Protocol of controlled odorant stimulation for reducing apnoeic episodes in premature newborns: a randomised open-label Latin-square study with independent evaluation of the main endpoint (PREMODEUR).

INTRODUCTION: Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature children with life-threatening apnoeas receive stimulants such as methylxanthines (mainly, caffeine) or doxapram (an analeptic unlicensed in children under 15). However, these products have undesirable effects (hyperarousal, irritability, sleep disorders, tachycardia) and are not always effective because apnoea does persist in some premature newborns. Previous studies have indicated that odorant stimulation, a non-invasive intervention, may stimulate the respiratory rhythm. The objective of the present protocol is to reduce the occurrence of apnoeic episodes in premature newborns by controlled odorant stimulation added to current pharmacological treatments. METHODS AND ANALYSIS: The project is a randomised open-label Latin-square trial with independent evaluation of the main endpoint. It will include 60 preterm neonates from two university hospital neonatal intensive care units over 2 years (2021-2023). Each newborn will receive no (S0), sham (S1) or real olfactory stimulation (S2) in random order. During S2, three distinct odorants (mint, grapefruit and vanilla) will be delivered successively, in puffs, over 24 hours. Mint and grapefruit odours stimulate the main and the trigeminal olfactory pathways, whereas vanilla odour stimulates only the main olfactory pathway. A statistical analysis will compare the incidence of apnoeic episodes during S1 versus S2 using a mixed effects Poisson model. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Comité de Protection des Personnes Île-de-France XI (# 2017-AO13-50-53). The results will be disseminated through various scientific meetings, specialised peer-reviewed journals and, whenever possible, posted on appropriate public websites. TRIAL REGISTRATION NUMBER: NCT02851979; Pre-results.

A beat-by-beat cardiovascular index, CARDEAN, to titrate opioid administration in the setting of orthopaedic surgery: a prospective randomized trial.

To determine whether a beat-by-beat cardiovascular index (CARDEAN: cardiovascular depth of analgesia, Alpha-2 Ltd, Lyon, France) reduces the incidence of tachycardia in ASA I-III patients undergoing orthopaedic surgery. A total of 76 patients were prospectively randomized into (1) a control group or (2) the CARDEAN group, in which the nurse anaesthetist was blinded to CARDEAN application. In addition to conventional signs, an external observer instructed the nurse anaesthetist to administer sufentanil 0.1 µg kg-1 when the CARDEAN crossed a threshold (≥ 60). The primary outcome was the incidence of tachycardia (> 120% of reference heart rate, HR). Non-invasive blood pressure (BP), electrocardiogram (ECG), O2 saturation-photoplethysmography and the bispectral index (40 < BIS < 60) were monitored. HR and an estimation of beat-by-beat BP changes acquired from photoplethysmography and ECG were combined in an algorithm that detected hypertension followed by tachycardia (index scaled 0-100). Sufentanil 0.1 µg kg-1 was administered when tachycardia, hypertension or movement ("conventional signs") was observed. Data for 66 patients (27 with known hypertension) were analysed. In the CARDEAN group, (a) the dose of sufentanil was higher (control: 0.46 µg kg-1 100 min-1, CARDEAN: 0.57 µg kg-1 100 min-1, p = 0.016), (b) the incidence rates of tachycardia and untoward events were lower (respectively: - 44%; control: 2.52 events 100 min-1 [1.98-3.22]; CARDEAN: 1.42 [1.03-1.96], p = 0.005, hazard ratio: 0.56; movement, muscular contraction, or coughing: control: 0.74 events 100 min-1 [0.47-1.16]; CARDEAN: 0.31 [0.15-0.62], p = 0.038), and (c) extubation occurred more often in the operating room (control: 76.5%, CARDEAN: 97%, p = 0.016). CARDEAN-titrated opioid administration was associated with a higher dose of sufentanil, a reduction in tachycardia and earlier emergence in ASA I-III patients undergoing major orthopaedic surgery.

Use of Gentamicin for Sepsis and Septic Shock in Anaesthesia-Intensive Care Unit: A Clinical Practice Evaluation.

