Marco Ghignone

Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation.

The effects of clonidine, a centrally acting α2-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 pre-medication, or Group 2 (n = 12), who received clonidine 5 μ;g·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-μ;g 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 · beat-1 · M-2 compared with Group 2, 35 ± 3.3 ml · beat-1 · m-2 (P < 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 μ;g· kg-1(P < 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 α2-adrenoceptor agonists on central sympathetic outflow.

Anesthesia and hypertension: the effect of clonidine on perioperative hemodynamics and isoflurane requirements

Thirty patients (ASA physical status II-III) with a history of arterial hypertension, whose blood pressure (BP) control varied from normotension to moderate hypertension (diastolic BP < 110 mmHg), scheduled for elective surgery under general anesthesia, were randomly assigned to two groups. Group 1 was premedicated 90–120 min prior to induction with diazepam 0.15 mg · kg1 po; group 2, in addition, received clonidine 5 μg · kg1 po. Anesthetic depth was assessed by on-line aperiodic analysis of the electroencephalogram. Following lidocaine 1 mg · kg1 and fentanyl 2 μg · kg1 (group 1 only), anesthesia was induced with thiopental 3–4 mg · kg1 and vecuronium 0.1 mg · kg1 was used to facilitate endotracheal intubation. Anesthesia was maintained with isoflurane in N2O/O2 and supplemented by fentanyl. In group 2, clonidine produced a rapid preoperative control of systolic and diastolic BP from 166 ± 32/95 ± 14 to 136 ± 80 ± 11 (P < 0.01), was more effective in blunting the reflex tachycardia associated with laryngoscopy and endotracheal intubation than lidocaine-fentanyl pretreatment. It significantly reduced the intraoperative lability (coefficient of variation) of systolic (P < 0.01) and diastolic BP and heart rate (HR) (P < 0.05), and resulted in significantly slower HR during recovery (P < 0.01). Anesthetic requirements for isoflurane were reduced 40% (P < 0.01) in group 2; narcotic supplementation was also significantly reduced (P < 0.005). The authors conclude that these effects of clonidine are explained by the inhibitory action of clonidine on central monoaminergic systems involved in cardiovascular control, modulation of sleep/wake cycle, cortical arousal, and of nociception.

Anesthesia for ophthalmic surgery in the elderly: the effects of clonidine on intraocular pressure, perioperative hemodynamics, and anesthetic requirement.

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 μg ± 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 < 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 < 0.01) following laryngoscopy and tracheal intubation, and significantly reduced intraoperative cardio vascular lability and anesthetic requirement for isoflurane (P < 0.05) and for fentanyl (P < 0.01). In patients managed with LA, intraoperative systolic (P < 0.01) and diastolic BP and HR variability (P < 0.05) were significantly lower in patients receiving clonidine as compared to controls. Intraoperatively, a significantly higher incidence of hypertension (P < 0.01) and tachycardia (P < 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 diazcpam as a premedicaltion; 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 < 0.01). Thus, clonidine may represent a useful adjunct in the management of the aged patient in the setting of ophthalmic surgery.

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.

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.

Catecholamine metabolism in the rat locus coeruleus as studied by in vivo differential pulse voltammetry. III: Evidence for the existence of an α2-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.

Haemodynamic effects of clonidine injected epidurally in halothane-anaesthetized dogs

