Clinical Practice: Should we Radically Alter our Sedation of Critical Care Patients, Especially Given the COVID-19 Pandemics?

The high number of patients infected with the SARS-CoV-2 virus requiring care for ARDS puts sedation in the critical care unit (CCU) to the edge. Depth of sedation has evolved over the last 40 years (no-sedation, deep sedation, daily emergence, minimal sedation, etc.). Most guidelines now recommend determining the depth of sedation and minimizing the use of benzodiazepines and opioids. The broader use of alpha-2 adrenergic agonists ('alpha-2 agonists') led to sedation regimens beginning at admission to the CCU that contrast with hypnotics+opioids ("conventional" sedation), with major consequences for cognition, ventilation and circulatory performance. The same doses of alpha-2 agonists used for 'cooperative' sedation (ataraxia, analgognosia) elicit no respiratory depression but modify the autonomic nervous system (cardiac parasympathetic activation, attenuation of excessive cardiac and vasomotor sympathetic activity). Alpha-2 agonists should be selected only in patients who benefit from their effects ('personalized' indications, as opposed to a 'one size fits all' approach). Then, titration to effect is required, especially in the setting of systemic hypotension and/or hypovolemia. Since no general guidelines exist for the use of alpha-2 agonists for CCU sedation, our clinical experience is summarized for the benefit of physicians in clinical situations in which a recommendation might never exist (refractory delirium tremens; unstable, hypovolemic, hypotensive patients, etc.). Because the physiology of alpha-2 receptors and the pharmacology of alpha-2 agonists lead to personalized indications, some details are offered. Since interactions between conventional sedatives and alpha-2 agonists have received little attention, these interactions are addressed. Within the existing guidelines for CCU sedation, this article could facilitate the use of alpha-2 agonists as effective and safe sedation while awaiting large, multicentre trials and more evidence-based medicine.

Hypothesis: Fever control, a niche for alpha-2 agonists in the setting of septic shock and severe acute respiratory distress syndrome?

During severe septic shock and/or severe acute respiratory distress syndrome (ARDS) patients present with a limited cardio-ventilatory reserve (low cardiac output and blood pressure, low mixed venous saturation, increased lactate, low PaO2/FiO2 ratio, etc.), especially when elderly patients or co-morbidities are considered. Rescue therapies (low dose steroids, adding vasopressin to noradrenaline, proning, almitrine, NO, extracorporeal membrane oxygenation, etc.) are complex. Fever, above 38.5-39.5°C, increases both the ventilatory (high respiratory drive: large tidal volume, high respiratory rate) and the metabolic (increased O2 consumption) demands, further limiting the cardio-ventilatory reserve. Some data (case reports, uncontrolled trial, small randomized prospective trials) suggest that control of elevated body temperature ("fever control") leading to normothermia (35.5-37°C) will lower both the ventilatory and metabolic demands: fever control should simplify critical care management when limited cardio-ventilatory reserve is at stake. Usually fever control is generated by a combination of general anesthesia ("analgo-sedation", light total intravenous anesthesia), antipyretics and cooling. However general anesthesia suppresses spontaneous ventilation, making the management more complex. At variance, alpha-2 agonists (clonidine, dexmedetomidine) administered immediately following tracheal intubation and controlled mandatory ventilation, with prior optimization of volemia and atrio-ventricular conduction, will reduce metabolic demand and facilitate normothermia. Furthermore, after a rigorous control of systemic acidosis, alpha-2 agonists will allow for accelerated emergence without delirium, early spontaneous ventilation, improved cardiac output and micro-circulation, lowered vasopressor requirements and inflammation. Rigorous prospective randomized trials are needed in subsets of patients with a high fever and spiraling toward refractory septic shock and/or presenting with severe ARDS.

Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception.

The difficulty of defining the three so-called components of « an-esthesia ¼ is emphasized: hypnosis, absence of movement, and adequacy of anti-nociception (intraoperative « analgesia ¼). Data obtained from anesthetized animals or humans delineate the activation of cardiac and vasomotor sympathetic reflex (somato-sympathetic reflex) and the cardiac parasympathetic deactivation observed following somatic stimuli. Sympathetic activation and parasympathetic deactivation are used as monitors to address the adequacy of intraoperative anti-nociception. Finally, intraoperative nociception through the administration of nonopioid analgesics vs. opioid analgesics is considered to achieve minimal postoperative side effects.

Acute iterative bronchospasm and "do not re-intubate" orders: sedation by an alpha-2 agonist combined with noninvasive ventilation.

