dampened in many diseases including depression, autoimmune diseases, hypertension, and heart failure. Thus, understanding the interactions that lead to heart rate variability, and its physiological role, could help with prevention, diagnosis, and treatment of cardiovascular diseases. In this review, we consider three types of cardiorespiratory interactions: respiratory sinus arrhythmia (variability in heart rate at the frequency of breathing), cardioventilatory coupling (synchronization between the heart beat and the onset of inspiration), and respiratory stroke volume synchronization (the constant phase difference between the right and the left stroke volumes over one respiratory cycle). While the exact physiological role of these oscillations continues to be debated, the redundancies in the mechanisms responsible for its generation and its strong evolutionary conservation point to the importance of cardiorespiratory interactions. The putative mechanisms driving cardiorespiratory oscillations as well as the physiological significance of these oscillations will be reviewed. We suggest that cardiorespiratory interactions have the capacity to both dampen the variability in systemic blood flow as well as improve the efficiency of work done by the heart while maintaining physiological levels of arterial CO2. Given that reduction in variability is a prognostic indicator of disease, we argue that restoration of this variability via pharmaceutical or device-based approaches may be beneficial in prolonging life.

Utility of a Novel Biofeedback Device for Within-Breath Modulation of Heart Rate in Rats: A Quantitative Comparison of Vagus Nerve vs. Right Atrial Pacing.

In an emerging bioelectronics era, there is a clinical need for physiological devices incorporating biofeedback that permits natural and demand-dependent control in real time. Here, we describe a novel device termed a central pattern generator (CPG) that uses cutting edge analog circuitry producing temporally controlled, electrical stimulus outputs based on the real time integration of physiological feedback. Motivated by the fact that respiratory sinus arrhythmia (RSA), which is the cyclical changes in heart rate every breath, is an essential component of heart rate variability (HRV) (an indicator of cardiac health), we have explored the versatility and efficiency of the CPG for producing respiratory modulation of heart rate in anesthetized, spontaneously breathing rats. Diaphragmatic electromyographic activity was used as the input to the device and its output connected to either the right cervical vagus nerve or the right atrium for pacing heart rate. We found that the CPG could induce respiratory related heart rate modulation that closely mimicked RSA. Whether connected to the vagus nerve or right atrium, the versatility of the device was demonstrated by permitting: (i) heart rate modulation in any phase of the respiratory cycle, (ii) control of the magnitude of heart rate modulation, and (iii) instant adaptation to changes in respiratory frequency. Vagal nerve pacing was only possible following transection of the nerve limiting its effective use chronically. Pacing via the right atrium permitted better flexibility and control of heart rate above its intrinsic level. This investigation now lays the foundation for future studies using this biofeedback technology permitting closer analysis of both the function and dysfunction of RSA.

Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance?

KEY POINTS: Sympathetic activity exhibits respiratory modulation that is amplified in hypertensive rats. Respiratory modulated sympathetic activity produces greater changes in vascular resistance than tonic stimulation of the same stimulus magnitude in normotensive but not hypertensive rats. Mathematical modelling demonstrates that respiratory modulated sympathetic activity may fail to produce greater vascular resistance changes in hypertensive rats because the system is saturated as a consequence of a dysfunctional noradrenaline reuptake mechanism. Respiratory modulated sympathetic activity is an efficient mechanism to raise vascular resistance promptly, corroborating its involvement in the ontogenesis of hypertension. ABSTRACT: Sympathetic nerve activity (SNA) exhibits respiratory modulation. This component of SNA is important - being recruited under cardiorespiratory reflex conditions and elevated in the spontaneously hypertensive (SH) rat - and yet the exact influence of this modulation on vascular tone is not understood, even in normotensive conditions. We constructed a mathematical model of the sympathetic innervation of an arteriole, and used it to test the hypothesis that respiratory modulation of SNA preferentially increases vasoconstriction compared to a frequency-matched tonic pattern. Simulations supported the hypothesis, where respiratory modulated increases in vasoconstriction were mediated by a noradrenergic mechanism. These predictions were tested in vivo in adult Wistar rats. Stimulation of the sympathetic chain (L3) with respiratory modulated bursting patterns, revealed that bursting increases vascular resistance (VR) more than tonic stimulation (57.8 ± 3.3% vs. 44.8 ± 4.2%; P < 0.001; n = 8). The onset of the VR response was also quicker for bursting stimulation (rise time constant = 1.98 ± 0.09 s vs. 2.35 ± 0.20 s; P < 0.01). In adult SH rats (n = 8), the VR response to bursting (44.6 ± 3.9%) was not different to tonic (37.4 ± 3.5%; P = 0.57). Using both mathematical modelling and in vivo techniques, we have shown that VR depends critically on respiratory modulation and revealed that this pattern dependency in Wistar rats is due to a noradrenergic mechanism. This respiratory component may therefore contribute to the ontogenesis of hypertension in the pre-hypertensive SH rat - raising VR and driving vascular remodelling. Why adult SH rats do not exhibit a pattern-dependent response is not known, but further modelling revealed that this may be due to dysfunctional noradrenaline reuptake.

Silicon central pattern generators for cardiac diseases.

Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronisation but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPGs) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPGs). We discuss the limitations of present CPGs and appraise the advantages of analog over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin-Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease.

Deep brain stimulation for the treatment of resistant hypertension.

Hypertension is a leading risk factor for the development of several cardiovascular diseases. As the global prevalence of hypertension increases, so too has the recognition of resistant hypertension. Whilst figures vary, the proportion of hypertensive patients that are resistant to multiple drug therapies have been reported to be as high as 16.4 %. Resistant hypertension is typically associated with elevated sympathetic activity and abnormal homeostatic reflex control and is termed neurogenic hypertension because of its presumed central autonomic nervous system origin. This resistance to conventional pharmacological treatment has stimulated a plethora of medical devices to be investigated for use in hypertension, with varying degrees of success. In this review, we discuss a new therapy for drug-resistant hypertension, deep brain stimulation. The utility of deep brain stimulation in resistant hypertension was first discovered in patients with concurrent neuropathic pain, where it lowered blood pressure and improved baroreflex sensitivity. The most promising central target for stimulation is the ventrolateral periaqueductal gray, which has been well characterised in animal studies as a control centre for autonomic outflow. In this review, we will discuss the promise and potential mechanisms of deep brain stimulation in the treatment of severe, resistant hypertension.

Central angiotensinergic mechanisms associated with hypertension.

Following its generation by both systemic and tissue-based renin-angiotensin systems, angiotensin II interacts with specific, G-protein coupled receptors to modulate multiple physiological systems, including the cardiovascular system. Genetic models in which the different components of the renin-angiotensin system have been deleted show large changes in resting blood pressure. Interruption of the generation of angiotensin II, or its interaction with these receptors, decreases blood pressure in hypertensive humans and experimental animal models of hypertension. Whilst the interaction of angiotensin II with the kidney is pivotal in this modulation of blood pressure, an involvement of the system in other tissues is important. Both systemic angiotensins, acting via the blood-brain barrier deficient circumventricular organs, and centrally-generated angiotensin modulate cardiovascular control by regulating fluid and electrolyte ingestion, autonomic activity and neuroendocrine function. This review discusses the pathways in the brain that are involved in this regulation of blood pressure as well as examining the sites in which altered angiotensin function might contribute to the development and maintenance of high blood pressure.