The Human Dive Reflex During Consecutive Apnoeas in Dry and Immersive Environments: Magnitude and Synchronicity

Introduction: The human dive reflex (HDR), an O2 conserving reflex, is characterised by an interplay of central parasympathetic and peripheral sympathetic reactions, which are presumed to operate independently of each other. The HDR is fully activated during apnoea with facial immersion in water and complete immersion in water is thought to increase the magnitude of HDR during consecutive apnoeas. A comparison of HDR activity between consecutive apnoeas in full-body immersion with consecutive apnoeas in dry conditions has not been fully explored. Also, the interplay between parasympathetic and sympathetic reactions involved in the HDR has not been thoroughly analysed. Methods: 11 human volunteers performed 3 consecutive 60 s apnoeas with facial immersion in dry conditions (FIDC) and 3 consecutive apnoeas with facial immersion in full immersion (FIFI). Heart rate (HR), R-R interval (RRI), finger pulse amplitude (FPA), splenic width (SW) and SpO2 were all measured before, during and after apnoeas. A one-way ANOVA using Dunn’s post hoc test was performed to assess HDR activity, and a Pearson’s correlation test was performed to assess HDR synchronisation between physiological parameters during both conditions. Results: Although HDR activity was not significantly different between both conditions, HR and RRI showed progressively greater changes during FIFI compared with FIDC, while SW and FPA changes were relatively equivalent. During FIDC, significant correlations were found between SW & SpO2 and FPA & SpO2. During FIFI, significant correlations were found between RRI & FPA, SW & FPA, HR & SpO2 and FPA & SpO2. Discussion: While there was no significant difference found between HDR activity during FIDC and FIFI, consecutive apnoeas during FIFI triggered a greater magnitude of cardiac activity. Furthermore, significant correlations between RRI and SW with FPA indicate a crosstalk between parasympathetic tone with splenic contraction and increased peripheral sympathetic outflow during FIFI compared to FIDC. In conclusion, HDR activity during consecutive apnoeas does not differ between FIDC and FIFI. There appears to be however a greater level of synchronicity during apnoeas in FIFI compared to FIDC and that this is most likely due to the physiological effects of immersion, which could induce neural recruitment and increased cross talk of HDR pathways

Orthostatic Resiliency During Successive Hypoxic, Hypoxic Orthostatic Challenge: Successful vs. Unsuccessful Cardiovascular and Oxygenation Strategies

Introduction: Rapid environmental changes, such as successive hypoxic-hypoxic orthostatic challenges (SHHOC) occur in the aerospace environment, and the ability to remain orthostatically resilient (OR) relies upon orchestration of physiological counter-responses. Counter-responses adjusting for hypoxia may conflict with orthostatic responses, and a misorchestration can lead to orthostatic intolerance (OI). The goal of this study was to pinpoint specific cardiovascular and oxygenation factors associated with OR during a simulated SHHOC. Methods: Thirty one men underwent a simulated SHHOC consisting of baseline (P0), normobaric hypoxia (Fi02 = 12%, P1), and max 60 s of hypoxic lower body negative pressure (LBNP, P2). Alongside anthropometric variables, non-invasive cardiovascular, central and peripheral tissue oxygenation parameters, were recorded. OI was defined as hemodynamic collapse during SHHOC. Comparison of anthropometric, cardiovascular, and oxygenation parameters between OR and OI was performed via Student's t-test. Within groups, a repeated measures ANOVA test with Holm-Sidak post hoc test was performed. Performance diagnostics were performed to assess factors associated with OR/OI (sensitivity, specificity, positive predictive value PPV, and odd's ratio OR). Results: Only 9/31 were OR, and 22/31 were OI. OR had significantly greater body mass index (BMI), weight, peripheral Sp02, longer R-R Interval (RRI) and lower heart rate (HR) at P0. During P1 OR exhibited significantly higher cardiac index (CI), stroke volume index (SVI), and lower systemic vascular resistance index (SVRI) than OI. Both groups exhibited a significant decrease in cerebral oxygenation (TOIc) with an increase in cerebral deoxygenated hemoglobin (dHbc), while the OI group showed a significant decrease in cerebral oxygenated hemoglobin (02Hbc) and peripheral oxygenation (TOIp) with an increase in peripheral deoxygenated hemoglobin (dHbp). During P2, OR maintained significantly greater CI, systolic, mean, and diastolic pressure (SAP, MAP, DAP), with a shortened RRI compared to the OI group, while central and peripheral oxygenation were not different. Body weight and BMI both showed high sensitivity (0.95), low specificity (0.33), a PPV of 0.78, with an OR of 0.92, and 0.61. P0 RRI showed a sensitivity of 0.95, specificity of 0.22, PPV 0.75, and OR of 0.99. Delta SVI had the highest performance diagnostics during P1 (sensitivity 0.91, specificity 0.44, PPV 0.79, and OR 0.8). Delta SAP had the highest overall performance diagnostics for P2 (sensitivity 0.95, specificity 0.67, PPV 0.87, and OR 0.9). Discussion: Maintaining OR during SHHOC is reliant upon greater BMI, body weight, longer RRI, and lower HR at baseline, while increasing CI and SVI, minimizing peripheral 02 utilization and decreasing SVRI during hypoxia. During hypoxic LBNP, the ability to remain OR is dependent upon maintaining SAP, via CI increases rather than SVRI. Cerebral oxygenation parameters, beyond 02Hbc during P1 did not differ between groups, suggesting that the during acute hypoxia, an increase in cerebral 02 consumption, coupled with increased peripheral 02 utilization does seem to play a role in OI risk during SHHOC. However, cardiovascular factors such as SVI are of more value in assessing OR/OI risk. The results can be used to implement effective aerospace crew physiological monitoring strategies

Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats

Purpose: Myocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation-contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure. Methods: Volume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls. Results: In ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls. Conclusion: Opioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload

Intraoperative Beat-to-Beat Pulse Transit Time (PTT) Monitoring via Non-Invasive Piezoelectric/Piezocapacitive Peripheral Sensors Can Predict Changes in Invasively Acquired Blood Pressure in High-Risk Surgical Patients

Background: Non-invasive tracking of beat-to-beat pulse transit time (PTT) via piezoelectric/piezocapacitive sensors (PES/PCS) may expand perioperative hemodynamic monitoring. This study evaluated the ability for PTT via PES/PCS to correlate with systolic, diastolic, and mean invasive blood pressure (SBPIBP, DBPIBP, and MAPIBP, respectively) and to detect SBPIBP fluctuations. Methods: PES/PCS and IBP measurements were performed in 20 patients undergoing abdominal, urological, and cardiac surgery. A Pearson’s correlation analysis (r) between 1/PTT and IBP was performed. The predictive ability of 1/PTT with changes in SBPIBP was determined by area under the curve (reported as AUC, sensitivity, specificity). Results: Significant correlations between 1/PTT and SBPIBP were found for PES (r = 0.64) and PCS (r = 0.55) (p < 0.01), as well as MAPIBP/DBPIBP for PES (r = 0.6/0.55) and PCS (r = 0.5/0.45) (p < 0.05). A 7% decrease in 1/PTTPES predicted a 30% SBPIBP decrease (0.82, 0.76, 0.76), while a 5.6% increase predicted a 30% SBPIBP increase (0.75, 0.7, 0.68). A 6.6% decrease in 1/PTTPCS detected a 30% SBPIBP decrease (0.81, 0.72, 0.8), while a 4.8% 1/PTTPCS increase detected a 30% SBPIBP increase (0.73, 0.64, 0.68). Conclusions: Non-invasive beat-to-beat PTT via PES/PCS demonstrated significant correlations with IBP and detected significant changes in SBPIBP. Thus, PES/PCS as a novel sensor technology may augment intraoperative hemodynamic monitoring during major surgery.German Government sponsored ZIM (Zentrales Innovationsprogramm Mittelstand) programPeer Reviewe

Perioperative echocardiography-guided hemodynamic therapy in high-risk patients: a practical expert approach of hemodynamically focused echocardiography

The number of high-risk patients undergoing surgery is growing. To maintain adequate hemodynamic functioning as well as oxygen delivery to the vital organs (DO2) amongst this patient population, a rapid assessment of cardiac functioning is essential for the anesthesiologist. Pinpointing any underlying cardiovascular pathophysiology can be decisive to guide inter ventions in the intraoperative setting. Various techniques are available to monitor the hemodynamic status of the patient, however due to intrinsic limitations, many of these methods may not be able to directly identify the underlying cause of cardiovascular impairment. Hemodynamic focused echocardiography, as a rapid diagnostic method, ofers an excellent opportunity to examine signs of flling impairment, cardiac preload, myocardial contractility and the function of the heart valves. We thus propose a 6-step-echocardiographic approach to assess high-risk patients in order to improve and maintain perioperative DO2. The summary of all echocardiographic based fndings allows a diferentiated assessment of the patient’s cardiovascular function and can thus help guide a (patho)physiological-orientated and individualized hemodynamic therapy

Ultrafast glutamate sensors resolve high-frequency release at Schaffer collateral synapses

