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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

The management of sedation in the setting of COVID-19 ("COVID") by Ego et al. [...].

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress is treated with volume expansion, administration of vasopressors (usually noradrenaline: NA), and inotropes. Ventilation and anti-infectious strategy shall not be discussed here. When circulation is considered, the literature is segregated between interventions directed to the systemic circulation vs. interventions directed to the micro-circulation. Our thesis is that, after stabilization of the acute cardioventilatory distress, the prolonged sympathetic hyperactivity is detrimental in the setting of septic shock. Our hypothesis is that the sympathetic hyperactivity observed in septic shock being normalized towards baseline activity will improve the microcirculation by recoupling the capillaries and the systemic circulation. Therefore, counterintuitively, antihypertensive agents such as beta-blockers or alpha-2 adrenergic agonists (clonidine, dexmedetomidine) are useful. They would reduce the noradrenaline requirements. Adjuncts (vitamins, steroids, NO donors/inhibitors, etc.) proposed to normalize the sepsis-evoked vasodilation are not reviewed. This itemized approach (systemic vs. microcirculation) requires physiological and epidemiological studies to look for reduced mortality.

Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.O manejo cardíaco, ventilatório e renal no ambiente de terapia intensiva tem melhorado nas últimas décadas. Cognição e sedação representam dois dos últimos desafios a vencer. Como a sedação convencional não é ideal, e a sedação evocada por agonistas adrenérgicos alfa-2 (sedação “cooperativa” com dexmedetomidina, clonidina ou guanfacina) representa uma alternativa valiosa, este artigo abrange três tópicos práticos para os quais há lacunas na medicina baseada em evidência. O primeiro deles é a mudança de sedação convencional para sedação cooperativa (“mudança”): a resposta curta consiste em retirada abrupta de sedação convencional, implantação imediata de infusão de um agonista alfa-2 e uso de “sedação de resgate” (bolos de midazolam) ou “sedação agressiva” (haloperidol em bolos) para estabilizar a sedação cooperativa. O segundo tópico é a mudança de sedação convencional para sedação cooperativa em pacientes instáveis (por exemplo: delirium tremens refratário, choque séptico, síndrome do desconforto respiratório agudo etc.), pois, para evitar a hipotensão e a bradicardia provocadas por desativadores simpáticos, a resposta curta é manter o volume sistólico por administração de volume, vasopressores e inotrópicos. Por fim, para evitar essas mudanças e dificuldades associadas, os agonistas alfa-2 podem ser sedativos de primeira linha. A resposta curta é administrar agonistas alfa-2 lentamente desde a admissão ou intubação endotraqueal, até estabilização da sedação cooperativa. Dessa forma, conclui-se que os agonistas alfa-2 são, ao mesmo tempo, agentes desativadores simpáticos e sedativos, bem como a desativação simpática implica na manutenção do volume sistólico e na avaliação persistente da volemia. A medicina baseada em evidência deve documentar esta proposta.

