AUTONOMIC OUTPUT IN HEALTH AND DISEASE: CLOSED-LOOP DYNAMICS OF BAROREFLEX CHANGES

Introduction Sympathetic\u2013parasympathetic interaction plays a critical role in the evolution and outcome of many cardiovascular disorders. It is well established that the sympathetic activation has an arrhythmogenic potential, contrariwise the vagal activation has an opposite effect. These findings are summarised in the generic concept of the \u201cautonomic balance\u201d, which generate the common perception that the loss of autonomic balance is a potentially proarrhythmic condition, and therapeutic strategies that aim at modulating the autonomic nervous system might increase the cardiac electrical stability. Several tools have been proposed to investigate the activity of the autonomic nervous system, and the analysis of the arterial baroreflex is considered an indirect measure of the cardiac vagal activity. In fact the spontaneous baroreflex sensitivity (BRS) is viewed as an index of the rise in the cardiac vagal efferent activity in response to an increase in arterial blood pressure. BRS has been assessed in a variety of conditions and with a variety of experimental techniques, focusing mostly on the cardiac-chronotropic efferent branch. Healthy subjects and several cardiovascular diseases have been extensively investigated by the analysis of baroreflexes with either a closed-loop and/or an open-loop approach. The latter allows computation of the characteristic parameters of the baroreflex curve, i.e. the centring point, the operating point, and the maximal gain. This approach can be applied only in steady state conditions, at rest and during exercise, since it make use of external factors (mechanical or pharmacological) to modify the operating range and to construct the responding range, in terms of heart rate (HR) or arterial blood pressure (BP) responses. Contrariwise, the closed-loop approach analyses the relationship between HR and BP to define the sensitivity of the baroreflex close to the operating point, which could be displaced toward the \u201cthreshold\u201d of the baroreflex curves in some conditions, i.e. during exercise. In closed-loop condition, Bertinieri and colleagues (1988) proposed the so-called sequence method which they applied in steady state condition. In practice, they computed the mean slope of several BRS sequences, of at least three beats, in which the R-R interval (RRi) of the ECG varied consensually to BP, regardless of the direction. Recently, this method was applied also in unsteady state conditions (Adami et al., 2013, Bringard et al., 2017; Fagoni et al., 2015; Sivieri et al. 2015); the only a-priori assumption behind the sequence method is that each heart beat has a biunivocal effect on the following beat: no upper limit was imposed to the length of baroreflex sequences (minimum three beats). Moreover, the BRS analysis was applied to estimate the prognosis in patients affected by cardiovascular diseases (Head, 1995; Korner et al., 1974; La Rovere et al., 1998, 2008, 2011). Autonomic output is different in health and disease and the BRS can be used to analyse these differences in several conditions. Thus, the purpose of this project was to perform a closed-loop baroreflex analysis, under different dynamic conditions (rest, exercise, apnoeas), in healthy subjects and in patients affected by mild arterial hypertension. The closed-loop approach was used to this aim, in order to deeply investigate the dynamics of the arterial baroreflex in the following unsteady state conditions: i) at exercise onset and ii) during apnoeas, in healthy volunteers; iii) during exercise, comparing healthy subjects and hypertensive patients. Commonly, the sequence method is computed starting from the R-R interval (RRi) of the ECG, and the systolic blood pressure (SAP). In literature, both HR and RRi are used to calculate BRS, even though RRi is the reciprocal of HR, and these two parameters provided two different information. To clarify this challenging point, a further detailed paper will be proposed to discuss this topic. In this thesis, we decided to use the relationship between HR and MAP to compute BRS. While HR has been an a-priori choice, the use of MAP was a consequence of the typology of experiments we carried out. The beginning of physical activity is accomplished by the sudden change in the total peripheral resistances (TPR), which predominantly acts on DAP; this modification affects more MAP than SAP, thus the former parameter was chosen to define