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The difficulty of defining the three so-called components of « an-esthesia » is emphasized: hypnosis, absence of movement, and adequacy of anti-nociception (intraoperative « analgesia »). 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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After local anesthesia of all incisions and surgical wounds and myorelaxation with metocurine, rats had halothane withdrawn for 60 min.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.

Objective: Unexpected intraoperative movement may be detrimental during delicate surgery. This study tested retrospectively an algorithm based on beat-by-beat circulatory variables (incorporated into a Cardiovascular depth of anesthesia index: CARDEAN in relationship to unexpected movement, and compared its performance to that of the electroencephalogram (EEG)-derived index: BIS-XP 4.0., Methods: 40 ASA I or II patients presenting for knee surgery had EEG (BIS XP 4.0), beat-by-beat (Finapres) finger non-invasive blood pressure (BP), conventional brachial BP and electrocardiogram (EKG) monitors attached. Anesthesia was induced and maintained with propofol and remifentanil. Before incision, the propofol concentration was set to maintain BIS < 60. From incision to emergence, the anesthesiologist was denied access to BIS or Finapres. Anesthesia adjustment was titrated at the discretion of the anesthesiologist according to conventional signs only: brachial BP, EKG, eyelash reflex, movement. Occurrences of movement and eye signs (divergence of eyeballs, tears, corneal reflex, eyelash reflex) were observed. The CARDEAN algorithm was written retrospectively and tested vs. BIS., Results: 11 movements occurred in 8 patients. CARDEAN > 60 predicted movement in 30% of the cases, 15 to 274 s before movement (sensitivity: 100%, specificity: 95%; relative operating curve ROC = 0.98; prediction probability pk = 0.98). BIS > 60 predicted movement in 19% of cases (sensitivity: 64%; specificity: 94%, ROC: 0.85, pk: 0.85)., Conclusion: Retrospectively, a cardiovascular index predicted unexpected intraoperative movements. Prospective validation is needed.

The rostral ventrolateral medulla (RVLM) controls the vascular system. It may contribute to postoperative hypertension observed upon emergence from anesthesia. This structure contains adrenergic cardiovascular neurons. Therefore, one question was addressed: does a change in RVLM catechol activity occur upon emergence from anesthesia? Halothane-anesthetized, paralyzed rats had their ventilatory, circulatory, and acid-base stability controlled. All pressure points and incisions were infiltrated with local anesthetic. With in vivo electrochemistry, a catechol signal was recorded in the RVLM in the following circumstances: (1) under stable halothane anesthesia for 120 minutes (halothane group), (2) during 120 minutes after halothane discontinuation (saline-emergence group), (3) during 60 minutes after halothane discontinuation followed by 60 minutes after halothane readministration (readministration group), (4) emergence in rats treated with atenolol and nitroprusside to hold blood pressure as close as possible to baseline, (5) emergence after morphine 1 mg.kg(-1) i.v., (6) emergence after decerebration, and (7) emergence upon recording in the mid-brain dopaminergic A10 area. Stable halothane anesthesia (n = 6) led to no change in mean arterial pressure (MAP), heart rate (HR), and catechol signal (CAOC). During emergence from anesthesia (n = 6), MAP, HR, and catechol signal increased and did not return to baseline. By contrast, a return of MAP, HR, and catechol signal to baseline was observed upon readministration of halothane (n = 6). Whereas blood pressure and heart rate were maintained as closely as possible to baseline, a large catechol activation (n = 5) was observed upon emergence from anesthesia. A catechol activation from a lowered baseline was observed upon emergence following morphine administration (n = 5). A minor circulatory activation without RVLM catechol activation was observed upon emergence following decerebration (n = 5). Recordings in the A10 area revealed no increase in the catechol signal following emergence (n = 5). Adrenergic RVLM neurons appear to be responsive upon emergence from anesthesia, possibly being activated by suprapontine afferents impinging on the RVLM.

