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.

Clonidine and dexmedetomidine increase the pressor response to norepinephrine in experimental sepsis: a pilot study.

OBJECTIVE: During septic shock, vasopressors are a cornerstone of therapy. In septic shock, very high doses of vasopressors sometimes have to be used due to vascular desensitization, the mechanisms of which are poorly understood. This study assesses whether α-2 agonists increase pressor responsiveness following lipopolysaccharide administration. DESIGN: Parallel groups of animals (n = 7 per group) subjected to pharmacologic interventions. SETTING: Physiology laboratory. SUBJECTS: Rats. INTERVENTIONS: In anesthetized rats, the pressor responses to increasing doses of norepinephrine (norepinephrine-systolic pressure curve) were assessed during a baseline period, after injection of saline or lipopolysaccharide, and after subsequent injection of saline, dexmedetomidine (100 µg/kg IV), or clonidine (200 µg/kg IV). MEASUREMENTS AND MAIN RESULTS: Differences in the slopes of the norepinephrine-pressure curves were assessed across drug treatments and intervals. The pressor dose of norepinephrine necessary to increase systolic pressure by 33 and 100 mm Hg (pressor dose 33 and pressor dose 100) was determined. Pressor responsiveness to norepinephrine decreased slightly over time in the saline-saline group (saline 1 or 2 vs baseline: mean decrease of the slope, 2 mm Hg/µg/kg norepinephrine; p < 0.05), whereas there was a large decrease after lipopolysaccharide (lipopolysaccharide vs baseline: mean decrease of the slope, 7.2; p < 0.001). Clonidine alone had no effect, but when administered following lipopolysaccharide, it caused a striking increase in pressor responsiveness (mean slope after lipopolysaccharide, 10.7 [95% CI, 9.9-11.6]; after clonidine, 17.5 [95% CI, 16.7-18.4]). Similarly, dexmedetomidine administered after lipopolysaccharide caused a large increase in pressor responsiveness above lipopolysaccharide values. Accordingly the pressor dose 33 and pressor dose 100 values were lowered following lipopolysaccharide and restored by α-2 agonists. CONCLUSIONS: The pressor response to norepinephrine was reduced following lipopolysaccharide and increased to baseline levels following α-2 agonists.

Surgical Instrument Designers and Inventors-Where are the Women?

Historically, surgical instruments were designed by men for male surgeons. Although instrumentation has changed with the changing paradigms of surgery, it has failed to adapt to the changing surgical workforce. Almost 30% of surgeons are female and nearly 90% of surveyed female surgeons report poor instrument design and associated musculoskeletal injuries from use. Understanding the current state of handheld surgical instrument design, published literature was reviewed, surgical instrument collections were contacted, and the U.S. Patent and Trademark databases were queried to identify public patents and pre-granted applications of female inventors of handheld surgical instruments. Twenty-five female inventors were identified from published literature and 1551 unique females hold patents. This number pales when the denominator of male inventors is considered. Hence, to address the female surgeon's lack of instrumentation and design, there is a critical need for participatory ergonomics whereby both the female surgeon and engineer collaborate on design.

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.

A beat-by-beat, on-line, cardiovascular index, CARDEAN, to assess circulatory responses to surgery: a randomized clinical trial during spine surgery.

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, P < 0.05), while it did not increase in the remifentanil Ce = 4 ng ml(-1) group (n = 7, P = 0.18). During surgery, retrospectively, CARDEAN > 60 was associated with tachycardia and hypertension (P (k) = 0.81 ± 0.10). Changes in CARDEAN appeared linked to adequacy of anti-nociception.

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.

Recruitment of cardiac parasympathetic activity: effects of clonidine on cardiac vagal motoneurones, pressure lability, and cardiac baroreflex slope in rats.

BACKGROUND: Association of low cardiac vagal activity and poor outcome is demonstrated in the cardiology setting. This has not been addressed in the postoperative setting. Cardiac vagal motoneurones (CVMs) in the brain stem generate sinus arrhythmia. They may reduce blood pressure (BP) variability ('pressure lability'). An alpha-2 agonist, clonidine, was administered to assess whether cardiac vagal activity could be recruited from a very low baseline activity, increase the sensitivity of the cardiac baroreflex and sinus arrhythmia, and reduce the pressure lability. METHODS: In ventilated anaesthetized rats, single-unit activity from antidromically identified CVMs was recorded. Given complex interactions within the cardiac ganglion, a peripherally acting beta-blocker, atenolol, was administered before clonidine. RESULTS: Atenolol 2 mg kg(-1) i.v. did not change systolic BP (SBP), CVM firing rate and slope of the cardiac baroreflex analysed at CVM (SBP-CVM unit activity relationship) level, or at the heart level (SBP-RR interval relationship) but evoked a significant bradycardia. In the presence of atenolol 2 mg kg(-1) h(-1), clonidine 10-100 microg kg(-1) i.v. evoked a significant reduction in SBP, a large increase of CVM firing rate from a very low base line [0.16 (sd 0.28) to 1.37 (1.21) spikes s(-1), n=7 cells], and increased the slope of the cardiac baroreflex analysed at the CVM level or at the heart level. sds of SBP were reduced, and that of RR interval was increased. CONCLUSIONS: Following peripheral beta-blockade, clonidine activated CVMs from a very low baseline, increased the slope of the cardiac baroreflex and sinus arrhythmia, and reduced pressure lability.

Reduced blood pressure lability during emergence from anaesthesia in rats: a pilot study using clonidine.