the BRS. First study: baroreflex at exercise onset This first experiment analysed the dynamics of baroreflex resetting at exercise onset. Baroreflex resetting is generally studied at steady state, by means of open-loop procedures, and it was demonstrated that during exercise the operating point is displaced upward and rightward with respect to rest, and its maximal gain is invariant (Rowell et al. 1996; DiCarlo and Bishop 2001; Raven et al. 2002; Raven et al. 2006; Raven 2008; Fadel and Raven 2012; Mitchell 2013). Notwithstanding, the dynamics of baroreflex displacement from rest to exercise was never described so far. We aimed at investigating the temporal components of the mechanisms that intervene in determining baroreflex resetting during transient. Ten healthy volunteers took parts in the experiments. They performed three repetition of a 50 W exercise on a cycle ergometer, lasting seven minutes, in supine and upright position; the different posture was used to have an a-priori displacement the BRS operating point (Schwartz et al., 2013) even at rest. HR was continuously recorded, on single beat basis, by electrocardiography. Arterial pressure was continuously recorded by a non-invasive finger pressure cuff. From pulse pressure profiles, we determined cardiac output (CO) by Modelflow, and we computed MAP; TPR was derived as the ratio between the former two parameters. We performed the closed-loop analysis of HR vs MAP relationship at rest before starting the exercise (BRS computed as the average of the mean slopes of all analysed sequences of each single subject, over one minute), during the transient (HR vs MAP relationship), and during exercise (BRS over one minute steady state recording). At exercise onset, HR was higher than in quiet rest. As exercise started, MAP fell to a minimum (MAPmin) of about 73 mmHg in both posture, while HR increased. The initial HR versus MAP relationship was linear, with flatter slope than resting baroreflex sensitivity, in both postures. TPR fell and CO increased. After MAPmin, both HR and MAP increased toward exercise steady state, with further CO increase. The sensitivity of baroreflex during steady state at exercise resulted lower than at rest, in both posture, and invariant compared to the beginning of exercise. These results suggest that, at exercise onset, the falling of MAP was corrected by a HR reduction along a baroreflex curve; the sensitivity of the baroreflex changed immediately during the transient, with lower sensitivity than at rest, and then BRS remained unchanged during the exercise steady state. After reaching MAPmin, the baroreflex resetting took place, yet with a delay after the beginning of exercise. Thus, the baroreflex resetting starts after the exercise onset, but the sensitivity of the baroreflex changes immediately, and this process is compatible with the central command hypothesis. However, the central command theory may not explain the resetting process, that lasted one minute upright, but not supine (it took more time), compatibly with a possible role of increasing sympathetic stimulation of the sinus node during exercise (Fagraeus and Linnarsson, 1976; Orizio et al., 1988). Second study: baroreflex in apnoea. The cardiovascular response to apnoea is characterised by three phases (Fagoni et al., 2015, 2017; Perini et al., 2008; Sivieri et al., 2015). The first dynamic phase (\u3c61) of the cardiovascular response to apnoea is characterised by a sudden drop in MAP, accompanied by an increase HR (Costalat et al, 2015; Fagoni et al., 2015; Perini et al, 2008, 2010; Sivieri et al., 2015). It was interpreted as a baroreflex attempt at correcting a MAP fall due to a reduction in venous return caused by an increase in intrathoracic pressure occurring at elevated lung volumes. The purpose was to perform the analysis of the HR vs MAP relationship during the \u3c61 of apnoeas performed at lung volumes close to the total lung capacity, at rest and during exercise. Indeed, during exercise apnoeas, the characteristics of \u3c61 would be different than in resting apnoeas, because the BRS slope at exercise is lower than at rest, and the operating point of the baroreflex should be displaced. We calculated BRS in steady state condition before apnoeas, during phase II (\u3c62), and we analysed the HR vs MAP relationship during \u3c61, before and after attainment MAPmin, in resting and exercise apnoeas. Ten healthy divers performed resting and exercise (30 W) apnoeas. HR and MAP were recorded on a beat-by-beat