Unlabelled: The rostral ventrolateral medulla (RVLM) controls the vascular system and may contribute to postoperative hypertension. It comprises adrenergic cardiovascular neurons, a site for action of alpha2-adrenergic agonists. Because alpha2 agonists minimize perioperative circulatory activation, we asked the following question: do alpha2 agonists, such as clonidine and mivazerol, blunt the catecholamine activation observed in the RVLM on emergence from anesthesia? Halothane-anesthetized, paralyzed rats had their ventilatory, circulatory, and acid-base stability controlled. All pressure points and incisions were infiltrated with local anesthetics. With in vivo electrochemistry, a catechol signal was recorded in the RVLM during 150 min of stable halothane anesthesia (saline-halothane group); for 120 min after halothane discontinuation (saline-emergence group); after emergence and administration of the reference alpha2 agonist, clonidine 7 microg/kg or 21 microg/kg I.V. (50% or 90% effective dose [ED50 or ED90], respectively); and after emergence and administration of a new alpha2 agonist, mivazerol 20 microg/kg or 150 microg/kg I.V. (ED50 or ED90). Under halothane, dose-response curves for the RVLM catecholamine signal were constructed for mivazerol and an alpha2 antagonist, idazoxan (ED50 2.3 mg/kg I.V.). Stable halothane anesthesia (n = 5) led to no change in mean arterial pressure (MAP), heart rate (HR), or catechol signal (CAOC). During emergence from anesthesia, the MAP, HR, and CAOC increased (n = 5). Clonidine led to a near total suppression of the RVLM catecholamine activation noticed on emergence from anesthesia (n = 5). Hypertension was partially blunted with clonidine 7 microg/kg (n = 5). Tachycardia was partially blunted with mivazerol 20 microg/kg (n = 5). Pretreatment with idazoxan suppressed all the effects of mivazerol (n = 5)., Implications: On emergence from anesthesia, alpha2 agonists modify the activity of adrenergic cardiovascular neurons located within the vasomotor center, as assessed by in vivo electrochemistry. We provide a rationale for the use of alpha2 agonists on emergence from anesthesia in coronary/hypertensive patients.

The rostral ventrolateral medulla (RVLM) is part of the vasomotor centre which controls the cardiovascular system and may therefore be critical to the genesis of postoperative hypertension. This area is probably a common site of termination of different inputs involved in the baroreflex. It contains at least two classes of neurons exhibiting spontaneous activities and projecting to sympathetic preganglionic neurons located in the intermediolateral cell-column (IML) of the spinal cord. The first class of neurons corresponds to cells with slow axonal conduction velocities (< 0.8 m s-1) and which contain immunoreactive phenylethanolamine-N-methyltransferase (CI cells); the second class, characterized by faster conduction velocities (2.5-8 m s-1), is considered as glutamatergic, although the C1 cells may also release glutamate alongside catecholamine. The purpose of the present study was to investigate the involvement of the "fast-conducting' RVLM barosensitive bulbospinal (RVLM-BB) neurons in the hypertension occurring upon emergence from halothane anaesthesia. Rats were anaesthetized with halothane, paralysed, and their lungs mechanically ventilated. Avoidable pain, distress or discomfort was consistently avoided as required by the fundamental principles of ethical animal research. Hence, all pressure points and surgical wounds, as well as tracheal tube were carefully covered or infiltrated with adequate local anaesthetic. Control experiments have been performed, allowing us to assert that hypertension accompanying halothane withdrawal was not due to suffering (see Discussion). Under halothane anaethesia, fast conducting (2.7 +/- 1.0 m s-1) RVLM-BB neurons (n = 10) exhibited a continuous discharge (8.4 +/- 7.5 Hz). Five minutes after discontinuing halothane, in increase in arterial blood pressure was recorded (AP 19 +/- 6 mmHg), which was accompanied by an increase in the unitary activities (n = 8.43 +/- 23%). Afterwards, both AP and unitary activity frequencies further increased to reach a maximum value at the end of the sequence (34 +/- 9 mmHg and 161 +/- 120% respectively, n = 10). After resumption of halothane administration, both AP and unitary activities fall down to the baseline level within 5 min (n = 10). This study shows that emergence from halothane anaesthesia reversibly induces RVLM-BB units activation, suggesting that a putative glutamatergic bulbospinal pathway may be involved in the genesis of hypertension occurring upon emergence from anaesthesia. These data may therefore contribute to better understanding of postoperative hypertension and to improve its pharmacological treatment in man.