BACKGROUND: In the post-operative setting, pressure lability is increased in hypertensive patients. alpha-2 agonists were shown qualitatively to reduce this lability qualitatively. Here, upon immobilization combined with emergence from anesthesia in rats and clonidine administration, pressure lability was quantitatively assessed and related to baroreflex sensitivity. METHODS: After local anesthesia of all incisions and surgical wounds and myorelaxation with metocurine, rats had halothane withdrawn for 60 min. Rats received (a) saline (n=8), (b) clonidine 30 microg/kg i.v (n=8) simultaneous to halothane discontinuation and (c) halothane readministration (n=8) 20 min after halothane discontinuation. Pressure lability was quantitatively assessed using occurrence/amplitude of peaks in systolic blood pressure (SBP) and cardiac baroreflex slope. RESULTS: Clonidine was associated with partial blunting of hypertension, reduced standard deviation of SBP, reduced number and amplitude of peaks in systolic pressure. Clonidine was also associated with increased slope of the cardiac baroreflex upon early intervals of emergence, but not at later intervals. CONCLUSION: Clonidine reduces pressure lability upon immobilization stress combined to emergence from anesthesia, via parasympathetic activation and possibly sympathetic inhibition during early emergence as opposed to sympathetic inhibition during late emergence.

Post-operative pressure lability and cardiac baroreflex in normotensive patients as a function of age.

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 CO(2) 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<0.09) existed between the slope of the cardiac baroreflex and pressure lability, irrespective of age. During the early post-operative period, young patients returned to their baseline slope of the cardiac baroreflex; no inverse relationship between increased SD of SBP and decreased SD of RR interval was observed. Middle-aged and elderly patients displayed a depressed slope of the cardiac baroreflex both before and after anesthesia. CONCLUSION: At variance with the pre-operative period, no simple inverse relationship was observed between increased pressure lability and depressed HR variability in young patients during the early post-operative period.

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.

Spontaneous cardiac baroreflex in humans. Comparison with drug-induced responses.

We compared two methods of assessment of baroreflex sensitivity in eight supine healthy volunteers during repeated baseline measurements and various conditions of cardiac autonomic blockade. The spontaneous baroreflex method involved computer scanning of recordings of continuous finger arterial pressure and electrocardiogram to locate sequences of three or more beats in which pressure spontaneously increased or decreased, with parallel changes in pulse intervals. The mean regression slope of all these sequences during each study condition was considered to represent the mean spontaneous baroreflex slope. In the drug-induced method, sigmoidal curves were constructed from data obtained by bolus injections of phenylephrine and nitroprusside; the tangents taken at the resting pressure of each of these curves were compared with the mean spontaneous baroreflex slopes. The two methods yielded slopes that were highly correlated (r = .96, P < .001), with significant but similar intraindividual baseline variability. Atropine virtually eliminated the baroreflex slope; subsequent addition of propranolol did not alter it further. Propranolol or clonidine alone increased average baroreflex slope to the extent that they increased resting pulse interval (r = .69 to .83). The spontaneous baroreflex method provides a reliable, noninvasive assessment of human vagal cardiac baroreflex sensitivity within its physiological operating range.

Variations in 3,4-dihydroxyphenylacetic acid concentration are correlated to single cell firing changes in the rat locus coeruleus.

The purpose of this study is to see whether variations in the catechol oxidation peak in the locus coeruleus would be closely related with variations in single cell firing, and would be independent of the mechanism triggering the variation of neuronal activity. Single unit and electrochemical (differential pulse voltammetry) recordings were performed, respectively on the left and right locus coeruleus of anaesthetized rats. The variations in single unit activity were induced using well known stimulatory mechanisms (yohimbine, hypovolemia, indirect activation using a 5-hydroxytryptamine central agonist RU 24969, RU 24722 known to activate noradrenergic metabolism), or inhibitory (clonidine, morphine) models. This was done in addition to successive activation or inhibition (reversal of oxotremorine with scopolamine, antagonism of clonidine by piperoxane). In all the experimental conditions, variations in the catechol oxidation current followed variations in single cell activity. Furthermore, the catechol oxidation current variations correlated significantly to changes in the firing rate. Such a close correlation between a catechol oxidation peak, and the electrical activity of the locus coeruleus cell bodies supports the use of catechol oxidation current variations as a good indirect index of functional activity in noradrenergic locus coeruleus perikarya. This suggests a close relationship between dopamine metabolism and electrical activity in locus coeruleus cell bodies.

Pharmacological and functional evidence for extracellular 3,4-dihydroxyphenylacetic acid as an index of metabolic activity of the adrenergic neurons: an in vivo voltammetry study in the rat rostral ventrolateral medulla.

Catecholamine metabolism was studied in vivo in the C1 adrenergic area of the rostral ventrolateral medulla oblongata in rats, using differential normal pulse voltammetry coupled with an activated carbon fiber microelectrode. Pharmacological evidence indicates that 3,4-dihydroxyphenylacetic acid, the major dopamine metabolite, is responsible for the electrochemical signal appearance in the C1 group, and that it reflects the catecholamine synthesis rate, as previously reported in the locus coeruleus. Indeed, 3,4-dihydroxyphenylacetic acid was estimated to be formed from 77% of the intracellular dopamine, since its synthesis was increased by only 23%, after blockade of the dopamine-beta-hydroxylase activity. Neuronal activation by retrograde electrical stimulation increased the electrochemical signal, as well as hemorrhage and hypotension, suggesting that the level of extracellular 3,4-dihydroxyphenylacetic acid is a good biochemical index of the C1 adrenergic cellular activity in baseline conditions and during cellular activation.