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Clonidine in paediatric anaesthesia: Pharmacokinetic and pharmacodynamic aspects
... A low-dose administration leads to more effective control of blood pressure in both standing and supine positions in severe or moderate hypertension [9]. Also, narcotics are utilized to improve withdrawal symptoms associated with the long-term use of nicotine, benzodiazepine and alcohol [13]. In the literature review, some analytical methods for clonidine hydrochloride have been identified, but no studies have been conducted on the determination of the stoichiometry of complexes between clonidine with Zn(II), Mg(II), Cd(II), Ca(II) and Cu(II). ...
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.
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 less than 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 X kg-1 po; group 2, in addition, received clonidine 5 micrograms X kg-1 po. Anesthetic depth was assessed by on-line aperiodic analysis of the electroencephalogram. Following lidocaine 1 mg X kg-1 and fentanyl 2 micrograms X kg-1 (group 1 only), anesthesia was induced with thiopental 3-4 mg X kg-1 and vecuronium 0.1 mg X kg-1 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 less than 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 less than 0.01) and diastolic BP and heart rate (HR) (P less than 0.05), and resulted in significantly slower HR during recovery (P less than 0.01). Anesthetic requirements for isoflurane were reduced 40% (P less than 0.01) in group 2; narcotic supplementation was also significantly reduced (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
A single oral dose of 0·15 mg/m2 of clonidine was given to eighteen healthy children and adolescents and to seven patients with hypopituitarism. In healthy subjects there was a pronounced increase in plasma growth hormone from 4·9±1·3 ng/ml (±SEM) to 34·4±4·5 ng/ml. In the patients with hypopituitarism there was no change in growth-hormone concentrations. Clonidine induced a slight increase in blood glucose in healthy subjects and a slight decrease in patients with hypopituitarism. During the test systolic blood-pressure decreased by a mean of 20 mm Hg in the healthy subjects and by 25 mm Hg in the patients with hypopituitarism. The only side-effect observed was drowsiness. Oral administration of clonidine, a well-tolerated drug, seems to be a simple test for of GH reserves in children and adolescents.
We have demonstrated previously that transfer function analysis can be used to precisely characterize the respiratory sinus arrhythmia (RSA) in normal humans. To further investigate the role of the autonomic nervous system in RSA and to understand the complex links between respiratory activity and arterial pressure, we determined the transfer functions between respiration, heart rate (HR), and phasic, systolic, diastolic, and pulse arterial pressures in 14 healthy subjects during 6-min periods in which the respiratory rate was controlled in a predetermined but erratic fashion. Pharmacological autonomic blockade with atropine, propranolol, and both, in combination with changes in posture, was used to characterize the sympathetic and vagal contributions to these relationships, as well as to dissect the direct mechanical links between respiration and arterial pressure from the effects of the RSA on arterial pressure. We found that 1) the pure sympathetic (standing + atropine) HR response is characterized by markedly reduced magnitude at frequencies greater than 0.1 Hz and a phase delay, whereas pure vagal (supine + propranolol) modulation of HR is characterized by higher magnitude at all frequencies and no phase delay; 2) both the mechanical links between respiration and arterial pressure and the RSA contribute significantly to the effects of respiration on arterial pressure; 3) the RSA contribution to arterial pressure fluctuations is significant for vagal but not for sympathetic modulation of HR; 4) the mechanical effects of respiration on arterial pressure are related to the negative rate of change of instantaneous lung volume; 5) the mechanical effects have a higher magnitude during systole than during diastole; and 6) the mechanical effects are larger in teh standing than the supine position. Most of these findings can be explained by a simple model of circulatory control based on previously published experimental transfer functions from our laboratory.
We evaluated the analgesic efficacy and hemodynamic and respiratory safety of clonidine when added to bupivacaine for caudal blocks in 58 children aged 38 +/-2 mo (mean +/- SEM). Patients scheduled for ambulatory hernia repair were randomly given a caudal injection (0.75 mL/kg) of either saline placebo (P group), bupivacaine, 0.25% (B group), bupivacaine plus epinephrine 1:200,000 (BE group), bupivacaine plus clonidine 1 micro g/kg (BC1 group), or bupivacaine plus clonidine 2 micro g/kg (BC2 group). Postoperative measurements included duration of analgesia, hemodynamics, and respiratory monitoring for 6 h. Thereafter, parents assessed their child's analgesic requirements at home every 3 h for 18 h. The duration of analgesia (median [range]) was significantly longer (P < 0.05) in the BC1 and BC2 groups (360 [270-360] min and 360 [355-360] min, respectively) compared with the P (77[45-190]), B (346[105-360]), or BE group (300[75-360]). Similarly, the BC1 and BC2 groups required less additional analgesic within the first 24 h. All groups showed a significant decrease in mean arterial pressure compared with baseline values, but the differences among the groups were not significant. Bradycardia and respiratory depression were not observed. Clonidine 1 and 2 micro g/kg can be safely added to bupivacaine caudal blockade in small children for ambulatory hernia repair to achieve an increased duration of analgesia compared with bupivacaine alone or bupivacaine plus epinephrine. Implications: The addition of clonidine, an antihypertensive drug with analgesic properties, to local anesthetics in caudal blocks prolongs postoperative pain relief and reduces the need for additional pain treatment in children after hernia operation.