OBJECTIVE: Numerous cases of gentamicin underdosing have been described in the literature in the context of sepsis and septic shock in anaesthesia-intensive care units (ICU). A survey of clinical practice was conducted with the aim to rationalise the use of gentamicin in the unit. The secondary objective was to propose a corrective formula for adjusting individual dosage. METHODS: A single-centre survey was used to determine the initial dose of gentamicin administered, in an anaesthesia-ICU, during the first hours of sepsis/septic shock. An initial retrospective phase allowed focusing on the points of improvement in terms of prescription. A second prospective phase enabled the evaluation of benefits following the implemented changes. RESULTS: Fifty-one patients were included during the retrospective phase (2014-2015) and 28 patients during the prospective phase (2016-2017). Out-of-guideline prescriptions significantly decreased between these two study periods (i.e., pulmonary infections decreased from 70.5% to 18%, p<0.001) and the mean±standard deviation administered dosage increased from 7.3±1.2 mg kg-1 to 9.5±1.5 mg kg-1 (p<0.001). Nevertheless, the proportion of Cmax (peak plasma concentration) ≥30 mg L-1 and the mean Cmax did not change significantly. A significant association (p<0.05) was found between Cmax, body mass index, haematocrit and creatinine, enabling a corrective formula to be proposed. CONCLUSION: The present study allowed improvement in gentamicin prescription in an anaesthesia-ICU. A Cmax ≥30 mg L-1 remains difficult to achieve, but a Cmax ≥16 mg L-1 could be considered relevant for community infections and would be more attainable. A corrective formula could be used to adjust the dosage.

Comprehensive assessment of coronary pulse wave velocity in anesthetized pigs.

BACKGROUND: Coronary stiffness represents a new paradigm for interventional cardiology and can be assessed by coronary pulse wave velocity (CoPWV). Assessing CoPWV is complex because of the coexistence of backward and forward waves. OBJECTIVES: Evaluate the feasibility, repeatability, and capacity of methods assessing CoPWV to detect predictable velocity changes. METHODS: CoPWV was measured from distal and proximal pressure guidewires in the left anterior descending artery of 10 pigs under general anesthesia. Four methods were studied: the tangent intersection method applied to the forward (FW) and backward (BK) waves, as well as the dicrotic notch (DIC) and template matching (TM) methods. All were evaluated at baseline, during various arterial pressure and heart rate conditions, during simulated flow limitation (balloon inflation), and after increasing coronary stiffness (stent insertion). RESULTS: All the methods were significantly different between them (p ≤ .05) showing a systematic trend toward higher CoPWV when compared to the FW method (.05 < p<.10). Results were found to be significantly correlated only between the BK and FW methods and between the DIC and TM methods (p ≤ .05). CoPWV increased with arterial pressure increase, this increase being significant for the DIC and TM methods and partly for the FW method (p ≤ .05). Conversely, heart rate had no systematic impact on CoPWV. The lowest variability was found for the DIC and TM methods (p ≤ .05). Only the BK and TM methods remained applicable during flow limitation; stent increased CoPWV when measured by the BK method only (p ≤ .05). CONCLUSION: Although CoPWV can be measured by various methods, the BK and TM methods seem the most appropriate for clinical studies.

Validity and variability of xBRS: instantaneous cardiac baroreflex sensitivity.

Spontaneous oscillations of blood pressure (BP) and interbeat interval (IBI) may reveal important information on the underlying baroreflex control and regulation of BP We evaluated the method of continuously measured instantaneous baroreflex sensitivity by cross correlation (xBRS) validating its mean value against the gold standard of phenylephrine (Phe) and nitroprusside (SNP) bolus injections, and focusing on its spontaneous changes quantified as variability around the mean. For this purpose, we analyzed data from an earlier study of eight healthy males (aged 25-46 years) who had received Phe and SNP in conditions of baseline and autonomic blocking agents: atropine, propranolol, and clonidine. Average xBRS corresponds well to Phe/SNP-BRS, with xBRS levels ranging from 1.2 (atropine) to 102 msec/mmHg (subject asleep under clonidine). Time shifts from BP- to IBI-signal increased from ≤1 sec (maximum correlations within the current heartbeat) to 3-5 sec (under atropine). Plotted on a logarithmic vertical scale, xBRS values show 40% variability (defined as SD/mean) over the whole range in the various conditions, except twice when the subjects had fallen asleep and it dropped to 20%. The xBRS oscillates at frequencies of 0.1 Hz and lower, dominant between 0.02-0.05 Hz. Although xBRS is the result of IBI/BP-changes, no linear coherence was found in the cross-spectra of the xBRS-signal and IBI or BP We speculate that the level of variability in the xBRS-signal may act as a probe into the central nervous condition, as evidenced in the two subjects who fell asleep with high xBRS and only 20% of relative variation.

Development of Coronary Pulse Wave Velocity: New Pathophysiological Insight Into Coronary Artery Disease.