Acute respiratory distress syndrome (ARDS) is not a failure of the neurological command of the ventilatory muscles or of the ventilatory muscles; it is an oxygenation defect. As positive pressure ventilation impedes the cardiac function, paralysis under general anaesthesia and controlled mandatory ventilation should be restricted to the interval needed to control the acute cardio-ventilatory distress observed upon admission into the critical care unit (CCU; “salvage therapy” during “shock state”). Current management of early severe diffuse ARDS rests on a prolonged interval of controlled mechanical ventilation with low driving pressure, paralysis (48 h, too often overextended), early proning and positive end-expiratory pressure (PEEP). Therefore, the time interval between arrival to the CCU and switching to spontaneous ventilation (SV) is not focused on normalizing the different factors involved in the pathophysiology of ARDS: fever, low cardiac output, systemic acidosis, peripheral shutdown (local acidosis), supine position, hypocapnia (generated by hyperpnea and tachypnea), sympathetic activation, inflammation and agitation. Then, the extended period of controlled mechanical ventilation with paralysis under general anaesthesia leads to CCU-acquired pathology, including low cardiac output, myoneuropathy, emergence delirium and nosocomial infection. The stabilization of the acute cardio-ventilatory distress should primarily itemize the pathophysiological conditions: fever control, improved micro-circulation and normalized local acidosis, ‘upright’ position, minimized hypercapnia, sympathetic de-activation (normalized sympathetic activity toward baseline levels resulting in improved micro-circulation with alpha-2 agonists administered immediately following optimized circulation and endotracheal intubation), lowered inflammation and ‘cooperative’ sedation without respiratory depression evoked by alpha-2 agonists. Normalised metabolic, circulatory and ventilatory demands will allow one to single out the oxygenation defect managed with high PEEP (diffuse recruitable ARDS) under early spontaneous ventilation (airway pressure release ventilation+SV or low-pressure support). Assuming an improved overall status, PaO2/FiO2≥150–200 allows for extubation and continuous non-invasive ventilation. Such fast-tracking may avoid most of the CCU-acquired pathologies. Evidence-based demonstration is required.

Background Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting. Methods In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [μg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4). Results Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] μg/kg/min in the DEX group and 0.04 [0.01, 0.16] μg/kg/min in the usual care group (p = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio. Conclusions In critically ill patients with septic shock, patients in the DEX group received similar vasopressor doses in the first 48 h compared to the usual care group. On multivariable adjusted analysis, dexmedetomidine appeared to be associated with lower vasopressor requirements to maintain the target MAP. Trial registration The SPICE III trial was registered at ClinicalTrials.gov (NCT01728558).

Objectives: In sepsis, prolonged, sympathetic overstimulation may lead to vasopressor-refractory hypotension. We therefore examined the effects of the α 2 -adrenergic agonist clonidine on mean arterial pressure, renal sympathetic nerve activity, and pressor responsiveness to phenylephrine and angiotensin II during hypotensive sepsis in conscious sheep. Design: Interventional study. Setting: Research institute. Subjects: Twelve adult Merino ewes (n = 6 per group). Interventions: Sepsis was induced by IV infusion of Escherichia coli for 32 hours. Pressor responses to increasing doses of phenylephrine and angiotensin II were measured at baseline and at 24, 28, and 32 hours of sepsis. Sheep were treated with clonidine (1 μg/kg/hr) or saline-vehicle from 24 to 32 hours of sepsis. Measurements and Main Results: Sepsis was characterized by hypotension (~12 mm Hg), increased heart rate (~80 beats/min), increased renal sympathetic nerve activity (~70%), and blunted pressor responses to phenylephrine and angiotensin II. In vehicletreated sheep, mean arterial pressure progressively declined from 25 to 32 hours of sepsis (73 ± 3 to 66 ± 3 mm Hg; p = 0.013) while the elevations in heart rate and renal sympathetic nerve activity and reduced pressor responsiveness to vasopressors persisted. Clonidine treatment prevented the further decline in mean arterial pressure, substantially reduced heart rate and renal sympathetic nerve activity and restored pressor responsiveness to both phenylephrine and angiotensin II toward preseptic levels. Conclusions: Administration of clonidine during hypotensive sepsis reduced renal sympathetic nerve activity, restored vascular sensitivity to both phenylephrine and angiotensin II, and resulted in better preservation of arterial pressure. Considering these findings, a clinical trial for the use of clonidine in the treatment of persistent vasopressor-refractory hypotension in patients with septic shock would be worthwhile. (Crit Care Med 2015; 43:e221–e229)