The haemodynamic effects of clonidine administered in the epidural space were studied in 16 halothane-anaesthetized dogs. The animals were randomly assigned to two groups; Group I received three doses of 3 ml of normal saline, Group II received three doses of 3 μg·kg-1 of clonidine, through an epidural catheter, whose tip was located between L2-T11. Control haemodynamic measurements were taken one hour after completion of the surgical preparation (period P1); they were repeated every 45 minutes after each incremental dose (periods P2, P3, P4) and 105 minutes after a total cumulative dose of 9 μg·kg-1 of clonidine or 9 ml of saline were given (period P5). No significant changes over time were observed in Group I. In Group II clonidine produced statistically significant reductions of systemic blood pressure (BP), mean left ventricular pressure (LV), heart rate (HR), cardiac output (CO) and peak LV dP/dt only after a total clonidine dose of 9 μg·kg-1 and these changes were sustained. BP fell 15 per cent, CO 21 per cent, HR 25 per cent, LV 20 per cent and peak LV dP/dt 30 per cent when P5 measurements were compared to control values within Group II (p < 0.05). These haemodynamic effects of clonidine are likely due to minimal systemic absorption and/or cephalad spread of the drug towards its site of action in the brain stem. The reductions of HR, CO, BP, and isovolemic indices of contractility are likely explained by a reduction of sympathetic outflow at the spinal cord and medulla oblongata levels as well as increased parasympathetic tone.If these observations can be extrapolated to clinical conditions, in view of the small haemodynamic changes observed only with the highest dose employed, and the potent analgesic effects, epidural administration of clonidine appears safe and may be useful for management of acute postoperative pain.RésuméLes effets hémodynamiques de ľadministration de clonidine dans ľespace épidural étaient étudiés chez 16 chiens anesthésiés à ľhalothane. Les animaux étaient divisés en deux groupes ďune façon randomisée: le groupe I a reçu trois doses de 3 ml de physiologique, le groupe II a reçu trois doses de 3 μg·kg-1 de clonidine, à travers un cathéter épidural dont le bout distal était localisé entre L2 et T11. Les mesures hémo-dynamiques de contrôle étaient prises une heure après ľaccomplissement de la préparation chirurgicale (période P1); elles étaient répétées chaque 45 minutes après chaque dose de rajout (période P2, P3, P4) et 105 minutes après avoir atteint une dose cumulative totale de 9 μg·kg-1 de clonidine ou 9 ml de salin (période P5). Aucun changement significatif à travers le temps n’a été observé dans le groupe I. Dans le groupe II la clonidine a produit une diminution statistiquement significative de la tension artérielle systémique (BP), de la pression du ventricule gauche (LV), de la fréquence cardiaque (HR), du débit cardiaque (CO) et dP/dt maximal uniquement après avoir atteint la dose maximale totale de 9 μg·kg-1. La BP a diminué de 15 pour cent, CO de 21 pour cent, HR de 25 pour cent, LV de 20 pour cent et le dP/dt de 30 pour cent quand les mesures faites au temps P5 étaient comparées aux valeurs de contrôle dans le groupe II (p < 0.05). Ces effets hémodynamiques de la clonidine sont probablement dus à une absorption systémique minime et/ou à une diffusion vers le haut du médicament vers son site ďaction dans le cerveau. La diminution de la fréquence cardiaque, débit cardiaque et la tension artérielle ainsi que les indices isovolumiques de contractilité sont probablement expliqués par une réduction de la réponse sympathique de la moëlle épinière et du bulbe rachidien ainsi qu’une augmentation du tonus parasympathique.Si on pouvait extrapoler ces observations expérimentales aux conditions cliniques et parce que les effets hémodynamiques ont été observés uniquement avec des fortes doses de clonidine qui est un puissant analgésique, ľadministration épidurale de cette drogue apparaît sécuritaire et pourrait être utile au point de vue thérapeutique contre les douleurs aigues postopératoires.

Swift recovery of severe acute hypoxemic respiratory failure under non-invasive ventilation.

BACKGROUND In the setting of severe acute respiratory distress syndrome (ARDS; PaO2/FiO2 < 100), the cut-off point for switching from non-invasive ventilation to intubation combined to mechanical ventilation is poorly defined. RESULTS The swift resolution over 10 h of a severe acute hypoxemic respiratory failure (P/F = 57) caused by aspiration following heroin overdose, using non-invasive ventilation (NIV)-high PEEP (15-20 cm H2O)-low pressure support (8 cm H20) is reported. The success in treating non-invasively severe hypoxia was presumably linked to a highly restricted subset: healthy young patient, minimal alteration of consciousness, non-combativeness, absence of severe metabolic acidosis, quick resolution of supraventricular arrhythmia, one-to-one supervision by the intensivist in the critical care unit. CONCLUSION Given the complications associated with tracheal intubation and mechanical ventilation on the one hand and with delayed intubation on the other hand, high PEEP-NIV may warrant study in a restricted set of patients closely monitored in a critical care environment.

Early severe acute respiratory distress syndrome: What’s going on? Part I: pathophysiology

Severe acute respiratory distress syndrome (ARDS, PaO₂/FiO₂ < 100 on PEEP ≥ 5 cm H₂O) is treated using controlled mechanical ventilation (CMV), recently combined with muscle relaxation for 48 h and prone positioning. While the amplitude of tidal volume appears set < 6 mL kg⁻¹, the level of positive end-expiratory pressure (PEEP) remains controversial. This overview summarizes several salient points, namely: a) ARDS is an oxygenation defect: consolidation/ difuse alveolar damage is reversed by PEEP and/or prone positioning, at least during the early phase of ARDS b) ARDS is a dynamic disease and partially iatrogenic. This implies that the management of the ventilator may be a life-saver by reducing the duration of mechanical ventilation, or detrimental by extending this duration, leading into critical care-acquired diseases. Indeed, a high PEEP (10-24 cm H₂O) appears to be a life-saver in the context of early severe diffuse ARDS; c) tidal volume and plateau pressure cannot be identical for all patients; d) the only remaining rationale for CMV and muscle relaxation is to suppress patient-ventilator asynchrony and to lower VO2, during the acute cardio-ventilatory distress. Therefore, in early severe diffuse ARDS, this review argues for a combination of a high PEEP (preferably titrated on transpulmonary pressure) with spontaneous ventilation + pressure support (or newer modes of ventilation). However, conditionalities are stringent: upfront circulatory optimization, upright positioning, lowered VO₂, lowered acidotic and hypercapnic drives, sedation without ventilatory depression and without lowered muscular tone. As these propositions require evidence-based demonstration, the accepted practice remains, in 2016, controlled mechanical ventilation, muscle relaxation, and prone position.

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.