A male patient presented with bronchospasm and acute respiratory distress. The patient had presented 2 previous episodes of severe bronchospasm following abdominal surgery, leading twice to intubation, mechanical ventilation, and conventional sedation. As the patient positively rejected a third episode of intubation + mechanical ventilation, noninvasive ventilation (pressure support = 8 cm H2O, positive end-expiratory pressure = 10 cm H2O), inhaled therapy, and clonidine orally (≈ 4 µg/kg) were combined. Over 1 to 2 hours, the acute respiratory distress disappeared. Noninvasive ventilation was discontinued on the next morning (day 2). The patient was discharged from the critical care unit on day 3 on good condition but died at a later interval from iterative bronchospasm. Evidence-based documentation of the effects of alpha-2 agonists in the setting of acute bronchospasm in the emergency department or status asthmaticus in the critical care unit is awaited.

Pressor Response to Noradrenaline in the Setting of Septic Shock: Anything New under the Sun-Dexmedetomidine, Clonidine? A Minireview.

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, α 2-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 that α 2-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.

Swift recovery of severe hypoxemic pneumonia upon morbid obesity.

A morbidly obese (body mass index = 55.5) female patient presented with severe hypoxemic community acquired pneumonia [PaO2/FiO2 (P/F) = 57] with primarily right basal atelectasis, but without bilateral opacities in the upper lobes on the chest X-ray. Major O2 desaturations led the nurses to object to moving the patient to the prone position: muscle relaxation combined to prone position was impossible. Therefore, stringent 60 degrees reverse Trendelenburg legs down position was constantly maintained during mechanical ventilation through the endotracheal tube, using low pressure support (pressure support = 5-10 cmH2O) and high positive end-expiratory pressure (PEEP). PEEP was progressively increased to 20 cmH2O, and little or no sedation was used. A P/F improvement from 57 to 200 over three days allowed removing the tracheal tube. The patient was discharged 13 days after admission. In this paper, the use of high PEEP in the context of morbid obesity, and low pressure support are discussed.

Is there a place for pressure-support ventilation and high positive end-expiratory pressure combined to alpha-2 agonists early in severe diffuse acute respiratory distress syndrome?

Acute respiratory distress syndrome (ARDS) is associated with a high mortality linked primarily to co-morbidities (sepsis, cardiac failure, multiple organ failure, etc.). When the lung is the single failing organ, quick resolution of ARDS should skip some complications arising from a prolonged stay in the critical care unit. In severe ARDS (PaO2/FIO2=P/F<100 with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O), current recommendations are to intubate the trachea of the patient and use mechanical ventilation, low tidal volume, high PEEP, prone positioning and possibly neuromuscular blockade in association with intravenous sedation. Another strategy is possible. Firstly, spontaneous ventilation (SV) coupled with pressure support (PS) ventilation and high PEEP is possible from tracheal intubation onwards, with the possible exception of the short period following immediately tracheal intubation. Secondly, using alpha-2 adrenergic agonists (e.g. clonidine, dexmedetomidine) can provide first-line sedation from the beginning of mechanical ventilation, as they preserve respiratory drive, lower oxygen consumption and pulmonary hypertension and increase diuresis. Alpha-2 agonists are to be supplemented, if appropriate, by drugs devoid of effect on respiratory drive (neuroleptics, etc.). The expected benefits would be to prevent acquired diaphragmatic weakness, accumulation of sedation, cognitive dysfunction, and presumably improved outcome. This hypothesis should be tested in a double blind randomized controlled trial.

[Dexmedetomidine and clonidine: a review of their pharmacodynamy to define their role for sedation in intensive care patients]. / Dexmédétomidine et clonidine : revue de leurs propriétés pharmacodynamiques en vue de définir la place des agonistes alpha-2 adrénergiques dans la sédation en réanimation.

Alpha-2 adrenergic agonists ("alpha-2 agonists") present multiple pharmacodynamic effects: rousable sedation, decreased incidence of delirium in the setting of critical care, preservation of respiratory drive, decreased whole body oxygen consumption, decreased systemic and pulmonary arterial impedance, improved left ventricular systolic and diastolic function, preserved vascular reactivity to exogenous catecholamines, preserved vasomotor baroreflex with lowered set point, preserved kidney function, decreased protein catabolism. These pharmacodynamic effects explain the interest for these drugs in the critical care setting. However, their exact role for sedation in critically ill-patients remains open for further studies. Given the few double-blind randomized multicentric trials available, the present non exhaustive analysis of the literature aims at presenting the utilization of alpha-2 agonists as potential first-line sedative agents, in the critical care setting. Suggestions regarding the use of alpha-2 agonists as sedatives are detailed.

