Luc Quintin

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.

OXYGEN UPTAKE AFTER MAJOR ABDOMINAL SURGERY : EFFECT OF CLONIDINE

To examine the effect of an alpha-2 agonist, clonidine, on oxygen uptake and on the incidence of postoperative shivering, 28 patients presenting for major abdominal surgery were randomly assigned in a double-blind manner to one of two groups. Intraoperatively, 14 patients received 5 micrograms.kg-1 clonidine infused over 3 h (clonidine group), and 14 patients received placebo (placebo group). Oxygen uptake was measured continuously over the first 3 postoperative hours with a mass spectrometer system. Circulatory variables, esophageal temperature, and skin temperature were measured over the first 6 postoperative hours. Heart rate, mean arterial pressure, rate pressure product, and norepinephrine concentration were decreased in the clonidine group (P less than 2 x 10(-4)). There were no differences among groups in the incidence of shivering and in the rate of increase of esophageal temperature. By contrast, oxygen uptake was lower in the clonidine group (P = 4 x 10(-4)). This contrasting pattern may be secondary to a reduction in the intensity of mean muscular tremor in the clonidine group.

Head injury: Clonidine decreases plasma catecholamines

Seven patients who had suffered head injury 3 to 5 days before the study was undertaken received clonidine (2.5 μg/kg iv over 10 min). This resulted in a reduction of plasma norepinephrine (p < .05) and in normalization of plasma epinephrine (p < .05). Neither common carotid blood flow nor diastolic blood flow as index of global cerebral perfusion as measured by pulsed Doppler changed. The reduction of sympathetic overactivity, probably due to the specific action of clonidine on α2-adrenoceptors within the rostral ventrolateral medulla, may be of interest in the management of head injury because of the maintenance of cephalic hemodynamics. (Crit Care Med 1990; 18:392)

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.

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.

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.

The Effects of Clonidine on Sensitivity to Phenylephrine and Nitroprusside in Patients with Essential Hypertension Recovering from Surgery

Clonidine reduces postoperative circulatory instability in patients with essential hypertension. It also increases the sensitivity to vasopressors before and during anesthesia. We investigated blood pressure responses to phenylephrine and nitroprusside pre- vs postoperatively and the effect of clonidine on these responses in patients with essential hypertension. Twenty patients received clonidine 6 mg/kg orally 120 min before anesthesia and 3 mg/kg IV over the final hour of surgery or an identical placebo. During increasing bolus doses of phenylephrine and nitroprusside (30 ‐300 mg), the maximal systolic pressure responses were recorded at baseline on the day before surgery, before the induction of anesthesia, and 1 and 3 h postoperatively. Sensitivity to phenylephrine and nitroprusside was interpolated from linear regression of the data. There was no difference between preoperative and postoperative sensitivity to phenylephrine or nitroprusside in either group. Clonidine increased sensitivity to phenylephrine versus placebo before and after surgery (response to dose of 1.5 mg/kg: 42 6 14 vs 27 6 8 mm Hg preinduction, 37 6 10 vs 26 6 8 mm Hg 3 h postoperatively; both P , 0.01), but not to nitroprusside (38 6 6v s 376 10 mm Hg preinduction and 40 6 6v s 396 8m m Hg postoperatively). Clonidine increases the sensitivity to phenylephrine but not nitroprusside at baseline and postoperatively in hypertensive patients. Implications: Clonidine increases the sensitivity to bolus injections of the vasoconstrictor phenylephrine, but not the vasodilator sodium nitroprusside, before and after surgery in patients with preexisting hypertension. The doses of vasopressors should be reduced accordingly in hypertensive patients receiving perioperative clonidine. (Anesth Analg 1999;88:1239 ‐43)

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.