BACKGROUND: Although aortic stiffness assessed by pulse wave velocity (PWV) is a strong predictor of coronary artery disease, the significance of local coronary stiffness has never been tackled. The first objective of this study was to describe a method of measuring coronary PWV (CoPWV) invasively and to describe its determinants. The second objective was to assess both CoPWV and aortic PWV in patients presenting with acute coronary syndromes or stable coronary artery disease. METHODS AND RESULTS: In 53 patients, CoPWV was measured from the delay in pressure wave and distance traveled as a pressure wire was withdrawn from the distal to the proximal coronary segment. Similarly, aortic PWV was measured invasively when the wire was pulled across the ascending aorta; carotid-femoral PWV was also measured noninvasively using the SphygmoCor system (AtCor Medical). Mean CoPWV was 10.3±6.1 m/s. Determinants of increased CoPWV were fractional flow reserve, diastolic blood pressure, and previous stent implantation in the recorded artery. CoPWV was lower in patients with acute coronary syndromes versus stable coronary artery disease (7.6±3 versus 11.5±6.4 m/s; P=0.02), and this persisted after adjustment for confounders. In contrast, aortic stiffness, assessed by aortic and carotid-femoral PWV, did not differ significantly. CONCLUSIONS: CoPWV seems associated with acute coronary events more closely than aortic PWV. High coronary compliance, whether per se or because it leads to a distal shift in compliance mismatch, may expose vulnerable plaques to high cyclic stretch. CoPWV is a new tool to assess local compliance at the coronary level; it paves the way for a new field of research.

Limits of permutation-based entropies in assessing complexity of short heart period variability.

The study compares permutation-based and coarse-grained entropy approaches for the assessment of complexity of short heart period (HP) variability recordings. Shannon permutation entropy (SPE) and conditional permutation entropy (CPE) are computed as examples of permutation-based entropies, while the k-nearest neighbor conditional entropy (KNNCE) is calculated as an example of coarse-grained conditional entropy. SPE, CPE and KNNCE were applied to ad-hoc simulated autoregressive processes corrupted by increasing amounts of broad band noise and to real HP variability series recorded after complete vagal blockade obtained via administration of a high dose of atropine (AT) in nine healthy volunteers and during orthostatic challenge induced by 90° head-up tilt (T90) in 15 healthy individuals. Over the simulated series the performances of SPE and CPE degraded more rapidly with the amplitude of the superimposed broad band noise than those of KNNCE. Over real data KNNCE identified the expected decrease of the HP variability complexity both after AT and during T90. Conversely SPE and CPE detected the decrease of HP variability complexity solely during T90 as a likely result of the more favorable signal-to-noise ratio during T90 than after AT. Results derived from both simulations and real data indicated that permutation-based entropies had a larger susceptibility to broad band noise than KNNCE. We recommend caution in applying permutation-based entropies in presence of short HP variability series characterized by a low signal-to-noise ratio.

Information domain analysis of the spontaneous baroreflex during pharmacological challenges.

The information carried by heart period (HP) given systolic arterial pressure (SAP) changes was assessed to characterize spontaneous baroreflex (i.e. the relation linking SAP variability to HP variability): the larger the information carried by HP given SAP changes, the greater the unpredictability of HP given SAP variations, the smaller the strength of the causal coupling from SAP series to HP series. It was typified according to two parameters: i) the information carried by HP given SAP changes within the same heart cycle (i.e. 0-step-ahead information) describing immediate effects of SAP variations on HP; ii) the rate of increase of the information carried by HP given SAP changes as a function of the temporal distance, k, between the conditioning SAP pattern and future HP value (i.e. the rate of increase of k-step-ahead information with k) describing short-term effects of SAP modifications on HP. Both parameters were found under vagal control. Indeed, i) 0-step-ahead information suggested that HP and SAP variabilities were significantly coupled from SAP to HP at baseline and after the reduction of the inhibitory effect of sympathetic control on vagal influences performed through the administration of propranolol or clonidine; and ii) during vagal blockade induced by atropine or combined vagal and sympathetic blockade induced by the administration of propranolol after atropine k-step-ahead information reached a level incompatible with coupled HP and SAP dynamics regardless of k. In addition, it was found that the 0-step-ahead information at baseline and after propranolol and the rate of increase of k-step-ahead information with k at baseline could be exclusively explained in terms of linear HP-SAP interactions. Conversely, the same parameters after clonidine suggested the raise of nonlinear mechanisms probably unveiled by the central sympathetic blockade. Comparison with more traditional parameters describing the HP-SAP variability relation such as baroreflex sensitivity and squared HP-SAP coherence confirmed the complementary value of the proposed information domain analysis.

Effect of clonidine on cardiac baroreflex delay in humans and rats.