basis by means of an electrocardiography and the Portapres\uae, respectively. The resulting slopes of the linear regression line of the HR versus MAP relationship, at rest, during steady \u3c62, before and after the attainment of MAPmin, were computed in both conditions. We also analysed the modification of the prevailing HR and MAP from the first part of \u3c61, before the MAPmin, and after MAPmin, to investigate if baroreflex resetting took place after attainment of MAPmin. Before the beginning of apnoeas, BRS was lower (p<0.05) during exercise than in resting apnoeas (-1.23 \ub1 0.23 and -0.87 \ub1 0.21 b min-1 mmHg-1, respectively). This difference was also reported for the HR vs MAP relationship in all the investigated conditions. In either resting and exercise apnoeas, slopes were lower at the beginning of \u3c61 (-0.49 \ub1 0.20 and -0.31 \ub1 0.08 b min-1 mmHg-1, resting and exercise, respectively), compared to rest, \u3c62 (-1.12 \ub1 0.33 and -0.82 \ub10.27 b min-1 mmHg-1, resting and exercise, respectively) and after MAPmin (-0.96 \ub1 0.24 and -0.70\ub1 0.31 b min-1 mmHg-1, resting and exercise, respectively). The prevailing HR and MAP at the beginning of apnoeas resulted different compared to after attainment of MAPmin, then both HR and MAP increased consensually to attain new levels: whereas at rest both HR and MAP increased, during exercise MAP was displaced upward and rightward, whilst the HR remained unchanged. The novelty of this study is that during the dynamic phase of apnoeas, the HR vs MAP relationship showed a baroreflex dynamic characterized by a sudden modification in the sensitivity compared to rest and to the steady phase II. After the attainment of MAPmin, a parallel rise in HR and MAP took place, which we interpreted as due to baroreflex resetting. Indeed, the prevailing HR and MAP resulted shifted upward and rightward during exercise compared to rest. During exercise, this process caused an increase in MAP after MAPmin, compared to before MAPmin, with an invariant HR: the prevailing sympathetic output during exercise might affects much more the vasomotor component of the cardiovascular responses compared to the cardiac one, resulting in higher TPR and lower HR values (Fagoni et al., 2015; Sivieri et al., 2015) Third study: baroreflex in hypertensive patients. The BRS in hypertensive patients is impaired (Bristow et al., 1969; Head, 1995; Korner et al., 1974; Mancia et al., 1978), and the modification in BRS is associated with worst outcome in cardiovascular patients (La Rovere et al., 1998, 2008, 2011; Osculati et al., 1990). Studies concerning the implantation of continuous baroreflex stimulators as a tool to diminish central sympathetic outflow (Mohaupt et al., 2007) and the introduction of catheter-based renal selective denervation for resistant hypertension show a significantly reduction in blood pressure (DiBona and Esler, 2010; Esler, 2011; Schlaich et al., 2009). These data suggest that the overall cardiovascular regulation in hypertensive patients may be different from normal, and the analysis of the dynamics of the baroreflex response to exercise might be different from healthy subjects. We aimed at investigating the steady-state and the dynamics of the HR vs MAP relationship in response to exercise in patients affected by essential hypertension compared to age-matched healthy controls, carried out in supine and upright postures, at two different workloads, 50 and 75W. Ten patients affected by grade I or II of arterial hypertension were age-matched with ten healthy controls. HR and MAP were recorded on a beat-by-beat basis by means of an electrocardiography and the Portapres\uae, respectively. The resulting slopes of the linear regression line of the HR versus MAP relationship, at rest, during the transient and at steady state during exercise, were computed in supine and upright position. Data were compared between patients and healthy volunteers, between positions, and among the different phases before and during exercises. BRS resulted steeper in controls than in hypertensive patients (supine -1.43 \ub1 0.19 and -1.16 \ub1 0.33 b min-1 mmHg-1 for controls and hypertensive patients, respectively; upright -1.22 \ub1 0.2 and -0.99 \ub1 0.19 b min-1 mmHg-1 for controls and hypertensive patients, respectively), as well as the linear relationship between HR and MAP at the beginning of exercise at 50 W, in both positions, resulted higher in controls than in patients. In supine position controls showed higher slopes at rest