This study was designed to evaluate the dose-response effects of different doses of clonidine on the stress response to laryngoscopy and endotracheal intubation. In a randomized, double-blind study, 48 coronary artery bypass grafting (CABG) patients received 0, 2, 4, or 6 micro gram/kg clonidine as an intravenous (IV) infusion during a 15-min period 30 min prior to induction of anesthesia with etomidate (0.3 mg/kg), fentanyl (5-7 micro gram/kg), and pancuronium (0.1 mg/kg). Sedation was assessed prior to induction of anesthesia. Cardiovascular variables and catecholamine plasma levels were measured at predefined intervals. Additional bolus doses of etomidate and fentanyl for suppression of stress-induced reactions were administered if predefined limits of heart rate and blood pressure were exceeded. Clonidine 4 and 6 micro gram/kg significantly attenuated hemodynamic and adrenergic reactions to stress, reduced pharmacologic interventions, and increased sedation. However, clonidine 6 micro gram/kg was not more effective than 4 micro gram/kg, and clonidine 2 micro gram/kg was equally effective as placebo. We conclude that clonidine 4 micro gram/kg IV is the appropriate dose to attenuate the stress response to laryngoscopy in CABG patients. Side effects limiting the use of IV clonidine were not observed.
(Anesth Analg 1995;80:263-8)
Used as the sole analgesic, clonidine produces analgesia after epidural, intrathecal, and intraarticular administration.We conducted this double-blinded study to determine whether clonidine has analgesic effects when administered into the brachial plexus sheath. At the conclusion of hand or forearm surgery, performed under axillary brachial plexus block, 45 patients were randomly divided into three groups of 15 each to receive, through an axillary catheter, 15 mL of saline (Group Saline), clonidine 150 [micro sign]g in 15 mL of saline (Group Clonidine), or bupivacaine 15 mL (Group Bupivacaine). The analgesic effects of the three solutions were evaluated for 6 h. Times to onset of pain and to first analgesic request were longer, and the total dose of pain medication was smaller in Group Bupivacaine compared with the other groups. Visual analog scores were significantly lower in Group Bupivacaine. There was no significant difference in time to onset of pain, time to first analgesic request, total dose of pain medication, and visual analog scores between Group Saline and Group Clonidine at any time. We conclude that the administration of clonidine 150 [micro sign]g into the brachial plexus sheath does not prolong the onset of postoperative pain. Implications: Used as the sole analgesic, clonidine produces analgesia after epidural, intrathecal, and intraarticular administration. It also prolongs the analgesic effect of brachial plexus block when mixed with local anesthetics. In this study, the administration of clonidine 150 [micro sign]g alone into the brachial plexus sheath did not produce postoperative analgesia.
(Anesth Analg 1999;88:1109-12)
Purpose of review:
This review aims to summarize results of recently published studies concerning clonidine application in paediatric anaesthesia, to analyse trends in these studies, and to discuss perspectives of the perioperative use of clonidine for children.
Recent findings:
Reassessment of clonidine premedication has revealed that oral clonidine is inferior to midazolam for preoperative sedation. Oral or intravenous clonidine has been successfully used for the prevention of sevoflurane-induced agitation during emergence from anaesthesia. Peripheral injection or caudal (epidural) administration of clonidine prolonged the duration and enhanced the quality of postoperative analgesia by local anaesthetics without severe side effects. However, some negative results concerning potentiation of postoperative analgesia with clonidine have been reported.
Summary:
Clonidine may be less favored than midazolam as premedication for children because of inferior clonidine-induced sedation. Additional comparative studies are required, however, to confirm this finding. On the other hand, clonidine-induced analgesia may well be useful and find wide application in paediatric anaesthesia. Prospective multicentre trials using a larger number of patients will be needed to verify the usefulness of caudal clonidine for postoperative pain relief. Prophylactic use of clonidine against sevoflurane-induced agitation may represent a new and promising application. Assessment of the efficacy of clonidine in potentiating regional anaesthesia/analgesia by local anaesthetics in children also needs more investigation. Moreover, it may be worthwhile to try new successful applications demonstrated in adults for paediatric anaesthesia.