The delay τ between rising systolic blood pressure (SBP) and baroreflex bradycardia has been found to increase when vagal tone is low. The α(2)-agonist clonidine increases cardiac vagal tone, and this study tested how it affects τ. In eight conscious supine human volunteers clonidine (6 µg/kg po) reduced τ, assessed both by cross correlation baroreflex sensitivity and sequence methods (both P < 0.05). Experiments on urethane-anaesthetized rats reproduced the phenomenon and investigated the underlying mechanism. Heart rate (HR) responses to increasing SBP produced with an arterial balloon catheter showed reduced τ (P < 0.05) after clonidine (100 µg/kg iv). The central latency of the reflex was unaltered, however, as shown by the unchanged timing with which antidromically identified cardiac vagal motoneurons (CVM) responded to the arterial pulse. Testing the latency of the HR response to brief electrical stimuli to the right vagus showed that this was also unchanged by clonidine. Nevertheless, vagal stimuli delivered at a fixed time in the cardiac cycle (triggered from the ECG R-wave) slowed HR with a 1-beat delay in the baseline state but a 0-beat delay after clonidine (n = 5, P < 0.05). This was because clonidine lengthened the diastolic period, allowing the vagal volleys to arrive at the heart just in time to postpone the next beat. Calculations indicate that naturally generated CVM volleys in both humans and rats arrive around this critical time. Clonidine thus reduces τ not by changing central or efferent latencies but simply by slowing the heart.

Scale exponents of blood pressure and heart rate during autonomic blockade as assessed by detrended fluctuation analysis.

How the autonomic nervous system influences the fractal dynamics of heart rate (HR) and blood pressure (BP) remains unclear. The purpose of our study was to separately assess cardiac vagal and sympathetic (cardiac vs. vascular) influences on fractal properties of HR and BP as described by scale exponents of detrended fluctuation analysis (DFA). R-R intervals, systolic and diastolic BP were measured in nine supine volunteers before and after administration of autonomic blocking agents (atropine, propranolol, atropine+propranolol, clonidine). Spectra of DFA scale exponents, α(t), were calculated for scales between 5 and 100 s. HR and BP scale structures differed at baseline, being α(t) of HR <1, with a minimum between 10 and 20 s followed by a higher plateau between 40 to 80 s, while α(t) of BP decreased with t from values >1. Comparison of atropine and propranolol with baseline and combined cardiac parasympathetic and sympathetic blockade (atropine+propranolol) indicated opposite influences of vagal and cardiac sympathetic outflows on HR exponents. The vagal outflow adds white-noise components, amplifying differences with BP exponents; the cardiac sympathetic outflow adds Brownian motion components at short scales and contributes to the plateau between 40 and 80 s. Overall sympathetic inhibition by clonidine decreased short- and long-term exponents of HR, and short-term exponents of BP, so that their α(t) spectra had different means but similar profiles. Therefore, cardiac vagal, cardiac sympathetic and vascular sympathetic outflows contribute differently to HR and BP fractal structures. Results are explained by different distribution and dynamics of acetylcholine receptors and of α- and ß-adrenergic receptors between heart and vasculature.

A beat-by-beat cardiovascular index, CARDEAN: a prospective randomized assessment of its utility for the reduction of movement during colonoscopy.

BACKGROUND: We sought to determine whether online use of a beat-by-beat cardiovascular index, CARDEAN (Alpha-2, Lyon, France), modifies the incidence of patient movement during colonoscopy under anesthesia. METHODS: Monitoring included an electrocardiogram, oscillometric and noninvasive beat-by-beat arterial blood pressure, O2 saturation, bispectral index (BIS), and CARDEAN. CARDEAN consists of beat-by-beat Finapres (Ohmeda, Madison, WI) combined with an algorithm that detects hypertension followed by tachycardia and produces an index scaled 0 to 100. The anesthesiologist was denied access to Finapres and CARDEAN. Propofol was adjusted to keep 4060. The primary outcome was the number of observed movements. RESULTS: Data were analyzed in 146 patients (control: 75; CARDEAN: 71). The doses of propofol and alfentanil were similar in both groups. When BIS was <60, movements were less frequent in the CARDEAN group (3.3 movements/100 min [2.3-4.8]) than in the control group (6.7 [5.3-8.5]) (odds ratio: 0.5 [0.32; 0.76], P = 0.001). During the first 10 minutes of the procedure, the incidence of movements was 38% and 59% in the CARDEAN and control groups, respectively (P = 0.04). CONCLUSION: With BIS <60, CARDEAN-guided opioid administration is associated with a reduction of 51% of clinically unpredictable movements in unparalyzed patients undergoing colonoscopy. More studies are required to refine the role of CARDEAN in surgical settings.

Cardioinhibitory actions of clonidine assessed by cardiac vagal motoneuron recordings.