than at the beginning and during exercise. In controls and hypertensive patients, at the beginning of exercise at 75 W the slopes were lower in upright than supine. These data showed a trend characterised by a reduced baroreflex sensitivity in all conditions with sympathetic hyperactivity: hypertension versus control, exercise versus rest, and upright versus supine. Moreover, several slopes resulted lower at the beginning of exercise and during steady state exercise compare to rest, confirming previous findings. It is noteworthy that during the transient at 75 W the baroreflex response was absent in several patients in supine position, probably due to sympathetic overactivity which limited the MAP fall demonstrated at the exercise onset because of the sudden drastic fall in TPR (Elstad et al., 2009; Faisal et al., 2010; Lador et al., 2006, 2008; Wieling et al., 1996). Conclusion The analysis of the relationship between HR and MAP by means of the closed-loop approach is a non-invasive method that can be easily applied in health and disease, and it can be used as an indirect measure of the autonomic nervous system activity. The reported results on the patterns of baroreflex changes in dynamic states suggested that the baroreflex resetting started after the beginning of exercise, but the modification of the sensitivity was almost immediate, as soon as the MAP fell and the baroreflex activity tried to counteract by increasing the HR. After the attainment of the MAPmin, which might be considered a trigger MAP value, the resetting phase took place. The change in slope at exercise onset might be attributed to the sudden vagal withdrawal, and compatibly more with the central command theory. Contrariwise, the resetting process may well be mediated by other neural mechanisms (Raven et al., 2006), and it is possible that the activation of the sympathetic efferent branch of the autonomic nervous system plays a role in the phase of the exercise transient after attainment MAPmin (Lador et al., 2006). At the same time, apnoea provided interesting information about the baroreflex function, since the first phase is characterized by dynamic and deep modifications in MAP, sustained for several beats, counteracted by adjustments in HR. In exercise apnoeas BRS was lower than resting apnoeas, in all the investigated conditions. In \u3c61, rapid cardiovascular adjustments affect the baroreflex responses with different pattern before and after MAPmin, showing higher values of the HR vs MAP slopes after the attainment of MAPmin compared to the onset of \u3c61. The baroreflex sensitivity restored immediately after reaching the MAPmin in \u3c61, indeed BRS in \u3c62 was similar to the one computed at the beginning of apnoea. Finally, the prevailing HR and MAP points during exercise apnoeas were displaced rightward and upward compared to resting apnoeas. During \u3c62, HR decreased, and the TPR increased, thus a modification in the autonomic output can occur, with a dissociation between heart (characterised by predominant vagal activity) and vascular system (with predominant sympathetic activity), that may explain why these modifications did not affect the baroreflex sensitivity during \u3c62 apnoeas. In the hypertension study, patients presented a reduced baroreflex gain, in agreement with previous findings (Bristow et al., 1969; Head, 1995; Korner et al., 1974; Mancia et al., 1978). The baroreflex sensitivity, in healthy and hypertensive subjects, changed immediately at the exercise onset, in both positions, and remained unchanged during the steady state of light-mild exercises: the baroreflex resetting acted in the same manner in healthy and hypertensive patients, but with a reduced gain in the latter compared to the former. The closed-loop approach allows the analysis of the BRS in several conditions, such as rest, exercise, apnoea and in pathologies (hypertension, orthostatic intolerance, dysautonomic diseases). BRS could be a useful tool, i.e. to assess improvements after rehabilitation in neurological as well as in cardiorespiratory diseases, or after prolonged bed rest, in healthy volunteers and in patients after prolonged hospital stay. The application of this technique might be used to monitor the efficacy of the undertaken treatment, whether behavioural or pharmacological. Thus, the modification in BRS might be considered as a mirror of cardiovascular adjustments following a different stimulation of the two branches of the autonomic nervous system, in health and disease