We studied the effects of intravenous clonidine treatment in a group of 24 patients with acute myocardial transmural anterior and/or lateral wall infarction. Clonidine, known as an antihypertonic agent, was administered as a bolus of 1–2 μg/kg body weight and repeated every 2–3 hr. However, maximal range of the time interval was 20 min to 4 hr, maximal range of doses 37 to 150 μg, depending on the hemodynamic status. The effects were measured by precordial electrocardiographic mapping as well as serial creatine phosphokinase determinations. A big decrease in ST-segment elevation was observed: ΣST reduction after 24 hr was 37% of initial value (140% in control group), after 48 hr - 30% (120% - control). NST fall after 24 hr - 45% (145% - control), after 48 hr - 41% (142% - control). NQ increased after 24 hr to 135% of initial value (156% - control), after 72 hr to 137% (167% - control). Detailed analysis revealed undoubted correlation between the dosage and favourable dynamics of precordial mapping parameters.Hemodynamic, antiarrhythmic and above all adrenolytic activity were noted. The treatment caused a distinct deterioration in daily adrenalinuria mean values to 5.99 μg in the first day (14.20 - control) and lower in the following days. No side effects were observed but sudden discontinuation of the therapy caused an unfavorable reaction. A temporal association between diminished adrenalinuria and both clinical improvement and limitation of infarct size was observed. Therapy with intravenous clonidine requires meticulous individualization of clonidine dosage depending on the patient's initial hemodynamic status.
Summary The possible involvement of cardiac presynaptic α2-adrenoceptors in the acute negative chronotropic effect of intravenous clonidine and four selected analogues was tested in pentobarbitone-anaesthetized normotensive rats by establishing the following parameters: 1) the peripheral presynaptic activity (inhibition of tachycardia to stimulation of the spinal cord in pithed rats); 2) central hypotensive potency in intact rats (decrease in mean arterial pressure); 3) overall bradycardiac activity in intact rats (decrease in cardiac frequency); 4) sympathetic bradycardia in bilaterally vagotomized rat; and 5) vagal bradycardia in β-blocked rats. The lipophilicity of the imidazolidines (log P′) was measure in the octanol/buffer (pH=7.4) reference system at 37°C. Central hypotensive activity as well as vagal bradycardiac potency correlated with the ability to penetrate the central nervous system, as indicated by the overall lipophilic behavior (log P′) of the compounds. In contrast, brain penetration was not a prerequisite for the provocation of bradycardia in bilaterally vagotomized rats. This sympathetic bradycardia resembled peripheral presynaptic inhibition. The hydrophilic — poor brain-penetrating — substances already induced maximal sympathetic bradycardia at doses which did not induce hypotension or vagal bradycardia. The lipophilic drugs, however, only showed a preferentially sympathetic bradycardiac effect over vagal bradycardia at low doses. In intact pentobarbitone-anaesthetized rats, the log dose-bradycardiac response curves of the hydrophilic imidazolidines displayed a bisigmoidal character in contrast to their lipophlic analogues, i.e. at the lower dose-range of the hydrophilic drugs, bradycardia in intact rats resembled peripheral presynaptic inhibition, whereas a contribution of increased vagal activity only was significant after maximal sympathoinhibition was achieved. These data provide evidence for the view that the bradycardiac action of clonidine in pentobarbitone-anaesthetized normotensive rats is due, at least in part, to the functional role of cardiac presynaptic α2-adrenoceptors. The stimulation of these receptors will inhibit the sympathetic neurotransmission in the heart.
Summary A case of multiple life-threatening postoperative apnoeas in a term neonate undergoing inguinal herniorrhaphy and orchidopexy who received light inhalation anaesthesia combined with caudal block with 1 ml.kg-1 ropivacaine 0.2% plus 2 μg·kg−1 clonidine is reported. The patient showed no apparent risk factors for postanaesthetic apnoea. Oxycardiorespirography five days after surgery only showed minor abnormalities. Clonidine though administered caudally in the usual dose of 2 μg·kg-1 appeared to be the most likely cause for postanaesthetic apnoea in this neonate.