Resume La dexmedetomidine a une autorisation de mise sur le marche pour la sedation en reanimation en France depuis 2013. Par rapport a la clonidine, les avantages de la dexmedetomidine sont les suivants : delai d’action plus court meme en cas d’administration sans dose de charge, delai d’elimination plus court par voie hepatique. L’interet de la dexmedetomidine par rapport aux protocoles de sedations conventionnels appliques en reanimation est lie a l’attenuation de certains effets deleteres (facilitation de l’emergence de la sedation, moindre incidence de delirium), a l’absence d’effets depresseurs respiratoires, a l’amelioration des conditions de pre-charge et post-charge des ventricules. Les medicaments coadministres avec la dexmedetomidine en vue d’une sedation plus profonde sont les neuroleptiques et les analgesiques non-morphiniques. Le developpement clinique de la dexmedetomidine doit etre poursuivi pour utiliser pleinement ses proprietes pharmacodynamiques, afin d’amener la sedation au niveau des progres realises en reanimation aux plans ventilatoire, circulatoire et renal.

BACKGROUND: In the setting of severe acute respiratory distress syndrome (ARDS; PaO 2 /FiO 2 < 100), the cut-off point for switching from non-invasive ventilation to intubation combined to mechanical ventilation is poorly defined. RESULTS: The swift resolution over 10 h of a severe acute hypoxemic respiratory failure (P/F = 57) caused by aspiration following heroin overdose, using non-invasive ventilation (NIV)-high PEEP (15-20 cm H 2 O)-low pressure support (8 cm H 2 0) is reported. The success in treating non-invasively severe hypoxia was presumably linked to a highly restricted subset: healthy young patient, minimal alteration of consciousness, non-combativeness, absence of severe metabolic acidosis, quick resolution of supraventricular arrhythmia, one-to-one supervision by the intensivist in the critical care unit. CONCLUSION: Given the complications associated with tracheal intubation and mechanical ventilation on the one hand and with delayed intubation on the other hand, high PEEP-NIV may warrant study in a restricted set of patients closely monitored in a critical care environment.

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.

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.

It has been proposed that sympathoexcitation is responsible for vascular desensitization to α 1 ‐adrenoceptor stimulation during lipopolysaccharide (LPS)‐induced systemic inflammation. The present study tested this hypothesis by examining the effects of sympatho‐deactivation with the α 2 ‐adrenoceptor agonist, dexmedetomidine, on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and vascular reactivity to phenylephrine in conscious rats with cardiac autonomic blockade (methylatropine and atenolol) following LPS administration. In male, adult Sprague‐Dawley rats ( n = 5 per group), RSNA and MAP were continuously recorded over 1‐h periods, before and after LPS administration (20 mg/kg iv), and finally after infusion of either saline or dexmedetomidine (5 μ g/kg, then 5 μ g/kg/h iv). A full dose – response curve to phenylephrine was constructed under each condition. After pooling data from both groups of rats ( n = 10), LPS significantly ( P = 0.005) decreased MAP (from 115 ± 1 to 107 ± 2 mmHg), increased RSNA (to 403 ± 46% of baseline values) and induced 4 to 5‐fold increases in the half‐maximal effective dose (ED 50 ) of phenylephrine (from 1.02 ± 0.09 to 4.76 ± 0.51 μ g/kg). During saline infusion, RSNA progressively decreased while vascular reactivity did not improve. Treatment with dexmedetomidine decreased MAP, returned RSNA to near pre‐endotoxemic levels, but only partially restored vascular reactivity to phenylephrine (ED 50 was still threefold increased as compared with baseline values). These findings indicate that only part of the decrease in vascular reactivity to α 1 ‐adrenoceptor stimulation during endotoxemia can be accounted for by sympathetic activation, at least on a short‐term basis.