BACKGROUND: Cardiac vagal activity is now considered as an important therapeutic target. However, there is a lack of direct data on how cardiac vagal motoneurons respond to parasympathomimetic agents. METHODS: Rats were anesthetized with urethane and mechanically ventilated. Single-unit activity was recorded in the nucleus ambiguus from cardiac vagal motoneurons, identified by antidromic activation from the cardiac vagal branch and their barosensitivity. RESULTS: Nitroprusside lowered systolic blood pressure, increased heart rate and inhibited cardiac vagal motoneuron activity (n = 5 cells in five rats). Clonidine 1-100 microg kg(-1) intravenously, however, lowered systolic blood pressure, but it increased cardiac vagal motoneuron activity (n = 8 cells in eight rats). It also enhanced their barosensitivity. An unsuspected further finding was that clonidine significantly increased the occurrence of cardiac vagal motoneuron firing spikes separated by short (< 30 ms) interspike intervals ('doublet'). CONCLUSION: Such grouped patterns are known to enhance neurotransmitter release. Therefore, these data provide a new mechanism by which clonidine can further potentiate parasympathetic actions on the heart.

Effect of catecholamine depletion on increased blood pressure lability upon emergence from halothane anesthesia in rats: the role of sympathetic nervous activity in postanesthetic circulatory instability.

PURPOSE: Circulatory instability is often observed upon emergence from general anesthesia. The increased blood pressure (BP) lability has been associated with poor clinical outcome. However, its underlying mechanisms are not fully understood. Thus, we investigated a possible role of the sympathetic nervous system (SNS) and cardiac baroreflex in the increased pressure lability observed upon emergence from general anesthesia. METHODS: Male rats (n = 16) were allocated to two groups, i.e., (1) a control group (n = 8) and (2) an alpha-methylparatyrosine (alpha-MPT; an inhibitor of tyrosine hydroxylase)-treated group (n = 8). In the alpha-MPT-treated group, in order to deplete catecholamines both in the central nervous system and in the SNS, alpha-MPT (300 mg x kg(-1)) was injected intraperitoneally (i.p.), administered twice, 4 and 2 h before halothane discontinuation (total dose, 600 mg x kg(-1) i.p.). In the control group, saline was administered at identical time-points. Systolic BP (SBP) lability was evaluated on a beat-by-beat basis, using the coefficient of variation of SBP, and the occurrence of slow and rapid rises in SBP and their amplitude, while the cardiac baroreflex slope was calculated using the "sequences" method. RESULTS: In the control group, heart rate, SBP, and the three indices of BP lability (i.e., the 3 indices of BP lability are: coefficient of variation of SBP, number of slow and rapid rises in pressure, amplitude of slow and rapid rises in pressure) all increased upon emergence from anesthesia (P < 0.05). Such increases were all blunted in the alpha-MPT-treated group, with the increases in the three indices of BP lability almost entirely suppressed (P < 0.05). The cardiac baroreflex slope was similarly decreased in both groups (P < 0.05). CONCLUSION: The postanesthetic increase in pressure lability seems largely a consequence of increased sympathetic activity, irrespective of any change in cardiac baroreflex sensitivity.

Comparison of various techniques used to estimate spontaneous baroreflex sensitivity (the EuroBaVar study).

This study compared spontaneous baroreflex sensitivity (BRS) estimates obtained from an identical set of data by 11 European centers using different methods and procedures. Noninvasive blood pressure (BP) and ECG recordings were obtained in 21 subjects, including 2 subjects with established baroreflex failure. Twenty-one estimates of BRS were obtained by methods including the two main techniques of BRS estimates, i.e., the spectral analysis (11 procedures) and the sequence method (7 procedures) but also one trigonometric regressive spectral analysis method (TRS), one exogenous model with autoregressive input method (X-AR), and one Z method. With subjects in a supine position, BRS estimates obtained with calculations of alpha-coefficient or gain of the transfer function in both the low-frequency band or high-frequency band, TRS, and sequence methods gave strongly related results. Conversely, weighted gain, X-AR, and Z exhibited lower agreement with all the other techniques. In addition, the use of mean BP instead of systolic BP in the sequence method decreased the relationships with the other estimates. Some procedures were unable to provide results when BRS estimates were expected to be very low in data sets (in patients with established baroreflex failure). The failure to provide BRS values was due to setting of algorithmic parameters too strictly. The discrepancies between procedures show that the choice of parameters and data handling should be considered before BRS estimation. These data are available on the web site (http://www.cbi.polimi.it/glossary/eurobavar.html) to allow the comparison of new techniques with this set of results.