Einleitung: Die kontinuierliche Periduralanästhesie ist bei Erwachsenen ein etabliertes Verfahren zur postoperativen Analgesie und Sympathikolyse. Bei Kindern dagegen wird diese Vorgehensweise in der Literatur sehr viel seltener beschrieben. Material und Methodik: Es wird über 77 Periduralkatheter bei Kindern berichtet, die in der Zeit vom Oktober 1991 bis zum November 1994 im Kinderkrankenhaus auf der Bult gelegt wurden. Davon waren 23 Lumbaikatheter und 54 Kaudalkatheter (19 subkutan getunnelt, 35 ohne Tunnelung). Der jüngste Säugling war 4 Wochen, der älteste Patient 19 Jahre alt. Das Patientengewicht lag zwischen 3,9 kg und 79 kg. Die Katheter dienten zur kontinuierlichen Infusion von Bupivacain 0,125 %. Die mittlere Katheterverweildauer betrug 84,2 h. Nach der Entfernung wurden die Katheterspitzen bakteriologisch untersucht. Ergebnisse: Bei den lumbalen Periduralkathetern wurden im Durchschnitt 0,18 mg/kg/h Bupivacain 0,125 % verabreicht, beim kaudalen Zugang eine deutlich höhere mittlere Dosis von 0,30 mg/kg/h. Durchschnittlich 33 h postoperativ hatten die Patienten Darmgeräusche, der erste Stuhl wurde nach 48 h abgesetzt. Von den 64 untersuchten Katheterspitzen waren 49 steril. 15 Katheter zeigten eine bakterielle Kolonisation. Bei den lumbalen und kaudal getunnelten Kathetern fanden sich Kolonisationsraten von 11,7 % respektive 10,5 %, die statistisch signifikant (p < 0,05 im Chi²-Test) niedriger waren als bei den nicht getunnelten Caudalkathetern (39 %). Klinische oder laborchemische Hinweise für eine lokale oder generalisierte Infektion ließen sich in keiner Gruppe nachweisen. Schlußfolgerung: Die Erfahrungen mit der kontinuierlichen Periduralanästhesie bezüglich Analgesie und Sympathikolyse im Kindesalter sind positiv. Diese Technik ist einfach durchführbar und komplikationsarm. Eine gute Analgesie und erfolgreiche Unterstützung der Darmmotilität wurde erreicht. Aufgrund der bakteriologischen Untersuchungsergebnisse wird empfohlen, Kaudalkatheter subkutan in kraniolateraler Richtung zu tunneln, da dies die bakterielle Kolonisationsrate signifikant vermindert.
Summary
Introduction: Continuous epidural anaesthesia is a well established procedure for postoperative analgesia as well as sympathicolysis in adult patients. It is, however, much less frequently reported in infants and children. Materials and methods: From October 1991 to November 1994 65 infants, children and adolescents aged 4 weeks to 19 years, body weight 3.9 kg to 79 kg, received 77 epidural catheters for postoperative analgesia. 54 catheters were inserted via the caudal approach either with (n = 19) or without (n = 35) subcutaneous tunnelling. 23 catheters were placed via a low midline lumbar epidural puncture either through interspace L5/S1 or L4/L5. The local anaesthetic of choice in this study was bupivacaine 0,125 % without adrenaline infused continuously via a constant-flow infusion pump. 20 patients received additional boluses of morphine and in 3 patients clonidine was added. The catheters were left in place for an average of 84.5 h. After removal the catheter-tip was submitted for bacteriological examination. The results of 64 specimens were available. Results: For satisfactory analgesia an average of 0.18 mg × kg⁻¹ × h⁻¹ bupivacaine 0.125 % had to be administered via the lumbar route, while the mean dose for caudal catheters was 0.3 mg × kg⁻¹ × h⁻¹. Intestinal peristalsis re-occurred within 33 h after surgery. The first stool was passed within 48 h. Of the 64 catheters which were microbiologically examined, 15 exhibited bacterial colonisation with a statistically significant difference between those subcutaneously tunnelled and those inserted directly (p < 0.05). There were, however, no signs of local or systemic infection. Conclusions: The results of continuous epidural anaesthesia and sympathicolysis in infants and children are encouraging. This technique is readily employable and complications seem to be rare. Satisfactory analgesia and sympathicolysis were achieved. Based on the results of our bacteriological studies we recommend that caudal catheters are tunnelled subcutaneously in cranio-lateral direction.
Radioligand binding experiments carried out in cell membranes from rat and human stomach revealed the existence of non-adrenoceptor [3H]clonidine and [3H]idazoxan binding sites and of [3H]DTG (1,2-di-(2-tolyl)guanidine) binding sites. In rat stomach, specific binding was inhibited by imidazolines and guanidines and by non-imidazoline σ-site ligands, respectively, at different rank orders of affinity, suggesting the existence of non-I1/non-I2 [3H]clonidine binding sites, I2-imidazoline binding sites as well as σ2-like-sites. These sites are not directly related to a postsynaptic contractile effect on rat gastric smooth muscle or to acid release from isolated gastric glands. Finally, we demonstrated that the gastric pathogen Helicobacter pylori is able to form and to release the endogenous imidazoline receptor ligand agmatine and that considerable amounts of agmatine are present in human gastric juice. The quantities of agmatine were higher in gastric juice from H. pylori-positive than H. pylori-negative patients.
