Bellomo achieved RASS ~ − 4, in both groups (results 1): The dex group received also propofol (95% of the patients), midazolam (43%) and higher doses of opioids (Table S1 1). ...any effect of dex is ...drowned as a consequence of adding usual sedation to dex. In such a setting, the effect of dexmedetomidine is markedly attenuated by the impact of these drugs. ...we agree that it is all the more remarkable that, in the dexmedetomidine group, the overall norepinephrine (noradrenaline) requirements were lower and that the dose required to achieve target mean arterial pressure was also decreased. ...we agree that comparing patients on dexmedetomidine only versus patients receiving usual care would be ideal. Nonetheless, within the limitations of the design and the population studied, we think that our findings are consistent with a substantial body of experimental data supporting the view that, in the septic, vasodilated state, dexmedetomidine (and central alpha-2 agonists) infusion does not exacerbate hypotension or increase vasopressor requirements but, in fact, appears to do the opposite 6,7,8,9.
Non‐technical summary
It is still unknown how the autonomic nervous system influences the fractal dynamics of cardiovascular signals. We show that in supine volunteers vagal and sympathetic outflows ...contribute differently to the fractal structures of heart rate and blood pressure. The vagal outflow contributes with a ‘white‐noise’ component to the heart rate dynamics, indirectly influencing also the fractal dynamics of blood pressure. The sympathetic outflow contributes with a Brownian motion component to the heart rate dynamics, increasing long‐term fractal coefficients, without affecting long‐term coefficients of blood pressure. Results are explained by the different distribution and dynamics of acetylcholine receptors and of α‐ and β‐adrenergic receptors. Our findings may allow better delineating alterations of cardiovascular fractal dynamics in physiological and pathophysiological settings.
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 β‐adrenergic receptors between heart and vasculature.
1 Institut National de la Santé et de la Recherche Médicale E107, Faculté de Médecine, 75006 Paris; 2 Laboratoire d'Exploration Fonctionnelles Vasculaires, CHU, 49033 Angers; 3 Laboratoire ...d'Explorations Fonctionnelles Rénales, Hôpital Jean Minjoz, 25030 Besançon; 5 CNRS UMR 5014, Facultéde Pharmacie, 69373 Lyon; 6 Laboratoire de Physiologie, Centre National de la Recherche Scientifique UMR 1523, Faculté de Médecine, 69373 Lyon, France; 4 LaRC, Unita' di Bioingegneria, Fondazione Don Carlo Gnocchi, 20148 Milano; 9 Department of Internal Medicine, University of Milano-Bicocca, II Department of Cardiology, San Luca Hospital, Istituto Auxologico Italiano, 20145 Milano; 11 Dipartimento di Scienze Precliniche, Universita' degli Studi di Milano, LITA di Vialba, 20157 Milano, Italy; 7 CARIM, Department of Pharmacology and Toxicology, 6200 Maastricht; 8 Department of Physiology, Academisch Medisch Centrum, 1105 AZ Amsterdam, The Netherlands; 10 Institut für Physiologie, Humboldt Universität, 10117 Berlin; 12 Institute of Occupational and Social Medicine, University of Technology, 01307 Dresden, Germany; and 13 Department of Exercise Science, The University of Iowa, Iowa City, Iowa 52242
Submitted 18 November 2002
; accepted in final form 12 September 2003
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 -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.
baroreceptor reflex; autonomic nervous system; spectral analysis; sequence technique
Address for reprint requests and other correspondence: D. Laude, INSERM E107, Faculté de Médecine, 15 rue de l'Ecole de Médecine, 75006 Paris, France (E-mail: dlaude{at}bhdc.jussieu.fr ).
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,
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,
, 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.
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), O
2
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.
Highlights ► Dexmedetomidine and clonidine are commonly used alpha-2 adrenoceptor agonists. ► Whether they depress breathing in the critical care setting is under debate. ► We then examined their ...effects on the mouse respiratory rhythm generator in vitro . ► Both drugs facilitated its activity and prevented its depression by benzodiazepine. ► Our results support dexmedetomidine and clonidine use in the critical care setting.
Introduction
Refractory septic shock (RSS) is characterized by high vasopressor requirements, as a consequence of vasopressor resistance, which may be caused or enhanced by sympathetic ...hyperactivation. Experimental models and clinical trials show a reduction in vasopressor requirements and improved microcirculation compared to conventional sedation. Dexmedetomidine did not reduce mortality in clinical trials, but few septic shock patients were enrolled. This pilot trial aims to evaluate vasopressor re-sensitization with dexmedetomidine and assess the effect size, in order to design a larger trial.
Methods
This is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, comparing dexmedetomidine versus placebo in RSS patients with norepinephrine dose ≥0.5μg/kg/min. The primary outcome is blood pressure response to phenylephrine challenge, 6 hours after completion of a first challenge, after study treatment initiation. Secondary outcomes include feasibility and safety outcomes (bradycardia), mortality, vasopressor requirements, heart rate variability, plasma and urine catecholamines levels. The sample size is estimated at 32 patients to show a 20% improvement in blood pressure response to phenylephrine. Randomization (1:1) will be stratified by center, sedation type and presence of liver cirrhosis. Blood pressure and ECG will be continuously recorded for the first 24 h, enabling high-quality data collection for the primary and secondary endpoints. The study was approved by the ethics committee “Sud-Est VI” (2019-000726-22) and patients will be included after informed consent.
Discussion
The present study will be the first randomized trial to specifically address the hemodynamic effects of dexmedetomidine in patients with septic shock. We implement a high-quality process for data acquisition and recording in the first 24 h, ensuring maximal quality for the evaluation of both efficacy and safety outcomes, as well as transparency of results. The results of the study will be used to elaborate a full-scale randomized controlled trial with mortality as primary outcome in RSS patients.
Trial registration
Registered with ClinicalTrials.gov (NCT03953677). Registered 16 May 2019,
https://clinicaltrials.gov/ct2/show/NCT03953677
.
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