Dexmedetomidine and clonidine: from second- to first-line sedative agents in the critical care setting?

In the critical care setting, α-2 agonists present a multifaceted profile: sedation combined with arousability, suppression of delirium, preservation of respiratory drive, reduced O(2) consumption, preserved renal function, and reduced protein metabolism. In addition, this review details the reduced arterial impedance, improved left ventricular performance, preserved vascular reactivity to exogenous amines, preserved cardiac baroreflex reactivity, preserved vasomotor baroreflex activity combined with a lowered pressure set point: these features may explain the good tolerance observed when α-2 agonists are used as continuous infusion without any loading dose. Reviewing the literature allows one to suggest that a new management appears possible with arousable sedation. However, it remains to be demonstrated whether this arousable sedation can be combined with the preservation of spontaneous ventilation, in the setting of severe respiratory distress, as opposed to conventional controlled mechanical ventilation combined with conventional sedation. Should such a speculative view be confirmed, then α-2 agonists will move from second-line sedative agents to first-line sedative agents. However, key studies are lacking to demonstrate the effect of α-2 agonists on physiological endpoints and outcome. Presently, the existing body of data suggests a niche for the use of α-2 agonists in the critical care setting.

Combination of clonidine sedation and spontaneous breathing-pressure support upon acute respiratory distress syndrome: a feasibility study in four patients.

INTRODUCTION: As alpha-2 agonists preserve ventilator drive, patients presenting with acute respiratory distress syndrome (ARDS, Pa02/FiO2 < 200) were managed using sedation with an alpha-2 agonist, clonidine, combined to spontaneous ventilation (SV) + pressure support ventilation (PS). METHODS: Sedation was provided by an alpha-2 agonist, clonidine 1-2 microg x kg(-1( x h(-1), without bolus administration, and supplemented with a neuroleptic, loxapine, if needed. Four patients presenting with ARDS were managed with pressure support ventilation (PS = 8 cm H20,rarely 10-12 cm H20) and high PEEP (10-20 cm H20). Energy requirements were minimized, if appropriate, with hypothermia caused by extra-renal replacement therapy or intentional hypothermia (35-36 degrees C). Repeated echocardiographic examinations revealed no right ventricular failure. RESULTS: Recovery of ARDS, i.e. sustained increase of P/F > 200 for > 24 h, was observed, over 2-5 days. CONCLUSION: Use of an alpha-2 agonist as first-line sedative agent led to absence of respiratory depression and spontaneous ventilation. Upon ARDS, the lowered intrathoracic pressure observed with SV+PSV allowed one to recruit alveoli with high levels of PEEP, without impairing right ventricle function.

Alpha-2 agonists to reduce vasopressor requirements in septic shock?

One of the unsolved problems of septic shock is the poor responsiveness, or reduced vascular reactivity, to vasopressors used to increase blood pressure (BP). Attempts to restore vascular reactivity with NO inhibitors or low dose steroids have met with little success. Low vascular reactivity, which may lead to refractory shock and death, is linked to desensitization or down-regulation of alpha-1 adrenergic receptors. Our working hypothesis is that the use of alpha-2 agonists (e.g. clonidine or dexmedetomidine) in septic shock, in addition to the state-of-the-art treatment (including volume load and vasopressors), will reduce the vasopressor requirements needed to restore adequate BP. This counter-intuitive proposal is based on the fact that alpha-2 agonists will reduce the massive release of endogenous catecholamines. A decrease in plasma endogenous catecholamine concentrations will be followed by reduced down-regulation of alpha-1 receptors and/or a gradual re-sensitization of alpha-1 adrenergic receptors. In turn, this will lead to lowered vasopressor requirement, with respect to dose and duration. Our hypothesis, based on a reverse "denervation hypersensitivity", is at variance with accepted treatments, which rest only on volume load and vasopressors and emphasizes restoration of blood pressure per se. Several observations in the cardiology and anesthesia setting have shown increased vascular reactivity following alpha-2 agonist administration. Our preliminary observations in the setting of septic shock again suggest such increased vascular reactivity. Improved outcome was also observed. Rigorous work is warranted to verify reduced vasopressor requirement and improved outcome, when an alpha-2 agonist is combined with state-of -the-art treatment of septic shock.