Clonidine was tested in a conflict-induced suppression paradigm (bar pressing for food reward suppressed by electric foot shock) in rats. This drug significantly and dose dependently (25–100 μg/kg) both increased punished responding and decreased unpunished responding. Clonidine at 200 μg/kg had no effect on punished bar pressing, although it markedly inhibited unpunished responding due to sedation. The effect of clonidine on shock-suppressed lever pressing was prevented by yohimbine 5 mg/kg and partially antagonized by phenoxybenzamine 2.5 mg/kg but was not significantly altered by phenoxybenzamine 1 mg/kg, atropine 5 mg/kg, methysergide 5 mg/kg, or naloxone 10 mg/kg.
This activity of clonidine does not seem to be due to its analgesic or food intake-increasing properties. It may be a true anxiolytic effect, brought about by presynaptic stimulation of noradrenergic neurons which could result in an inhibitory influence on the locus coeruleus.
In klinischen Untersuchungen wurde der Einflu von 2-(2,6-Dichlorphenylamino)-2-imidazolin-hydrochlorid (Catapresan) auf die Magensaftsekretion sowie die exokrine und endokrine Pankreassekretion geprft. Nach intravenser Gabe von 4 g/kg Catapresan wird die nichtstimulierte sowie die Insulin-, Betazol-und Pentagstrin-stimulierte Suresekretion des Magens gehemmt. Die secretininduzierte Pankreassekretion wird gleichfalls durch Catapresan vermindert. Eine Beeintrchtigung der basalen Insulinsekretion konnte bei Personen ohne Kohlenhydratstoffwechselstrung und einer Patientin mit Hyperinsulinismus nicht nachgewiesen werden.The effect of 2-(2,6-dichlorophenylamino)-2-imidazolin hydrochloride (Catapresan) on gastric secretion, duodenal bicarbonate secretion and plasma insulin levels has been examined in clinical studies. The acidity and bicarbonate concentration were not affected, but the basal gastric secretion, and the betazol (2 mg/kg) —, pentagastrin 6 g/kg — and insulin (0.2 U/kg) induced gastric secretion and the secretin (1 U/kg) induced duodenal bicarbonate secretion were decreased after the intravenous administration of 4 g/kg of this substance. There was no change in blood sugar and basal insulin levels in normal persons.
We conducted a prospective, randomized, double-blind, controlled clinical trial to examine (1) whether plasma catecholamine (CA) concentrations increased in response to tracheal intubation in children, and (2) the effects of clonidine on the CA responses. Sixty children (ASA physical status I) aged 7- 13 yr were allocated to one of three groups (n = 20 for each group): diazepam 0.4 mg · kg- 1 (active control), clonidine 2 μg · kg- 1, or clonidine 4 μg · kg- 1 po. These agents were administered 105 min before induction of anaesthesia followed by oral atropine 0.03 mg · kg- 1 given 60 min before anaesthesia which was induced with thiamylal 5 mg · kg- 1 and tracheal intubation was facilitated with vecuronium 0.2 mg · kg- 1. Laryngoscopy, lasting 30 sec, was attempted two minutes after administration of the induction agents. Serial values for blood pressure, heart rate, and venous plasma CA concentrations were compared among the three groups and with the respective preinduction measurements. Children receiving diazepam or clonidine 2 μg · kg- 1 showed remarkable increases in systolic and diastolic blood pressures, heart rate, and plasma CA concentrations in response to tracheal intubation (P < 0.05). The increases were similar for the two regimens. These haemodynamic and CA changes were smaller in children receiving clonidine 4 μg · kg- 1 (P < 0.05). The haemodynamic responses were positively correlated with the CA responses. These findings indicate that tracheal intubation following rapid sequence induction of anaesthesia in children provokes a reflex increase in sympathetic activity characterized by increased plasma CA concentrations, and that attenuation of the cardiovascular changes with a high oral dose of clonidine may be due to suppression of the increase in sympathetic activity evoked by the intubation.