Visualizing Impending Cerebral Circulatory Arrest Caused by Intracranial Hypertension Following Aneurysmal Subarachnoid Hemorrhage.

Intracranial hypertension may represent an important complication during the early phase following aneurysmal subarachnoid hemorrhage. 1 Timely diagnosis of intracranial hypertension is essential to avoid secondary brain ischemia; however, intracranial pressure (ICP) monitoring requires the insertion of catheters either within the brain ventricles or parenchyma, and hence, invasive ICP monitoring is not frequently utilized.2 Transcranial Doppler can be used for noninvasive ICP estimation through calculation of the pulsatility index (PI).3 We describe a case where noninvasive ICP monitoring with transcranial colorcoded Doppler (TCCD) rapidly identified a condition of severe intracranial hypertension, which led to a life-saving treatment

Intensive care unit–acquired weakness: unanswered questions and targets for future research [version 1; peer review: 3 approved]

Intensive care unit–acquired weakness (ICU-AW) is the most common neuromuscular impairment in critically ill patients. We discuss critical aspects of ICU-AW that have not been completely defined or that are still under discussion. Critical illness polyneuropathy, myopathy, and muscle atrophy contribute in various proportions to ICU-AW. Diagnosis of ICU-AW is clinical and is based on Medical Research Council sum score and handgrip dynamometry for limb weakness and recognition of a patient’s ventilator dependency or difficult weaning from artificial ventilation for diaphragmatic weakness (DW). ICU-AW can be caused by a critical illness polyneuropathy, a critical illness myopathy, or muscle disuse atrophy, alone or in combination. Its diagnosis requires both clinical assessment of muscle strength and complete electrophysiological evaluation of peripheral nerves and muscles. The peroneal nerve test (PENT) is a quick simplified electrophysiological test with high sensitivity and good specificity that can be used instead of complete electrophysiological evaluation as a screening test in non-cooperative patients. DW, assessed by bilateral phrenic nerve magnetic stimulation or diaphragm ultrasound, can be an isolated event without concurrent limb muscle involvement. Therefore, it remains uncertain whether DW and limb weakness are different manifestations of the same syndrome or are two distinct entities. Delirium is often associated with ICU-AW but a clear correlation between these two entities requires further studies. Artificial nutrition may have an impact on ICU-AW, but no study has assessed the impact of nutrition on ICU-AW as the primary outcome. Early mobilization improves activity limitation at hospital discharge if it is started early in the ICU, but beneficial long-term effects are not established. Determinants of ICU-AW can be many and can interact with each other. Therefore, future studies assessing early mobilization should consider a holistic patient approach with consideration of all components that may lead to muscle weakness

Validation of the peroneal nerve test to diagnose critical illness polyneuropathy and myopathy in the intensive care unit: the multicentre Italian CRIMYNE-2 diagnostic accuracy study

Objectives: To evaluate the accuracy of the peroneal nerve test (PENT) in the diagnosis of critical illness polyneuropathy (CIP) and myopathy (CIM) in the intensive care unit (ICU). We hypothesised that abnormal reduction of peroneal compound muscle action potential (CMAP) amplitude predicts CIP/CIM diagnosed using a complete nerve conduction study and electromyography (NCS-EMG) as a reference diagnostic standard. Design: prospective observational study. Setting: Nine Italian ICUs. Patients: One-hundred and twenty-one adult (≥18 years) neurologic (106) and non-neurologic (15) critically ill patients with an ICU stay of at least 3 days. Interventions: None. Measurements and main results: Patients underwent PENT and NCS-EMG testing on the same day conducted by two independent clinicians who were blind to the results of the other test. Cases were considered as true negative if both NCS-EMG and PENT measurements were normal. Cases were considered as true positive if the PENT result was abnormal and NCS-EMG showed symmetric abnormal findings, independently from the specific diagnosis by NCS-EMG (CIP, CIM, or combined CIP and CIM). All data were centrally reviewed and diagnoses were evaluated for consistency with predefined electrophysiological diagnostic criteria for CIP/CIM. During the study period, 342 patients were evaluated, 124 (36.3%) were enrolled and 121 individuals with no protocol violation were studied. Sensitivity and specificity of PENT were 100% (95% CI 96.1-100.0) and 85.2% (95% CI 66.3-95.8). Of 23 patients with normal results, all presented normal values on both tests with no false negative results. Of 97 patients with abnormal results, 93 had abnormal values on both tests (true positive), whereas four with abnormal findings with PENT had only single peroneal nerve neuropathy at complete NCS-EMG (false positive). Conclusions: PENT has 100% sensitivity and high specificity, and can be used as a screening test to diagnose CIP/CIM in the ICU

Vagal blockade suppresses the phase I heart rate response but not the phase I cardiac output response at exercise onset in humans

