Chronobiology and anaesthesia.

PURPOSE OF REVIEW: It has been shown that biological rhythms influence the pharmacology and effects of anaesthetic agents such as local anaesthetics, hypnotics and muscle relaxants. This review discusses the latest findings and their consequences for anaesthesiological practice. RECENTS FINDINGS: Opioids and new local anaesthetics exhibit circadian changes when they are injected into spinal or epidural spaces for labour pain analgesia. Other studies have demonstrated that propofol and ketamine have maximal duration of action when they are injected during a period of rest in animals (at night in humans). It has been also shown that propofol can perturb the central circadian pacemaker and so cause a phase-shifted advance in effect on activity in rats. SUMMARY: Although studies are lacking for most newer anaesthetic agents used in humans, recent findings emphasize once again that chronobiology should be considered in studies of anaesthetic drugs. Circadian rhythms should be considered in pharmacokinetic and pharmacodynamic analyses so that proper research protocols can be designed. The implications of chronobiology for the practice of clinical anaesthesia are probably of lesser importance because of the use of patient-controlled devices for pain management, monitoring of muscle paralysis and depth of anaesthesia monitors.

Erythromycin promotes gastric emptying during acute pain in volunteers.

In this double-blind cross-over study, we assessed whether erythromycin infusion is effective as a prokinetic drug against gastroparesis from acute pain. The effect of erythromycin on gastric emptying (GE) was measured in seven volunteers subjected to a standardized acute painful stimulus. The GE rate for solids was measured using the octanoic acid breath test. An acetaminophen absorption test measured the GE rate for liquids. Five minutes after ingestion of a 13C-labeled meal, the subjects received in randomized order either a test (placebo and erythromycin groups) or a control (control group) stimulus consisting of repeated 1-min immersion of a hand into 4 degrees C (test) or 37 degrees C (control) water, with 15 s for recovery between immersions, for a total of 20 min. While the stimulus was applied, 250 mL saline (control and placebo groups) or 250 mg erythromycin (erythromycin group) was infused. Pain and stress were evaluated using visual analog scales, and standard hemodynamic values were recorded throughout the study. Our results show that acute stress decreased GE for solids, which was significantly accelerated in the erythromycin group in comparison with the placebo group. GE for liquids was similar in the three groups. We conclude that erythromycin is effective as a prokinetic drug for solids in acute painful situations.

Spinal muscarinic and nicotinic subtypes activated by clonidine in postincisional pain.

BACKGROUND: A recent model of acute incisional pain has been characterized that strongly parallels the postoperative period in patients experiencing evoked pain. In that setting, abundant literature has revealed antihypersensitive effects produced by intrathecally administered alpha2-adrenergic receptor agonists, such as clonidine, in both animals and humans. Recent reports have suggested an obligatory role of spinal acetylcholine receptors in the analgesic action of intrathecal clonidine. The authors sought to determine the involvement of spinal muscarinic and nicotinic receptor subpopulations in the antihypersensitivity effect of intrathecal clonidine in a rodent model for human postoperative pain. METHODS: After intrathecal catheterization, rats underwent superficial plantar incision. Clonidine or a combination of clonidine and muscarinic receptor subtype antagonists (M1, M2, M3, and M4) or nicotinic receptor subtype antagonists (alpha4beta2 and alpha7) were intrathecally administered, and withdrawal thresholds to mechanical stimuli were examined. RESULTS: Spinal clonidine maximally reduced hypersensitivity adjacent to the wound 30 min after its injection. When animals were intrathecally pretreated with the M1 muscarinic antagonist toxin MT-7, the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine, and the M4 muscarinic antagonist toxin MT-3, clonidine lost its antihypersensitive action. When animals were intrathecally pretreated with the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine, but not with the alpha7 nicotinic receptor antagonist methyllycaconitine, the antihypersensitivity action of clonidine was abolished. CONCLUSIONS: These data indicate for the first time that the clonidine-induced increase in punctuate mechanical threshold is mediated via the activation of all but M2 muscarinic receptor subtypes, and via the activation of alpha4beta2 but not alpha7 nicotinic receptor subtypes in a rodent model for human postoperative pain.

Spinal nerve ligation increases alpha2-adrenergic receptor G-protein coupling in the spinal cord.