Clonidine is approved in the US for epidural administration in the treatment of intractable neuropathic cancer pain, but is also administered intrathecally for this indication and both epidurally and intrathecally in the treatment of acute, postoperative pain. The purpose of the current study was to estimate the relative potency of clonidine by epidural and intrathecal routes in the treatment of capsaicin-induced hyperalgesia and allodynia as a model of central hypersensitivity and of noxious heat as a model of acute pain. Twenty-four healthy volunteers were randomized to receive either intrathecal clonidine (75, 150, or 300 μg) or epidural clonidine (150, 300, or 600 μg) and rated pain from a Peltier-controlled thermode at a lumbar, thoracic, and cervical dermatomal site before and after drug administration. In addition, they rated pain from intradermal capsaicin injections at a lumbar dermatome before and 60 min after clonidine injection and described areas of hyperalgesia and allodynia to mechanical stimuli. Clonidine's effect differed with route of administration and modality of sensory testing. For acute thermal pain, intrathecal clonidine produced a dose-dependent analgesia with a lumbar>thoracic>cervical gradient, whereas only one dose of epidural clonidine reduced thermal pain and this was at the thoracic testing site. In contrast, the potency of clonidine to reduce capsaicin-induced allodynia was similar between the two routes of injection, and, for hyperalgesia, clonidine was only slightly more potent after intrathecal than epidural injection. These data support clinical studies from non-comparative trials and suggest there is a >6-fold potency ratio of intrathecal: epidural administration of clonidine for acute pain, but a <2-fold potency ratio for these routes for mechanical hypersensitivity.
The need for a research tool to measure recovery from sedation was identified during the design phase of a study investigating sedative protocols following open heart surgery in children. A thorough review of the literature failed to show any scales that measure degree of sedation in children at various times after initial awakening. The Vancouver Sedative Recovery Scale (VSRS) was developed through an iterative process during which we identified numerous indicators of levels of alertness among sedated children, and then determined the applicability and face validity of these indicators. The VSRS evaluated in this study consists of 12 distinct items that encompass three categories of indicators (response; eye appearance and function; and body movement). Total possible VSRS scoring ranges from 0 to 22 (higher score indicating more alert) because some of the 12 items have more than two rating levels. The VSRS was administered to 82 pediatric intensive care unit and postanesthesia recovery patients, with each patient assessed simultaneously by at least two observers. Internal consistency as measured by Cronbach's α was excellent: 0.85. Interobserver agreement or reliability as measured by intraclass correlation was also very high: 0.90; and for individual items Cohen's κ ranged from 0.65 to 0.89. We consider the VSRS to be a good beginning in our effort to quantify level of alertness after sedation in the pediatric patient population.
1.1. Sixteen imidazol(in)e derivative drugs were tested with regards to their aggregatory and antiaggregatory effects on human blood platelets.2.2. Platelet aggregation in response to fixed concentrations of the agents was quantified by the turbidimetric method of Born.3.3. Inhibitory effects of the imidazol(in)es against the epinephrine (10−5 M) induced aggregation was related to concentration of the agents. Of the compounds studied, UK 14,304 elicited an aggregatory effect of a magnitude similar to epinephrine.4.4. A strong aggregatory agent appeared also moxonidine.5.5. Small aggregation was observed in response to clonidine, antazoline and tetryzoline.6.6. For all the group of imidazol(in)e drugs, excepting UK 14,304 and moxonidine, a significant inhibition of the epinephrine induced aggregation was noted.7.7. Analysing inhibitory activity of imidazol(in)es one notes the drugs commonly assumed to interact with alpha 2 adrenoceptor among the most potent inhibitors, and those classified as alpha 1 adrenoceptor agonists among the less active agents.8.8. The results here obtained suggest some similarity between the platelet adrenoceptor and the alpha 2 subtype of adrenoceptor identified in human circulatory system.9.9. Differences appear between the two types of receptors and the existence of a separate alpha 3 class of adrenoceptors in human blood platelets should be considered.
A new iterative polyexponential curve stripping technique for the provision of initial pharmacokinetic parameter estimates has been developed. Such estimates are required for nonlinear least-squares curve fitting. In contrast to conventional curve stripping, this new technique does not make any assumption about the relative magnitudes of the exponential rate constants. Hence, the parameter estimates which it provides are free of the bias which may arise in conventional curve stripping. A BASIC program called JANA has been developed to implement the new curve stripping procedure.
Although yohimbine (YOH) has been available for the treatment of male erectile dysfunction (ED) for longer than Viagra®, there is a perception that little is known about the clinical performance of the drug. This review attempts, by comprehensive analysis of the literature, to cover the clinical, pharmacological, and therapeutic profiles of YOH, relevant to its potential utility in the management of patients with ED. Relatively few well-designed studies have been completed. From these, however, it can be concluded that YOH as monotherapy possesses only modest efficacy in ED patients. In acute and chronic (long-term) studies, YOH has been found to be relatively free of side effects over the dose range predicted to be effective in ED. At much higher doses, the most frequently observed effects, consistent with the primary pharmacological action of the drug, are elevation of blood pressure, a slight anxiogenic action, and increased frequency of urination. These side effects are all easily reversible on termination of YOH therapy. There is increasing evidence that the erectogenic action of YOH can be augmented by concomitant administration of agents that augment the release and/or action of nitric oxide in the corpus cavernosum. YOH has yet to be studied in female sexual dysfunction. Overall, the benefit risk profile of YOH would indicate that it has potential, more probably as part of a combination strategy, e.g., with a drug that enhances the nitric oxide pathway, in the treatment of ED.