Complexity analysis of short-term cardiovascular control is traditionally performed using entropy-based approaches including corrective terms or strategies to cope with the loss of reliability of conditional distributions with pattern length. This study proposes a new approach aiming at the estimation of conditional entropy (CE) from short data segments (about 250 samples) based on the k-nearest-neighbor technique. The main advantages are: (i) the control of the loss of reliability of the conditional distributions with the pattern length without introducing a priori information; (ii) the assessment of complexity indexes without fixing the pattern length to an arbitrary low value. The approach, referred to as k-nearest-neighbor conditional entropy (KNNCE), was contrasted with corrected approximate entropy (CApEn), sample entropy (SampEn) and corrected CE (CCE), being the most frequently exploited approaches for entropy-based complexity analysis of short cardiovascular series. Complexity indexes were evaluated during the selective pharmacological blockade of the vagal and/or sympathetic branches of the autonomic nervous system. We found that KNNCE was more powerful than CCE in detecting the decrease of complexity of heart period variability imposed by double autonomic blockade. In addition, KNNCE provides indexes indistinguishable from those derived from CApEn and SampEn. Since this result was obtained without using strategies to correct the CE estimate and without fixing the embedding dimension to an arbitrary low value, KNNCE is potentially more valuable than CCE, CApEn and SampEn when the number of past samples most useful to reduce the uncertainty of future behaviors is high and/or variable among conditions and/or groups.

It is unclear whether the complexity of the variability of the systolic arterial pressure (SAP) provides complementary information to that of the heart period (HP). The complexity of HP and SAP variabilities was assessed from short beat-to-beat recordings (i.e., 256 cardiac beats). The evaluation was made during a pharmacological protocol that induced vagal blockade with atropine or a sympathetic blockade (beta-adrenergic blockade with propranolol or central sympathetic blockade with clonidine) alone or in combination, during a graded head-up tilt, and in patients with Parkinson's disease (PD) without orthostatic hypotension undergoing orthostatic challenge. Complexity was quantified according to the mean square prediction error (MSPE) derived from univariate autoregressive (AR) and multivariate AR (MAR) models. We found that: 1) MSPEMAR did not provide additional information to that of MSPEAR; 2) SAP variability was less complex than that of HP; 3) because HP complexity was reduced by either vagal blockade or vagal withdrawal induced by head-up tilt and was unaffected by beta-adrenergic blockade, HP was under vagal control; 4) because SAP complexity was increased by central sympathetic blockade and was unmodified by either vagal blockade or vagal withdrawal induced by head-up tilt, SAP was under sympathetic control; 5) SAP complexity was increased in patients with PD; and 6) during orthostatic challenge, the complexity of both HP and SAP variabilities in patients with PD remained high, thus indicating both vagal and sympathetic impairments. Complexity indexes derived from short HP and SAP beat-to-beat series provide complementary information and are helpful in detecting early autonomic dysfunction in patients with PD well before circulatory symptoms become noticeable.

Resume Les agonistes alpha-2 adrenergiques (« agonistes alpha-2 ») presentent de multiples effets pharmacodynamiques : sedation dite « eveillable » ( rousable sedation ), diminution de l’incidence du syndrome confusionnel en reanimation, preservation du controle respiratoire (neurogenese respiratoire), diminution de la consommation d’oxygene, diminution de l’impedance arterielle systemique et pulmonaire, amelioration de la performance systolique et diastolique du ventricule gauche, preservation de la reactivite vasculaire aux catecholamines exogenes, preservation de l’activite baroreflexe vasomotrice avec point de consigne en pression plus faible, fonction renale preservee, diminution du catabolisme proteique. Ces effets pharmacodynamiques, potentiellement interessants en reanimation, expliquent l’interet porte aux agonistes alpha-2 pour la sedation en reanimation. Toutefois, la place exacte des agonistes alpha-2 en sedation de reanimation reste a determiner. Compte tenu de la paucite d’essais randomises multicentriques en double insu, cette analyse, non exhaustive, de la litterature a pour objectif de presenter l’utilisation potentielle des agonistes alpha-2 comme sedatifs de premiere intention en reanimation. Un protocole d’utilisation de ces molecules est propose.