Cardiac baroreflex during the postoperative period in patients with hypertension: effect of clonidine.

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.

Clonidine for major vascular surgery in hypertensive patients: a double-blind, controlled, randomized study.

The utility of clonidine for hypertensive patients presenting for major vascular procedures remains debatable. Twenty-one hypertensive patients presenting for aortic surgery were given clonidine (n = 11) or placebo (n = 10) in a double-blind, randomized manner. Clonidine was administered 6 micrograms/kg per os 120 min before induction of anesthesia and 3 micrograms/kg intravenously (i.v.) over 60 min from aortic declamping to skin closure. Anesthesia was induced with alfentanil 20 micrograms/kg, midazolam, and atracurium and maintained with nitrous oxide 70%, an alfentanil infusion (0.25 microgram.kg-1. min-1), and isoflurane. Anesthetic requirements, circulatory variables, interventions, and isoproterenol dose-response curves (pre- and postoperatively) were determined. Plasma concentrations of clonidine, alfentanil, and vasoactive hormones were measured. When the clonidine group was compared with the placebo group, (a) isoflurane, alfentanil, and midazolam requirements were reduced by 38%, 42%, and 41%, respectively (P = 0.04, 0.03, 0.0002, respectively); (b) supplemental circulatory and anesthetic adjustments were reduced by 51% (P = 0.0006); (c) interventions with vasopressors were not significantly increased (placebo: two; clonidine: five); (d) systolic and mean arterial pressures and heart rate were reduced; (e) increases in norepinephrine, epinephrine, and plasma renin activity were suppressed, whereas vasopressin surge was attenuated; and (f) chronotropic response to isoproterenol was unaffected. Clonidine was effective in reducing anesthetic requirements and in improving circulatory stability in hypertensive patients presenting for major vascular procedures.

Effect of clonidine on the circulation and vasoactive hormones after aortic surgery.

After completion of abdominal aortic graft, 29 patients received an i.v. infusion of placebo (n = 16) or clonidine 7 micrograms kg-1 (n = 13) over 120 min in a double-blind study. Cardiovascular variables were measured and plasma samples obtained up to 5 h after arrival in the recovery room, for assay of noradrenaline, adrenaline, vasopressin and renin concentrations. Noradrenaline, adrenaline and vasopressin concentrations decreased in the clonidine group throughout recovery (P less than 0.001, 0.05 and 0.05, respectively, vs placebo). Heart rate was less in the clonidine group (P less than 0.01). There was no significant difference in mean arterial pressure between groups. Stroke volume was larger (P less than 0.01) and there were fewer episodes of hypertension (P less than 0.05) and tachycardia in the clonidine group. In addition, a reduction in the number of circulatory interventions (P less than 0.05) and episodes of shivering was noted in the clonidine group. Mean (SD) postoperative volume requirements were larger in the clonidine group (total postoperative input: clonidine 1462 (604) ml; placebo 1064 (348) ml (P less than 0.05]. These data are consistent with the observation that clonidine modifies endocrine and circulatory status after major surgery.

Aortic surgery: effect of clonidine on intraoperative catecholaminergic and circulatory stability.

Twenty-eight patients presenting for aortic surgery were randomly assigned in a double-blind, placebo-controlled protocol to receive placebo (n = 14) or clonidine (4.7 +/- 1.2 micrograms.kg-1 po; n = 14), in addition to flunitrazepam 120 min before induction of anesthesia. Plasma catecholamines (CA) and hemodynamic variables were determined at 7 stages during surgery. In the placebo group, plasma epinephrine (E) and norepinephrine (NE) had risen twofold at skin closure compared to baseline (E: from 109 +/- 51 pg.ml-1 to 294 +/- 161 pg.ml-1; NE: from 658 +/- 226 to 1150 +/- 494 pg.ml-1). Plasma CA were significantly lower in the clonidine group (P less than 0.001 and 0.01 vs placebo for NE and E respectively). In both groups, similar directional changes were observed for the circulatory variables, upon aortic clamping and declamping. In the clonidine group, however, mean arterial pressure was lower at most stages (P less than 0.05 vs placebo); moreover, stroke volume index was greater in the clonidine group (P less than 0.05) upon declamping. This improved stability in the clonidine group was achieved with a halving in the number of anesthetic/circulatory interventions (P less than 0.05 vs placebo). Provided intravascular volume is adequate, clonidine suppresses the increase in plasma catecholamines induced by aortic surgery and improves circulatory stability, with a reduced number of anesthetic, circulatory adjustments.