Intrathecal administration of neostigmine has been shown to produce analgesia in both animals and humans. The concurrent administration of intrathecal neostigmine and clonidine has been reported to produce no neurotoxicity in sheep. The purpose of the present study was to evaluate the efficacy and safety of the combining intrathecal neostigmine and clonidine for the relief of pain in patients after cesarean delivery.
After giving their consents, 80 parturients who were scheduled for cesarean delivery during spinal anesthesia were enrolled by a double-blind randomized design into four groups: bupivacaine group (n = 20) received intrathecal (i.t.) 10 mg bupivacaine; bupivacaine + neostigmine group (n = 19) received i.t. 10 mg bupivacaine + 50 microg neostigmine; bupivacaine + clonidine group (n = 20) received i.t. 10 mg bupivacaine + 150 microg clonidine; and bupivacaine + both (n = 21) received i.t. 10 mg bupivacaine + 50 microg neostigmine + 150 microg clonidine. The maximum spread of anesthesia, duration of analgesia and motor block, vital signs, and incidence of adverse effects were recorded for 14 hours postinjection. Fifty milligrams intramuscular meperidine was given as a rescue analgesic whenever patient's pain score was greater than 5/10 by the visual analog scale.
The demographic data were similar for all four groups. Bupivacaine + both group had a significantly higher maximum spread of anesthesia of 23.3 +/- 2.9 segments than bupivacaine group of 20.5 +/- 2.9 segment. Bupivacaine + both group showed a later onset of postsurgical pain of 6.5 +/- 1.5 hours as compared to bupivacaine group of 1.3 +/- 0.6 hours. The pain score in bupivacaine + both group was significantly lower than that of bupivacaine group during the first 10 hours. The 24-hour meperidine consumption also was lower in bupivacaine + both group than that of bupivacaine group. However, motor block was significantly prolonged from 3.5 +/- 1.1 hours in bupivacaine group to 7.1 +/- 1.6 hours in bupivacaine + both group. In addition, other side effects such as nausea and vomiting and dizziness were significantly increased in bupivacaine + both group.
Our study showed that the combination of 150 microg i.t. clonidine and 50 microg neostigmine provided longer postsurgical analgesia than with either drug used alone. However, this combination also produced significantly more adverse effects of prolonged motor block and nausea and vomiting. A further study combining the two study drugs but using a lower dose of i.t. neostigmine (e.g., 25 microg) is recommended.
We examined the effect of oral midazolam premedication on postoperative behaviour. Seventy children (ASA Physical Status 1 and 2; aged 1-10 yrs) were assigned randomly in a prospective, blinded fashion to receive either midazolam 0.5 mg.kg-1 (maximum 10 mg) or placebo. Behaviour assessments were made prior to medication, during induction of anaesthesia and 15 min following arrival to recovery room. The baseline behavioural evaluation scores were not significantly different. The children receiving midazolam cried significantly less during induction (P < or = 0.02). At one week follow-up, eight of 35 subjects receiving placebo had experienced adverse behaviour changes (nightmares, night terrors, food rejection, anxiety, negativism); 19 of 35 of the midazolam group experienced these changes (P < or = 0.02). At four week follow-up, most behaviour changes had resolved. Children given preoperative oral midazolam were less likely to cry and fight while being anaesthetized, and preoperative sedation was associated with increased incidence of adverse postoperative behaviour changes.
A single oral dose of 300 microng of clonidine lowered systolic blood pressure by 20 +/- 4 mm Hg and diastolic blood pressure by 13 +/- 4 mm Hg in five healthy normotensive subjects (controls). Heart rate fell from 56 +/- 2 to 52 +/- 2 beats/min. In six tetraplegic subjects with physiologically complete chronic cervical spinal cord transection above the level of the sympathetic outflow, the same dose of clonidine did not significantly lower either systolic or diastolic blood pressure. Heart rate fell from 67 +/- 4 to 53 +/- 2 beats/min. Peak plasma concentrations of clonidine, measured by mass fragmentography, and elimination of the drug from plasma were similar in tetraplegic and control subjects and there was no difference in the incidence of the principal side effects of clonidine--sedation and dry mouth. Although the number of subjects studied is small, the absence of a fall in blood pressure after clonidine in the tetraplegic subjects suggests that the hypotensive action of clonidine in man is dependent on intact descending bulbospinal pathways and is mediated by withdrawal of sympathetic tone and provides direct evidence that some antihypertensive drugs may lower blood pressure in man by a direct action on the brain.