Automated assessment of circulatory response to surgical stimuli is unsolved. Would detection of cardiac baroreflex inhibition assess adequacy of intra-operative anti-nociception upon incision, as performed on-line on a beat-by-beat basis by a cardiovascular index, CARDEAN™? 18 ASA I-II patients undergoing spinal disc repair were studied, in a prospective randomized single-blinded trial (observational study). During infusion of propofol to maintain bispectral index between 40 and 60, patients were allocated to receive an effect site target-controlled infusion of remifentanil at Ce = 2 or 4 ng ml(-1). Upon incision and during surgery, circulatory response was assessed using beat-by-beat measurements of minor hypertension and tachycardia to give a cardiovascular index, CARDEAN, scaled between 0 and 100. Upon skin incision, CARDEAN increased in the remifentanil Ce = 2 ng ml(-1) group (n = 7, P0.05), while it did not increase in the remifentanil Ce = 4 ng ml(-1) group (n = 7, P = 0.18). During surgery, retrospectively, CARDEAN60 was associated with tachycardia and hypertension (P (k) = 0.81 ± 0.10). Changes in CARDEAN appeared linked to adequacy of anti-nociception.

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. 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 β-adrenergic receptors between heart and vasculature.

Detrended fluctuation analysis (DFA) is the most popular method for assessing the fractal characteristics of heart rate (HR). Traditionally, short-term and long-term scale coefficients, α(1) and α(2), are calculated from DFA. We recently showed that the traditional approach oversimplifies a more complex phenomenon better represented by a continuous spectrum of scale coefficients. In this paper we present a DFA based method for describing the HR fractal dynamics with a temporal spectrum of scale exponents, α(t), rather than by a model of lumped parameters, α(1) and α(2). Since α(t) is a function of the temporal scale, its interpretation is facilitated when conditions with different mean HR are compared. In this work, we reanalyze HR data, collected by our group in previous studies, by applying the proposed α(t) spectrum. We quantify the effects of gender, ageing, posture and activity level, and the alterations induced by exposure to high and very-high altitude hypoxia, on α(t). Most of the results may be interpreted in terms of changes of cardiac autonomic regulation, and indicate clearly that the new proposed DFA spectrum provides a more faithful and interpretable description of the HR fractal dynamics than traditional α(1) and α(2) scale coefficients.

Background: Pressure lability may be linked to the loss of the cardiac baroreflex. The reduction of the sensitivity of the cardiac baroreflex has not been delineated in the post-operative period according to age in normotensive patients. This study addresses pressure lability and slope of the cardiac baroreflex as a function of age. Methods: Patients were allocated to the following three groups: young (20–39 years, n=7), middle aged (40–59 years, n=7) and elderly (60–79 years, n=6), and studied before minor intra-abdominal surgery under CO2 peritoneal insufflation and nitrous oxide–isoflurane–sufentanil anesthesia, up to 24 h after extubation. An electrocardiogram and non-invasive beat-by-beat pressure monitoring (Finapres®) allowed offline calculation of the sensitivity of the cardiac baroreflex (‘sequence’ technique) and standard deviation (SD) of heart rate (HR; HR variability) and systolic blood pressure (SBP; pressure lability). Results: Before anesthesia, (a) an inverse relationship was observed between the slope of the cardiac baroreflex and age and (b) a trend (P

A juxtaposition of long and short RR intervals was observed in 2 hypertensive patients recovering from major surgery under spontaneous ventilation. Sinus rhythm was ascertained throughout the recording. These oscillations could not be linked one-to-one to ventilatory cycles.

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.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.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 (P0.05). Such increases were all blunted in the alpha-MPT-treated group, with the increases in the three indices of BP lability almost entirely suppressed (P0.05). The cardiac baroreflex slope was similarly decreased in both groups (P0.05).The postanesthetic increase in pressure lability seems largely a consequence of increased sympathetic activity, irrespective of any change in cardiac baroreflex sensitivity.

