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.

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.

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.

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.

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.

Continuous volume infusion improves circulatory stability in anesthesized rats.

'Optimized' management (OM) was provided to chloralose-anesthetized rats for 12 h by combining continuous infusion (7 ml.kg-1). mechanical ventilation and strict control of acid-base equilibrium (n = 7). The chloralose-anesthetized rats managed conventionally (conventional management: CM, n = 9) received neither volume infusion, nor mechanical ventilation, nor correction of acid-base disturbances. All the OM rats completed the study while 6 out of 9 CM rats died before the end of the study period. Mean arterial pressure (MAP) remained at 100 mmHg for 12 h in the OM group. MAP stayed close to 70 mmHg in the CM group for 6 h and declined to very low levels thereafter (mean +/- S.E.M.: 46.0 +/- 3.9 mmHg at 12 h, P less than 10(-4) when compared to the other group). Central venous pressure and cardiac output remained close to baseline values for 12 h in the OM group. Acid-base equilibrium was preserved in the OM group in contrast to a severe metabolic acidosis in the CM group (pH = 7.14 +/- 0.03 at 12 h; P less than 10(-4). Such as 'optimized' management involving mechanical ventilation with oxygen, continuous infusion and acid-base monitoring may be of value to maintain circulatory stability in anesthetized rodent preparations during long periods of time, as in neurophysiological experiments.

Clonidine modulates the ventrolateral medullary catechol metabolic hyperactivity induced by hypotension.

In vivo electrochemistry allowed recording of a catechol oxidation current in the ventrolateral medulla, caudal to the obex, in anesthetized rats whose ventilatory, metabolic and hemodynamic parameters were rigorously controlled. Hemorrhage or controlled hypotension induced an increase in the metabolism of catecholamines in the A1 noradrenergic group, which remained activated after full hemodynamic recovery. Clonidine (200 micrograms.kg-1 i.p.) given 30 min prior to hemorrhage or immediately before controlled hypotension suppressed partially the increased metabolism of catecholamines especially during the recovery period. This suggests that clonidine preserved phasic reactivity upon circulatory disturbances and decreased tonic hyperactivity following circulatory recovery.

Catecholamine metabolism in the rat locus coeruleus as studied by in vivo differential pulse voltammetry. III. Evidence for the existence of an alpha 2-adrenergic tonic inhibition in behaving rats.

One of the various regulations controlling the noradrenergic (NA) locus coeruleus (LC) activity has been proved to be alpha 2 adrenergic specific, on the basis of electrophysiological data obtained in anesthetized preparations. To assess, under rigorously chronic conditions, the existence of such an inhibition, recordings of LC catechol metabolic activity were performed with in vivo differential pulse voltammetry. A guiding cannula and appropriate wires were implanted under anesthesia. After 48 h of recovery a carbon fiber electrode was threaded to the LC through this cannula to monitor the LC catechol oxidation current. Piperoxane 60 mg/kg i.p. and yohimbine 10 mg/kg i.p. induced an increase in catechol oxidation current to approximately 300% of baseline (100%) values. Graded doses of piperoxane (1-100 mg/kg i.p.) induced a dose dependent increase in LC catechol metabolic activity (ED50 = 29.7 mg/kg). These changes in catechol oxidation current were confirmed either by combined electrophysiological and electrochemical recordings in the LC of an anesthetized preparation, or by postmortem HPLC catechol determinations on LC microdissections. By contrast, guanfacine 1 mg/kg and clonidine (10-200 micrograms/kg i.p.) induced a dose dependent decrease in catechol peak height. Clonidine 50 micrograms/kg reversed the effect of piperoxane 30 mg/kg i.p. On the other hand, a highly selective alpha 1 antagonist, such as prazosin (1 mg/kg i.p.), evoked only a small increase in catechol peak (11% above saline effect). This data is consistent with previously reported electrophysiological, biochemical and autoradiographic data. They confirm the presence of a tonic alpha 2 adrenergic inhibition on NA-LC cell activity, in behaving rats.

Baroreflex-linked variations of catecholamine metabolism in the caudal ventrolateral medulla: an in vivo electrochemical study.

In vivo electrochemical recordings of the metabolism of catecholamines were obtained in the caudal ventrolateral medulla in anesthetized rats submitted to various experimental changes in systemic arterial pressure. Hypertension induced with phenylephrine and reversal of hypovolemia decreased the catechol metabolic activity. In contrast, controlled or hypovolemic hypotension, induced respectively with sodium nitroprusside or blood withdrawal (30% of blood volume), reversibly elicited the opposite pattern. This was suppressed by deafferentation. The changes in catechol metabolic activity in response to hypovolemia were accompanied by similar trends of variations of plasma vasopressin levels. By contrast with the increased catechol metabolic activity secondary to hypotension induced by either prazosin, sodium nitroprusside or hypovolemia, clonidine elicited a decrease in catechol metabolic activity. These data show a dynamic and specific involvement of the metabolism of catecholamines themselves promoted by changes in systemic arterial pressure. This pattern of functioning of catechol metabolism in the caudal ventrolateral medulla appears to be negatively related to systemic arterial pressure changes, a finding which does not fit with the proposed vasodepressor role of the A1-group.

Clonidine modulates locus coeruleus metabolic hyperactivity induced by stress in behaving rats.

To assess, under rigorously chronic conditions, whether clonidine would modulate the increased activity engendered by stress in the locus coeruleus (LC), rats implanted for recordings by in vivo voltammetry, were subjected to immobilization (10 min). When injected 30-60 min before stress, clonidine 50-200 micrograms/kg i.p. modulated the increased catechol metabolic activity in a dose-dependent manner. This provides a biochemical basis, obtained in behaving rats, for using clonidine as a stabilizer in syndromes where central noradrenergic or peripheral sympathetic activities are heightened.

Presynaptic effect of clonidine on unmyelinated afferent fibers in the spinal cord of the cat.

The effects of clonidine (Clo) were investigated on the excitability of intraspinal primary afferent terminals of both A- and C-fibers of cutaneous origin. Primary afferent terminal excitability was tested by delivering constant current pulses to the dorsal horn of acutely spinalized cats anesthetized with pentobarbital. Clo given i.v. selectively increased the excitability of the C-fiber primary afferent terminals (mean 85%). Primary afferent terminal excitability of A-fibers was not affected. This effect of Clo was reversed by yohimbine or phentolamine, thus suggesting mediation by alpha2-adrenoceptors. These findings suggest a presynaptic inhibitory effect of Clo in spinal nociceptive pathways that might explain the mechanism of action of this drug.

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.

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.