Intrathecal and epidural administration of the alpha2-adrenergic receptor agonist clonidine in humans results in analgesia to both acute nociceptive and chronic neuropathic pain. The potency of clonidine increases with hypersensitivity to mechanical stimuli after nerve injury, although the reasons for this change are unknown. In the present study, we tested the hypothesis that peripheral nerve injury alters either spinal alpha2-adrenergic receptor-mediated G-protein activity or alpha2-adrenergic receptor number. Rats were randomized to left spinal nerve ligation (SNL) or sham surgery. Tactile hypersensitivity in the hindpaw was confirmed and lumbar spinal cords were removed for binding assays. To examine agonist-induced G-protein coupling, [35S]GTP gamma S binding experiments were performed in spinal cord membranes and sections using norepinephrine as an alpha2-adrenergic agonist. SNL was associated with an increase in maximal efficacy, but not potency, of norepinephrine-stimulated [35S]GTP gamma S binding in dorsal horn. SNL had no effect on basal [35S]GTP gamma S binding or on muscarinic cholinergic-stimulated [35S]GTP gamma S binding. [35S]GTP gamma S autoradiography showed that this increase in alpha2-adrenergic-activated G-proteins occurred both ipsilateral and contralateral to SNL surgery. SNL did not alter total alpha2-adrenergic receptor number or affinity to [3H]-rauwolscine binding, and displacement studies with the alpha2A-adrenergic antagonist BRL44408 revealed that most of the binding was associated with the alpha2A-adrenergic subtype. These data suggest that the increased potency of clonidine in neuropathic pain could reflect increased efficiency of G-protein coupling from spinal alpha2-adrenergic receptors.

Patient-controlled regional analgesia is effective in children: a preliminary report.

PURPOSE: To report a preliminary analysis of prospectively recorded data in 27 children in whom patient-controlled regional analgesia (PCRA) was used for postoperative pain control following lower limb surgery. METHODS: Under general anesthesia, perineural catheters (popliteal and fascia iliaca compartment block) were inserted and infused with ropivacaine 0.2% (0.02 mL.kg(-1).hr(-1)). Additional demand doses were left to the child's discretion (0.1 mL.kg(-1)and a 30-min lockout interval). RESULTS: The average total dose of ropivacaine administered was 4.9 +/- 2 mg.kg(-1)over 48 hr. Visual analogue scale and Children's Hospital of Eastern Ontario Pain Scale scores were always inferior to 5/10 and 6/13, respectively. Motor block was observed in two children and two children needed rescue analgesia. CONCLUSIONS: Our preliminary observations indicate that PCRA in children provides satisfactory postoperative pain relief following lower limb surgery.

[Remifentanil is an effective alternative to propofol for patient-controlled analgesia during digestive endoscopic procedures]. / Le rémifentanil est une alternative efficace au propofol pour l'analgésie auto-contrôlée en endoscopie digestive.

PURPOSE: Unlike propofol, the self-administration of remifentanil for sedation in gastrointestinal endoscopies has never been evaluated formally. We wanted to compare the efficacy and tolerance of patient self-administration of remifentanil vs propofol during gastrointestinal endoscopy. METHOD: This prospective randomized, single-blinded study, included 77 patients undergoing gastrointestinal endoscopy. Patients were divided into two groups: group R received remifentanil (5 microg.kg(-1).hr(-1) infusion, 25 microg boli, refractory period of five minutes) and group P received propofol (2 mg.kg(-1).hr(-1) infusion, 0.5 mg.kg(-1) boli, refractory period of ten minutes). A 1 mg.kg(-1) bolus of propofol was administered before the procedure began in cases of marked anxiety. Additional boli of 25 microg of remifentanil or 0.5 mg.kg(-1) of propofol were administered when patients complained during the refractory period. The evaluation targeted analgesic efficacy during the procedure and patient satisfaction. The degree of sedation during the procedure and the occurrence of adverse reactions were analyzed. RESULTS: Patient satisfaction was high and comparable in both groups, with the number of awake and oriented patients being significantly higher in group R. Hemodynamic and respiratory tolerance was comparable in both groups, despite two episodes of desaturation in group R. The incidence of nausea was significantly higher in group R. CONCLUSIONS: The self-administration of remifentanil for sedation during gastrointestinal endoscopies is as effective as the self-administration of propofol and can be offered to patients, especially when it is desirable that they remain conscious during the procedure.

Patient-controlled epidural analgesia versus continuous epidural infusion with ropivacaine for postoperative analgesia in children.