Physiology, CNRS 5123-University of Lyon, Lyon, FranceBackground: In the post-operative setting, pressure labi-lity is increased in hypertensive patients.a-2 agonists wereshown qualitatively to reduce this lability qualitatively.Here, upon immobilization combined with emergencefrom anesthesia in rats and clonidine administration,pressure lability was quantitatively assessed and relatedto baroreflex sensitivity.Methods: After local anesthesia of all incisions and surgi-cal wounds and myorelaxationwithmetocurine,ratshadhalothane withdrawn for 60min. Rats received (a) saline(n 58), (b) clonidine 30mg/kg i.v (n 58) simultaneous tohalothane discontinuation and (c) halothane readministra-tion (n 58) 20min after halothane discontinuation.Pressure lability was quantitatively assessed using occur-rence/amplitude of peaks in systolic blood pressure (SBP)and cardiac baroreflex slope.Results: Clonidine was associated with partial blunting ofhypertension, reduced standard deviation of SBP, reducednumber and amplitude of peaks in systolic pressure.Clonidine was also associated with increased slope of thecardiac baroreflex upon early intervals of emergence, butnotatlaterintervals.Conclusion: Clonidine reduces pressure lability uponimmobilization stress combined to emergence fromanesthesia, via parasympathetic activation and possiblysympathetic inhibition during early emergence as opposedto sympathetic inhibition during late emergence.

Intravenous B-type natriuretic peptide (BNP) enhances the bradycardia of reflexes from the heart, including the von Bezold-Jarisch reflex, but its site of action is unknown. The peptide is unlikely to penetrate the blood-brain barrier but could act on afferent or efferent reflex pathways. To investigate the latter, two types of experiment were performed on urethane-anesthetized (1.4 g/kg iv) rats. First, the activity was recorded extracellularly from single cardiac vagal motoneurons (CVMs) in the nucleus ambiguus. CVMs were identified by antidromic activation from the cardiac vagal branch and by their barosensitivity. Phenyl biguanide (PBG), injected via the right atrium in bolus doses of 1–5 μg to evoke the von Bezold-Jarisch reflex, caused a dose-related increase in CVM activity and bradycardia. BNP infusion (25 pmol·kg−1·min−1 iv) significantly enhanced both the CVM response to PBG ( n = 5 rats) and the reflex bradycardia, but the log-linear relation between those two responses over a range of PBG doses was unchanged by BNP. The reflex bradycardia was not enhanced in five matched time-control rats receiving only vehicle infusions. In five other rats the cervical vagi were cut and the peripheral right vagus was stimulated supramaximally at frequencies of 1–20 Hz. The bradycardic responses to these stimuli were unchanged before, during, and after BNP infusion. We conclude that systemic BNP in a moderate dose enhances the von Bezold-Jarisch reflex activation of CVM, in parallel with the enhanced reflex bradycardia. That enhancement is due entirely to an action before the vagal efferent arm of the reflex pathway.

Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. Treatment aims at reestablishing circulation within a “central” compartment (i.e., brain, heart, and lung) but fails to reestablish a disorganized microcirculation or an adequate response to noradrenaline, the most widely used vasopressor. Indeed, steroids, nitric oxide synthase inhibitors, or donors have not achieved overwhelming acceptance in the setting of septic shock.Counterintuitively,α2-adrenoceptor agonists were shown to reduce noradrenaline requirements in two cases of human septic shock. This has been replicated in rat and sheep models of sepsis. In addition, some data show thatα2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock.