Purpose We tested the vagal withdrawal concept for heart rate (HR) and cardiac output (CO) kinetics upon moderate exercise onset, by analysing the effects of vagal blockade on cardiovascular kinetics in humans. We hypothesized that, under atropine, the φ1 amplitude (A1) for HR would reduce to nil, whereas the A1 for CO would still be positive, due to the sudden increase in stroke volume (SV) at exercise onset. Methods On nine young non-smoking men, during 0–80 W exercise transients of 5-min duration on the cycle ergometer, preceded by 5-min rest, we continuously recorded HR, CO, SV and oxygen uptake (˙O2) upright and supine, in control condition and after full vagal blockade with atropine. Kinetics were analysed with the double exponential model, wherein we computed the amplitudes (A) and time constants (τ) of phase 1 (φ1) and phase 2 (φ2). Results In atropine versus control, A1 for HR was strongly reduced and fell to 0 bpm in seven out of nine subjects for HR was practically suppressed by atropine in them. The A1 for CO was lower in atropine, but not reduced to nil. Thus, SV only determined A1 for CO in atropine. A2 did not differ between control and atropine. No effect on τ1 and τ2 was found. These patterns were independent of posture. Conclusion The results are fully compatible with the tested hypothesis. They provide the first direct demonstration that vagal blockade, while suppressing HR φ1, did not affect φ1 of CO

Testing the vagal withdrawal hypothesis during light exercise under autonomic blockade: a heart rate variability study

Introduction. We performed the first analysis of heart rate variability (HRV) at rest and exercise under full autonomic blockade on the same subjects, to test the conjecture that vagal tone withdrawal occurs at exercise onset. We hypothesized that, between rest and exercise: i) no differences in total power (PTOT) under parasympathetic blockade; ii) a PTOT fall under β1-sympathetic blockade; iii) no differences in PTOT under blockade of both ANS branches. Methods. 7 males (24±3 years) performed 5-min cycling (80W) supine, preceded by 5-min rest during control and with administration of atropine, metoprolol and atropine+metoprolol (double blockade). Heart rate and arterial blood pressure were continuously recorded. HRV and blood pressure variability were determined by power spectral analysis, and baroreflex sensitivity (BRS) by the sequence method. Results. At rest, PTOT and the powers of low (LF) and high (HF) frequency components of HRV were dramatically decreased in atropine and double blockade compared to control and metoprolol, with no effects on LF/HF ratio and on the normalised LF (LFnu) and HF (HFnu). At exercise, patterns were the same as at rest. Comparing exercise to rest, PTOT varied as hypothesized. For SAP and DAP, resting PTOT was the same in all conditions. At exercise, in all conditions, PTOT was lower than in control. BRS decreased under atropine and double blockade at rest, under control and metoprolol during exercise. Conclusions. The results support the hypothesis that vagal suppression determined disappearance of HRV during exercise

Neuromuscular disorders and acquired neuromuscular weakness

Neuromuscular disorders include pathological processes involving one or more components of the motor unit comprising a motor neuron with its axon and myelin sheath, neuromuscular transmission, and all the muscle fibres it innervates. This chapter will discuss the general care of patients with neuromuscular disease and then describe the more common conditions seen in the intensive care setting

Dynamics of cardiovascular and baroreflex readjustments during a light-to-moderate exercise transient in humans

We hypothesised that, during a light-to-moderate exercise transient, compared to an equivalent rest-to-exercise transient, (1) a further baroreflex sensitivity (BRS) decrease would be slower, (2) no rapid heart rate (HR) response would occur, and (3) the rapid cardiac output (CO) response would have a smaller amplitude (A1). Hence, we analysed the dynamics of arterial baroreflexes and the HR and CO kinetics during rest-to-50&nbsp;W (0-50&nbsp;W) and 50-to-100&nbsp;W (50-100&nbsp;W) exercise transients

Visualizing Impending Cerebral Circulatory Arrest Caused by Intracranial Hypertension Following Aneurysmal Subarachnoid Hemorrhage

Intracranial hypertension may represent an important complication during the early phase following aneurysmal subarachnoid hemorrhage. 1 Timely diagnosis of intracranial hypertension is essential to avoid secondary brain ischemia; however, intracranial pressure (ICP) monitoring requires the insertion of catheters either within the brain ventricles or parenchyma, and hence, invasive ICP monitoring is not frequently utilized.2 Transcranial Doppler can be used for noninvasive ICP estimation through calculation of the pulsatility index (PI).3 We describe a case where noninvasive ICP monitoring with transcranial colorcoded Doppler (TCCD) rapidly identified a condition of severe intracranial hypertension, which led to a life-saving treatment