UNLABELLED: Epidural ropivacaine infusion has been used in children; however, patient-controlled epidural analgesia (PCEA) has not been evaluated in the pediatric population. In this study, we compared the clinical efficiency of PCEA and of continuous epidural infusion analgesia (CEA) in children. Forty-eight children undergoing orthopedic surgery were randomized to receive PCEA or CEA with ropivacaine 0.2%. All patients underwent a standard general anesthetic. Children also received ketoprofen and propacetamol. Pain scores and side effects were recorded for 48 h. If the visual analog score scale score was >4 of 10, analgesia was considered inadequate, and rescue treatment was administered. Both groups obtained effective pain relief. Children in the PCEA group received significantly less local anesthetic than those in the CEA group (0.20 +/- 0.08 mg x kg(-1) x h(-1) versus 0.40 +/- 0.08 mg x kg(-1) x h(-1); P < 0.001). Motor effects, supplemental analgesic requirements, and side effects did not differ. We concluded that PCEA with ropivacaine 0.2% can provide adequate postoperative analgesia for pediatric orthopedic procedures with smaller dose requirements than CEA. IMPLICATIONS: We studied patient-controlled epidural analgesia (PCEA) and continuous epidural infusion analgesia (CEA) with 0.2% ropivacaine during the postoperative period in children. We found that either PCEA or CEA with plain ropivacaine 0.2% provided adequate pain relief in children during the first 48-h postoperative course. However, adequate analgesia was obtained with 50% less volume infused with PCEA compared with CEA.

Steady-state plasma and intrapulmonary concentrations of cefepime administered in continuous infusion in critically ill patients with severe nosocomial pneumonia.

OBJECTIVE: To determine the steady-state plasma and epithelial lining fluid concentrations of cefepime administered in continuous infusion in critically ill patients with severe bacterial pneumonia. DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Twenty adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled. INTERVENTIONS: All subjects received a 30-min intravenous infusion of cefepime 2 g followed by a continuous infusion of 4 g over 24 hrs. The concentrations of cefepime in plasma and epithelial lining fluid were determined at steady state after 48 hrs of therapy with high performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The mean +/- sd steady-state plasma and epithelial lining fluid concentrations of cefepime 4 g in continuous infusion were 13.5 +/- 3.3 microg/mL and 14.1 +/- 2.8 microg/mL, respectively, with a mean percentage penetration of cefepime into epithelial lining fluid of about 100%. CONCLUSIONS: The administration of 4 g of cefepime in continuous infusion in critically ill patients with severe nosocomial pneumonia appears to optimize the pharmacodynamic profile of this beta-lactam by constantly providing concentrations in excess of minimal inhibitory concentration of most of susceptible organisms over the course of therapy in both serum and epithelial lining fluid.

Spinal adrenergic and cholinergic receptor interactions activated by clonidine in postincisional pain.

BACKGROUND: Previous pharmacologic and molecular studies suggest that the alpha(2)-adrenoceptor subtype A is the target for spinally administered alpha(2)-adrenergic agonists, i.e., clonidine, for pain relief. However, intrathecally administered alpha(2) C antisense oligodeoxynucleotide was recently reported to decrease antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. The current study sought to determine the subtype of alpha(2) adrenoceptors activated by clonidine in a rodent model for human postoperative pain, and to examine its interaction with spinal cholinergic receptors. METHODS: Postoperative hypersensitivity was produced in rats by plantar incision of the hind paw and punctuate mechanical stimuli were applied around the wound 24 h after surgery. Effects of intrathecal clonidine and 2-(2,6-diethylphenylamino)-2-imidazoline (ST91) on withdrawal thresholds to the stimulus were determined. To examine the adrenoceptor subtype and its interaction with spinal cholinergic receptors, animals were intrathecally pretreated with vehicles BRL44408 (an alpha(2) A subtype-preferring antagonist), ARC239 (an alpha(2) non-A subtype-preferring antagonist), atropine (a muscarinic antagonist), and mecamylamine (a nicotinic antagonist). RESULTS: Intrathecal ST91 showed a significantly greater efficacy when compared with clonidine. The analgesic effect of clonidine was diminished by pretreatment with either adrenoceptor antagonist, whereas the effect of ST91 was solely blocked by ARC239 pretreatment. Atropine and mecamylamine abolished the effect of clonidine effect but not the effect of ST91. CONCLUSIONS: Both alpha(2) A and alpha(2) non-A adrenoceptors, as well as spinal cholinergic activation, are important to the antihypersensitivity effect of clonidine after surgery. ST91 is more efficacious in this model than clonidine and relies entirely on alpha(2) non-A adrenoceptors.