Glutamatergic synapses display a rich repertoire of plasticity mechanisms on many different time scales, involving dynamic changes in the efficacy of transmitter release as well as changes in the number and function of postsynaptic glutamate receptors. The genetically encoded glutamate sensor iGluSnFR enables visualization of glutamate release from presynaptic terminals at frequencies up to ∼10 Hz. However, to resolve glutamate dynamics during high-frequency bursts, faster indicators are required. Here, we report the development of fast (iGluf) and ultrafast (iGluu) variants with comparable brightness but increased Kd for glutamate (137 μM and 600 μM, respectively). Compared with iGluSnFR, iGluu has a sixfold faster dissociation rate in vitro and fivefold faster kinetics in synapses. Fitting a three-state model to kinetic data, we identify the large conformational change after glutamate binding as the rate-limiting step. In rat hippocampal slice culture stimulated at 100 Hz, we find that iGluu is sufficiently fast to resolve individual glutamate release events, revealing that glutamate is rapidly cleared from the synaptic cleft. Depression of iGluu responses during 100-Hz trains correlates with depression of postsynaptic EPSPs, indicating that depression during high-frequency stimulation is purely presynaptic in origin. At individual boutons, the recovery from depression could be predicted from the amount of glutamate released on the second pulse (paired pulse facilitation/depression), demonstrating differential frequency-dependent filtering of spike trains at Schaffer collateral boutons

Peripheral skin cooling during hyper-gravity: hemodynamic reactions

Introduction: Orthostatic dysregulation occurs during exposure to an increased gravitational vector and is especially common upon re-entering standard Earth gravity (1 g) after an extended period in microgravity (0 g). External peripheral skin cooling (PSC) has recently been described as a potent countermeasure against orthostatic dysregulation during heat stress and in lower body negative pressure (LBNP) studies. We therefore hypothesized that PSC may also be an effective countermeasure during hyper-gravity exposure (+Gz). Methods: To investigate this, we designed a randomized short-arm human centrifuge (SAHC) experiment (“Coolspin”) to investigate whether PSC could act as a stabilizing factor in cardiovascular function during +Gz. Artificial gravity between +1 g and +4 g was generated by a SAHC. 18 healthy male volunteers completed two runs in the SAHC. PSC was applied during one of the two runs and the other run was conducted without cooling. Each run consisted of a 10-min baseline trial followed by a +Gz step protocol marked by increasing g-forces, with each step being 3 min long. The following parameters were measured: blood pressure (BP), heart rate (HR), stroke volume (SV), total peripheral resistance (TPR), cardiac output (CO). Furthermore, a cumulative stress index for each subject was calculated. Results: +Gz led to significant changes in primary as well as in secondary outcome parameters such as HR, SV, TPR, CO, and BP. However, none of the primary outcome parameters (HR, cumulative stress-index, BP) nor secondary outcome parameters (SV, TPR, CO) showed any significant differences—whether the subject was cooled or not cooled. Systolic BP did, however, tend to be higher amongst the PSC group. Conclusion: In conclusion, PSC during +Gz did not confer any significant impact on hemodynamic activity or orthostatic stability during +Gz. This may be due to lower PSC responsiveness of the test subjects, or an insufficient level of body surface area used for cooling. Further investigations are warranted in order to comprehensively pinpoint the exact degree of PSC needed to serve as a useful countermeasure system during +Gz

Current Anesthetic Care of Patients Undergoing Transcatheter Aortic Valve Replacement in Europe:Results of an Online Survey

Objectives: Transcatheter aortic valve replacement (TAVR) has become an alternative treatment for patients with symptomatic aortic stenosis not eligible for surgical valve replacement due to a high periprocedural risk or comorbidities. However, there are several areas of debate concerning the pre-, intra- and post-procedural management. The standards and management for these topics may vary widely among different institutions and countries in Europe. Design: Structured web-based, anonymized, voluntary survey. Setting: Distribution of the survey via email among members of the European Association of Cardiothoracic Anaesthesiology working in European centers performing TAVR between September and December 2018. Participants: Physicians. Measurements and main results: The survey consisted of 25 questions, including inquiries regarding number of TAVR procedures, technical aspects of TAVR, medical specialities present, preoperative evaluation of TAVR candidates, anesthesia regimen, as well as postoperative management. Seventy members participated in the survey. Reporting members mostly performed 151-to-300 TAVR procedures per year. In 90% of the responses, a cardiologist, cardiac surgeon, cardiothoracic anesthesiologist, and perfusionist always were available. Sixty-six percent of the members had a national curriculum for cardiothoracic anesthesia. Among 60% of responders, the decision for TAVR was made preoperatively by an interdisciplinary heart team with a cardiothoracic anesthesiologist, yet in 5 countries an anesthesiologist was not part of the decision-making. General anesthesia was employed in 40% of the responses, monitored anesthesia care in 44%, local anesthesia in 23%, and in 49% all techniques were offered to the patients. In cases of general anesthesia, endotracheal intubation almost always was performed (91%). It was stated that norepinephrine was the vasopressor of choice (63% of centers). Transesophageal echocardiography guiding, whether performed by an anesthesiologist or cardiologist, was used only Conclusion: The results indicated that requirements and quality indicators (eg, periprocedural anesthetic management, involvement of the anesthesiologist in the heart team, etc) for TAVR procedures as published within the European guideline are largely, yet still not fully implemented in daily routine. In addition, anesthetic TAVR management also is performed heterogeneously throughout Europe. (C) 2020 Elsevier Inc. All rights reserved