A patient, with known left ventricular failure presented with severe pulmonary edema, an ejection fraction of 10% to 15%, knee mottling, and lactates of 7 mM L⁻¹. He was treated with unusually high-dose nitroglycerin (NTG) intravenously (IV; NTG ≈ 70 mg for 1 hour). To suppress dyspnea, systolic blood pressure had to be lowered from ≈ 150-160 to ≈ 100-120 mm Hg. To lower NTG requirement, an α-2 agonist, clonidine, was administered (300 μg IV for 2 hours). Dyspnea, tachypnea, and tachycardia subsided for 1 to 2 hours, allowing to reduce NTG infusion to 2 to 4 mg h⁻¹. State-of the-art treatment was superimposed: sitting position with leg down, noninvasive ventilation, positive end-expiratory pressure, bolus of furosemide 250 mg, and administration of 1000 mL of crystalloid for 1 hour under echocardiographic guidance. We ascribed the resistance to NTG to the activation of the sympathetic, vasopressin, and renin-angiotensin systems ("neurohormonal activation"). α-2 agonists reduce the sympathetic activation observed during severe left ventricular failure and overall oxygen consumption, evoke systemic and pulmonary arterial dilation, increase diastolic time, and improve diastolic function and diuresis. Because the α-2 agonist, dexmedetomidine, is available as an IV drug on the North American market, a niche may exist in the setting of emergency medicine/coronary care. This awaits evidence-based documentation.

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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.

The study compares permutation and coarse-grained entropy approaches for the assessment of short-term complexity of the cardiovascular control from heart period (HP) variability recordings. Approaches were applied to simulations and to HP variability series recorded during complete vagal blockade obtained via administration of a high dose of atropine (AT). Differences between the estimated complexity indexes derived from both simulations and real data indicated that permutation entropy has a larger sensitivity to noise than coarse-grained entropy. We recommend caution in applying permutation entropy in presence of short HP variability series characterized by a low signal-to-noise ratio such as after complete vagal blockade induced by AT.

Clonidine reduces postoperative circulatory instability in patients with essential hypertension. It also increases the sensitivity to vasopressors before and during anesthesia. We investigated blood pressure responses to phenylephrine and nitroprusside pre- vs postoperatively and the effect of clonidine on these responses in patients with essential hypertension. Twenty patients received clonidine 6 mg/kg orally 120 min before anesthesia and 3 mg/kg IV over the final hour of surgery or an identical placebo. During increasing bolus doses of phenylephrine and nitroprusside (30 ‐300 mg), the maximal systolic pressure responses were recorded at baseline on the day before surgery, before the induction of anesthesia, and 1 and 3 h postoperatively. Sensitivity to phenylephrine and nitroprusside was interpolated from linear regression of the data. There was no difference between preoperative and postoperative sensitivity to phenylephrine or nitroprusside in either group. Clonidine increased sensitivity to phenylephrine versus placebo before and after surgery (response to dose of 1.5 mg/kg: 42 6 14 vs 27 6 8 mm Hg preinduction, 37 6 10 vs 26 6 8 mm Hg 3 h postoperatively; both P , 0.01), but not to nitroprusside (38 6 6v s 376 10 mm Hg preinduction and 40 6 6v s 396 8m m Hg postoperatively). Clonidine increases the sensitivity to phenylephrine but not nitroprusside at baseline and postoperatively in hypertensive patients. Implications: Clonidine increases the sensitivity to bolus injections of the vasoconstrictor phenylephrine, but not the vasodilator sodium nitroprusside, before and after surgery in patients with preexisting hypertension. The doses of vasopressors should be reduced accordingly in hypertensive patients receiving perioperative clonidine. (Anesth Analg 1999;88:1239 ‐43)