Ropivacaine 0.15% plus sufentanil 0.5 microg/mL and ropivacaine 0.10% plus sufentanil 0.5 microg/mL are equivalent for patient-controlled epidural analgesia during labor.

UNLABELLED: We compared the administration of 0.15% ropivacaine plus 0.5 microg/mL of sufentanil with that of 0.10% ropivacaine plus 0.5 microg/mL of sufentanil for labor analgesia with patient-controlled epidural analgesia (PCEA) to determine whether a decreased concentration of ropivacaine could produce equally effective analgesia. One-hundred-thirty healthy pregnant women at term were randomized in a double-blinded fashion. The PCEA settings were as follows: 12-mL initial bolus, 5-mL bolus dose, 5-min lockout interval, and 10 mL/h basal infusion. Patient demographics and labor characteristics were comparable in both groups. No differences were observed for pain scores, maternal satisfaction, volume of anesthetic solution administered, number of boluses requested and delivered, need for supplemental boluses, mode of delivery, motor block, side effects, or Apgar scores. Patients in the 0.10% ropivacaine group used significantly less drug than those in the 0.15% group (mean, 57 mg; 95% confidence interval, 50.5-63.5 mg; versus mean, 88.0 mg; 95% confidence interval, 74.4-93.3 mg, respectively; P < 0.0001). Ropivacaine 0.10% plus 0.5 microg/mL of sufentanil administered via PCEA for labor analgesia is equally effective as ropivacaine 0.15% plus 0.5 microg/mL of sufentanil, with a 30% local anesthetic-sparing effect and a 40% reduction in cost. However, this reduction in local anesthetic is not associated with a decrease in the incidence of motor block, side effects, or instrumental deliveries. IMPLICATIONS: Ropivacaine 0.10% plus 0.5 microg/mL of sufentanil given via patient-controlled epidural anesthesia for labor analgesia is equally as effective as ropivacaine 0.15% plus 0.5 microg/mL of sufentanil, with a 30% local anesthetic-sparing effect and a 40% reduction in cost. This reduction in ropivacaine concentration is not associated with a decrease in the incidence of motor block, side effects, or instrumental deliveries.

Clonidine-induced neuronal activation in the spinal cord is altered after peripheral nerve injury.

BACKGROUND: Alpha 2 adrenoceptor agonists produce antinociception in normal animals and alleviate mechanical allodynia in animals with nerve injury, although their mechanism of action may differ in these situations. The purpose of this study was to examine the location and number of cells in the spinal cord activated by intrathecal clonidine in these two circumstances and to test whether one class of interneurons, cholinergic, express alpha 2 adrenoceptors. METHODS: Intrathecal saline or clonidine, 10 and 30 microg, was injected in normal rats or those with mechanical allodynia following partial sciatic nerve section. Two hours later, animals were anesthetized and pericardially perfused. The number of cells in superficial and deep dorsal horn laminae at the L4-L5 level immunostained for phosphorylated cAMP response element binding protein (pCREB) were quantified. In separate studies, the authors colocalized alpha2C adrenoceptors with cholinergic neurons. RESULTS: Intrathecal clonidine increased pCREB immunoreactive cells in both superficial and deep laminae by 50-100% in normal animals. The number of pCREB immunoreactive cells increased in nerve-injured compared to normal rats. Intrathecal clonidine decreased pCREB immunoreactive cells in the deep dorsal horn of injured animals. Alpha2C adrenoceptors colocalized with cholinergic neurons in both superficial and deep dorsal horn. DISCUSSION: Previous studies suggest a shift in alpha 2 adrenoceptor subtype and the involvement of cholinergic interneurons in antinociception in the spinal cord after nerve injury. The current results suggest that intrathecal clonidine, by direct or indirect methods, increases neuronal activation in normal animals, presumably leading to net inhibition of pain signaling, whereas it reduces the increase in neuronal activity induced by nerve injury.

The induction of apoptosis by local anesthetics: a comparison between lidocaine and ropivacaine.