Ultrafast glutamate sensors resolve high-frequency release at Schaffer collateral synapses

ABSTRACT Glutamatergic synapses display a rich repertoire of plasticity mechanisms on many different time scales, involving dynamic changes in the efficacy of transmitter release as well as changes in the number and function of postsynaptic glutamate receptors. The genetically encoded glutamate sensor iGluSnFR enables visualization of glutamate release from presynaptic terminals at frequencies up to ∼10 Hz. However, to resolve glutamate dynamics during high frequency bursts, faster indicators are required. Here we report the development of fast (iGlu f ) and ultrafast (iGlu u ) variants with comparable brightness, but increased K d for glutamate (137 μM and 600 μM, respectively). Compared to iGluSnFR, iGlu u has a 6-fold faster dissociation rate in vitro and 5-fold faster kinetics in synapses. Fitting a three-state model to kinetic data, we identify the large conformational change after glutamate binding as the rate-limiting step. In rat hippocampal slice culture stimulated at 100 Hz, we find that iGlu u is sufficiently fast to resolve individual glutamate release events, revealing that glutamate is rapidly cleared from the synaptic cleft. Depression of iGlu u responses during 100 Hz trains correlates with depression of postsynaptic EPSPs, indicating that depression during high frequency stimulation is purely presynaptic in origin. At individual boutons, the recovery from depression could be predicted from the amount of glutamate released on the second pulse (paired pulse facilitation/depression), demonstrating differential frequency-dependent filtering of spike trains at Schaffer collateral boutons. Significance Statement Excitatory synapses convert presynaptic action potentials into chemical signals that are sensed by postsynaptic glutamate receptors. To eavesdrop on synaptic transmission, genetically encoded fluorescent sensors for glutamate have been developed. However, even the best available sensors lag behind the very fast glutamate dynamics in the synaptic cleft. Here we report the development of an ultrafast genetically encoded glutamate sensor, iGlu u , which allowed us to image glutamate clearance and synaptic depression during 100 Hz spike trains. We found that only boutons showing paired-pulse facilitation were able to rapidly recover from depression. Thus, presynaptic boutons act as frequency-specific filters to transmit select features of the spike train to specific postsynaptic cells

Gender-Specific Cardiovascular Reactions to +Gz Interval Training on a Short Arm Human Centrifuge

Cardiovascular deconditioning occurs in astronauts during microgravity exposure, and may lead to post-flight orthostatic intolerance, which is more prevalent in women than men. Intermittent artificial gravity is a potential countermeasure, which can effectively train the cardiovascular mechanisms responsible for maintaining orthostatic integrity. Since cardiovascular responses may differ between women and men during gravitational challenges, information regarding gender specific responses during intermittent artificial gravity exposure plays a crucial role in countermeasure strategies. This study implemented a +Gz interval training protocol using a ground based short arm human centrifuge, in order to assess its effectiveness in stimulating the components of orthostatic integrity, such as diastolic blood pressure, heart rate and vascular resistance amongst both genders. Twenty-eight participants (12 men/16 women) underwent a two-round graded +1/2/1 Gz profile, with each +Gz phase lasting 4 min. Cardiovascular parameters from each phase (averaged last 60 sec) were analyzed for significant changes with respect to baseline values. Twelve men and eleven women completed the session without interruption, while five women experienced an orthostatic event. These women had a significantly greater height and baseline mean arterial pressure than their counterparts. Throughout the +Gz interval session, women who completed the session exhibited significant increases in heart rate and systemic vascular resistance index throughout all +Gz phases, while exhibiting increases in diastolic blood pressure during several +Gz phases. Men expressed significant increases from baseline in diastolic blood pressure throughout the session with heart rate increases during the +2Gz phases, while no significant changes in vascular resistance were recorded. Furthermore, women exhibited non-significantly higher heart rates over men during all phases of +Gz. Based on these findings, this protocol proved to consistently stimulate the cardiovascular systems involved in orthostatic integrity to a larger extent amongst women than men. Thus the +Gz gradients used for this interval protocol may be beneficial for women as a countermeasure against microgravity induced cardiovascular deconditioning, whereas men may require higher +Gz gradients. Lastly, this study indicates that gender specific cardiovascular reactions are apparent during graded +Gz exposure while no significant differences regarding cardiovascular responses were found between women and men during intermittent artificial gravity training