Background Patients with essential hypertension show altered baroreflex control of heart rate, and during the perioperative period they demonstrate increased circulatory instability. Clonidine has been shown to reduce perioperative circulatory instability. This study documents changes in measures of heart rate control after surgery in patients with essential hypertension and determines the effects of clonidine on postoperative heart rate control in these patients. Methods Using a randomized double-blind placebo-controlled design, 20 patients with essential hypertension (systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg for > or =1 yr) were assigned to receive clonidine (or placebo), 6 microg/kg orally 120 min before anesthesia and 3 microg/kg intravenously over 60 min before the end of surgery. The spontaneous baroreflex ("sequence") technique and analysis of heart rate variability were used to quantify control of heart rate at baseline, before induction of anesthesia, and 1 and 3 h postoperatively. Results Baroreflex slope and heart rate variability were reduced postoperatively in patients given placebo but not those given clonidine. Clonidine resulted in greater postoperative baroreflex slope and power at all frequency ranges compared with placebo (4.9+/-2.9 vs. 2.2+/-2.1 ms/mm Hg for baroreflex slope, 354+/-685 vs. 30+/-37 ms2/Hz for high frequency variability). Clonidine also resulted in lower concentrations of catecholamine, decreased mean heart rate and blood pressure, and decreased perioperative tachycardia and hypertension. Conclusions Patients with hypertension exhibit reduced heart rate control during the recovery period after elective surgery. Clonidine prevents this reduction in heart rate control. This may represent a basis for the improved circulatory stability seen with perioperative administration of clonidine.

Heart rate variability is a recognized parameter for assessing autonomous nervous system activity. Fourier transform, the most commonly used method to analyze variability, does not offer an easy assessment of its dynamics because of limitations inherent in its stationary hypothesis. Conversely, wavelet transform allows analysis of nonstationary signals. We compared the respective yields of Fourier and wavelet transforms in analyzing heart rate variability during dynamic changes in autonomous nervous system balance induced by atropine and propranolol. Fourier and wavelet transforms were applied to sequences of heart rate intervals in six subjects receiving increasing doses of atropine and propranolol. At the lowest doses of atropine administered, heart rate variability increased, followed by a progressive decrease with higher doses. With the first dose of propranolol, there was a significant increase in heart rate variability, which progressively disappeared after the last dose. Wavelet transform gave significantly better quantitative analysis of heart rate variability than did Fourier transform during autonomous nervous system adaptations induced by both agents and provided novel temporally localized information.

UNLABELLED The rostral ventrolateral medulla (RVLM) controls the vascular system and may contribute to postoperative hypertension. It comprises adrenergic cardiovascular neurons, a site for action of alpha2-adrenergic agonists. Because alpha2 agonists minimize perioperative circulatory activation, we asked the following question: do alpha2 agonists, such as clonidine and mivazerol, blunt the catecholamine activation observed in the RVLM on emergence from anesthesia? Halothane-anesthetized, paralyzed rats had their ventilatory, circulatory, and acid-base stability controlled. All pressure points and incisions were infiltrated with local anesthetics. With in vivo electrochemistry, a catechol signal was recorded in the RVLM during 150 min of stable halothane anesthesia (saline-halothane group); for 120 min after halothane discontinuation (saline-emergence group); after emergence and administration of the reference alpha2 agonist, clonidine 7 microg/kg or 21 microg/kg I.V. (50% or 90% effective dose [ED50 or ED90], respectively); and after emergence and administration of a new alpha2 agonist, mivazerol 20 microg/kg or 150 microg/kg I.V. (ED50 or ED90). Under halothane, dose-response curves for the RVLM catecholamine signal were constructed for mivazerol and an alpha2 antagonist, idazoxan (ED50 2.3 mg/kg I.V.). Stable halothane anesthesia (n = 5) led to no change in mean arterial pressure (MAP), heart rate (HR), or catechol signal (CAOC). During emergence from anesthesia, the MAP, HR, and CAOC increased (n = 5). Clonidine led to a near total suppression of the RVLM catecholamine activation noticed on emergence from anesthesia (n = 5). Hypertension was partially blunted with clonidine 7 microg/kg (n = 5). Tachycardia was partially blunted with mivazerol 20 microg/kg (n = 5). Pretreatment with idazoxan suppressed all the effects of mivazerol (n = 5). IMPLICATIONS On emergence from anesthesia, alpha2 agonists modify the activity of adrenergic cardiovascular neurons located within the vasomotor center, as assessed by in vivo electrochemistry. We provide a rationale for the use of alpha2 agonists on emergence from anesthesia in coronary/hypertensive patients.