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.

A centrally acting antihypertensive, clonidine, combined to a venous dilator, nitroglycerin, to handle severe pulmonary edema.

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.

Clonidine Restores Pressor Responsiveness to Phenylephrine and Angiotensin II in Ovine Sepsis.

OBJECTIVES: In sepsis, prolonged, sympathetic overstimulation may lead to vasopressor-refractory hypotension. We therefore examined the effects of the α2-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 vehicle-treated 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.

Avoiding, Not Managing, Drug Withdrawal Syndrome in the Setting of COVID-19 Acute Respiratory Distress Syndrome. Comment on Ego et al. How to Manage Withdrawal of Sedation and Analgesia in Mechanically Ventilated COVID-19 Patients? J. Clin. Med. 2021, 10, 4917.

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

How should dexmedetomidine and clonidine be prescribed in the critical care setting? / Como a dexmedetomidina e a clonidina devem ser prescritas no ambiente de terapia intensiva?

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.

Dexmedetomidine to reduce vasopressor resistance in refractory septic shock: Protocol for a double-blind randomized controlled pilot trial (ADRESS Pilot study).

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.

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.

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.

Is the Sympathetic System Detrimental in the Setting of Septic Shock, with Antihypertensive Agents as a Counterintuitive Approach? A Clinical Proposition.

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.

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.