The effects of clonidine, a centrally acting alpha 2-adrenergic receptor agonist, on depth of fentanyl anesthesia and on cardiovascular response to laryngoscopy and intubation were studied. Twenty-four patients undergoing aortocoronary bypass surgery (ACBS) with a history of arterial hypertension, coronary artery disease (NYHA class 3-4), and well-preserved left ventricular function were assigned randomly to either Group 1 (n = 12), who received standard premedication, or Group 2 (n = 12), who received clonidine 5 micrograms X kg-1 po in addition to standard premedication 90 min before estimated induction time. Depth of anesthesia was assessed by on-line aperiodic computerized analysis of the electroencephalogram (Lifescan EEG Monitor). Fentanyl was administered in 250-micrograms increments to shift the EEG to the 0.5-3-Hz frequency range (delta activity) in all subjects. In both groups, the anesthetic regimen effectively prevented hyperdynamic cardiovascular responses to laryngoscopy and intubation. No significant differences in measured or derived hemodynamic variables were observed between the two groups during the awake control period, except for stroke volume index (SVI), which was significantly greater in Group 1, 44 +/- 9 ml X beat-1 X m-2 compared with Group 2, 35 +/- 3.3 ml X beat-1 X m-2 (P less than 0.05). By contrast, fentanyl requirements in Group 2 were significantly reduced by 45% when compared with Group 1, i.e., from 110 +/- 23 to 61 +/- 19 micrograms X kg-1 (P less than 0.001). The authors conclude that at a similar anesthetic depth, as assessed by the EEG shift into the lower frequency range (0.5-3 Hz), a markedly reduced fentanyl dose effectively prevented the hyperdynamic cardiovascular response to laryngoscopy and intubation in the group of patients premedicated with clonidine. This is likely explained by the known synergistic inhibitory action of opiates and alpha 2-adrenoceptor agonists on central sympathetic outflow.

'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.

The effects of clonidine on intraocular pressure and perioperative cardiovascular variables were studied by a randomized double blind design in 80 elderly patients (ASA physical status I-III) scheduled for elective ophthalmic surgery under general anesthesia (GA) and local anesthesia (LA). Group 1 (n = 40), the control group, received diazepam po (0.1 mg.kg-1) 90-120 min prior to arrival to the operating room. Group 2 (n = 40) received clonidine po approximately 5 micrograms.kg-1 po at the same time. Each group was divided into subgroups of 20 patients each to be managed with GA (GA subset) or LA (LA subset). Ninety to 120 minutes after the premedication, a large decrease in IOP from 20 +/- 3 to 12 +/- 3 mmHg (P less than 0.01) and a small but significant reduction of both systolic and diastolic BP and HR were observed in patients receiving clonidine, while no changes occurred in controls. In the patients managed with GA, clonidine effectively prevented IOP rise and attenuated the associated cardiovascular response (P less than 0.01) following laryngoscopy and tracheal intubation, and significantly reduced intraoperative cardiovascular lability and anesthetic requirement for isoflurane (P less than 0.05) and for fentanyl (P less than .001). In patients managed with LA, intraoperative systolic (P less than 0.01) and diastolic BP and HR variability (P less than 0.05) were significantly lower in patients receiving clonidine as compared to controls. Intraoperatively, a significantly higher incidence of hypertension (P less than 0.01) and tachycardia (P less than 0.05) were respectively observed in the LA subset and GA subset of the controls when contrasted with the corresponding subset of those receiving clonidine. Moreover, clonidine was more effective than diazepam as a premedication; in fact, satisfactory intraoperative sedation and cardiovascular stability were observed in 85% of the patients who received clonidine, and in 50% of those patients who did not receive clonidine (P less than 0.01). Thus, clonidine may represent a useful adjunct in the management of the aged patient in the setting of ophthalmic surgery.

In the critical care setting, α-2 agonists present a multifaceted profile: sedation combined with arousability, suppression of delirium, preservation of respiratory drive, reduced O2 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. [ABSTRACT FROM PUBLISHER]

Summary: 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. [ABSTRACT FROM AUTHOR]