The antihypertensive agent, clonidine, has a marked sedative effect. We studied whether clonidine also deepens halothane anaesthesia. Eight rabbits were anaesthetized with and without clonidine premedication in a cross-over study. Clonidine premedication (50 microgram/kg subcutaneously) was administered three times daily for 3 days. Tolerance to pain during halothane anaesthesia was tested by compressing the ear with a vessel clamp. Halothane concentrations were determined by gas chromatography. The rabbits premedicated with clonidine tolerated painful stimuli without reactions at lower halothane concentrations in arterial blood and inspired air than unpremedicated rabbits. MAC calculated from blood concentrations was 1.29% for unpremedicated and 1.09% for clonidine-premedicated rabbits. The results suggest that clonidine diminishes the anaesthetic requirement in halothane anaesthesia.
The abrupt cessation of clonidine therapy can induce a withdrawal syndrome. This may also appear immediately after anaesthesia if clonidine medication is discontinued during the operation day. We studied (1) whether the withdrawal syndrome occurs postoperatively as often as otherwise when clonidine therapy is discontinued, and (2) the action of this clonidine withdrawal on the circulation as compared to patients who received clonidine without interruption during the operation day. During the recovery period in 2 out of 10 patients in whom clonidine medication was discontinued, a hypertensive crisis occurred, which was relieved by clonidine readministration. Clonidine given with premedication eliminated high rises in blood pressure during anaesthesia. During the recovery period, the regular intramuscular administration of the same dose of clonidine as the patients had used orally decreased blood pressure to almost normotensive levels. The slightly increased urinary catecholamine excretion and plasma renin activity in these patients might, however, indicate that the circulatory homeostasis was disturbed in some degree. The results suggest that it is important to give clonidine continuously, even during the operation day. The dose may be the same as, or preferably somewhat smaller than that which the patients have previously received orally.
Little is known of the clinical efficacy and pharmacokinetics of clonidine in patients with renal insufficiency. Therefore we evaluated the effects of clonidine in blood pressure, serum electrolytes, and plasma renin activity in six hypertensive patients with end-stage renal disease maintained on chronic hemodialysis. Average daily dose was 0.15 mg. Mean cuffed arterial blood pressure determined in the sitting position decreased from a control value of 111±4 to 103±3 mm Hg (p<0.05) with chronic clonidine therapy, increased to 114±2 mm Hg on discontinuation, and decreased to 106±2 (p<0.05) with reinstitution. Plasma renin activity was initially low but decreased further in each patient during clonidine administration. It is known that two thirds of the total 14C, injected as 14C-clonidine, is recovered in the urine of man and experimental animals with normal renal function, but the effect of renal insufficiency on clonidine elimination has not been reported. Therefore 14C-clonidine plasma disappearance (K) was evaluated in normal volunteers (N=3) and patients with graded degrees of renal insufficiency (N=9). K varies directly with clearance [K(hr-1)=0.0169+0.000189 C (creat); r=0.87 (p<0.001)], corresponding to a greater than twofold increase (17.5 to 41 hr) in plasma half-life as creatinine clearance varies from 120 to 0 ml/min/1.73 m2. Hemodialyzer 14C-clonidine clearance measurements suggest that a maximum of 5% of body clonidine stores is removed during routine hemodialysis. In summary, clonidine is an effective antihypertensive agent in hemodialysis patients. Dosing schedules should be modified in accordance with the prevailing glomerular filtration rate; clonidine elimination by the hemodialyzer does not substantially alter dosing requirements.
1 The kinetics of clonidine and its relation to the blood pressure response after single intravenous doses of 75 micrograms--275 micrograms in hypertensive patients were determined. 2 Clonidine disposition could be described by a two compartment open model and pharmacokinetic parameters show a rapid distribution phase of 20--30 min and a mean plasma clearance of 4.6 ml min-1 kg-1 (75--200 microgram). The half-life of the beta-phase was found to be in the range of 7.4--11.4 h. Indications of dose dependent kinetics were obtained. 3 A dose-dependent decrease in blood pressure was obtained. 4 The maximal reduction in MAP (mean arterial blood pressure) was significantly (P less than 0.01) related to plasma concentrations of clonidine. 5 The reduction in MAP was always related to plasma concentrations of clonidine (r = 0.88, P less than 0.01) when pseudoequilibrium of distribution of the drug was achieved.