IMPLICATIONS: This study suggests that lidocaine can induce apoptosis (detected by dual staining with Annexin V and propidium iodide) on T-cell line cultures in a time-dependent manner. This was not observed with ropivacaine.

Peripheral nerve injury alters the alpha2 adrenoceptor subtype activated by clonidine for analgesia.

BACKGROUND: Previous studies suggest that the alpha adrenoceptor subtype is the target for spinally administered alpha -adrenergic agonists, clonidine, for pain relief. However, ST 91, a preferential alpha adrenoceptor subtype agonist, induces antinociception, and intrathecally administered alpha antisense oligodeoxynucleotide decreases antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. Therefore, the authors examined the subtype of alpha adrenoceptor activated by clonidine and ST 91 in normal rats and those with nerve injury-induced hypersensitivity. METHODS: The same mechanical stimulus was applied to normal rats and those following spinal nerve ligation, and the effect of intrathecal clonidine and ST 91 on withdrawal threshold to the stimulus was determined. To further examine subtypes, animals were spinally pretreated with vehicle, BRL 44408 (an alpha subtype-preferring antagonist), and ARC 239 (an alpha subtype-preferring antagonist). RESULTS: In normal animals, clonidine's effect was diminished by pretreatment with either antagonist, whereas ST 91's antinociceptive effect was solely blocked by pretreatment with ARC 239. In nerve-injured animals, the antihypersensitivity action of both clonidine and ST 91 was blocked by administration of ARC 239, whereas BRL 44408 was ineffective. CONCLUSIONS: These data agree with previous studies supporting that the alpha adrenoceptor is important to the antinociceptive effect of clonidine in normal animals. Nerve injury alters this and results in a total reliance on alpha adrenoceptors.

Effects of subhypnotic doses of propofol on gastric emptying in volunteers.

BACKGROUND: Drugs which accelerate gastric emptying (GE) decrease nausea and vomiting. This could contribute to the antiemetic potential of subhypnotic doses of propofol. On the contrary, subhypnotic doses of propofol used for sedation could decrease GE and thus favor regurgitation and pulmonary inhalation. Therefore, the aim of this study was to assess the effect of low-dose propofol infusion on GE. METHODS: On three separate occasions, 10 volunteers received either a propofol infusion at a rate set to achieve a target plasma concentration of 0.5 microg/ml or equivalent volumes of 10% Intralipid(R) or 0.9% saline. GE for solids was measured by using the octanoic acid breath test. An acetaminophen absorption technique measured the GE rate for liquids. Blood samples were assayed for acetaminophen and propofol. Breath samples were analyzed for (13)CO(2) concentration by isotope-ratio mass spectrometry. Carbon dioxide production (VCO(2)) was measured instead of calculated by indirect calorimetry. Sedation was evaluated by the Bispectral Index of the electroencephalogram. RESULTS: Propofol blood concentrations were 0.32 +/- 0.20 and 0.45 +/- 0.18 microg/ml at 60 and 165 min, respectively. These concentrations were not sedative. Propofol or its solvent did not modify GE for solids or liquids. In all groups, differences in GE were obtained if measured VCO(2) was integrated in the formula instead of calculated VCO(2) (P < 0.002). CONCLUSIONS: Subhypnotic doses of propofol known to be antiemetic do not inhibit GE. These results suggest that the antiemetic properties of propofol are not peripheral and that propofol cannot be considered as a prokinetic agent. V(13)CO(2) must be measured instead of calculated to accurately determine GE.

Chronobiology of epidural ropivacaine: variations in the duration of action related to the hour of administration.

BACKGROUND: A temporal pattern of the kinetics of local anesthetics is demonstrated in dental and skin anesthesia, with an important variation in the duration of action related to the hour of administration. The aim of this study is to determine whether the hour of injection influences the duration of epidurally administered ropivacaine during labor. METHODS: One hundred ninety-four women in the first stage of labor were assigned to one of four groups throughout the day period: group 1 (night: from 1:01 to 7:00 am), group 2 (morning: from 7:01 am to 1:00 pm), group 3 (afternoon: from 1:01 to 7:00 pm), and group 4 (evening: from 7:01 pm to 1:00 am). Each patient received 14 ml ropivacaine, 0.17%, epidurally, and analgesia duration was measured. RESULTS: Pain assessed by a visual analog score was not differ-ent among groups before the first injection of local anesthetic. Analgesia duration was greater in the diurnal period (group 2: 110 +/- 25 min and group 3: 117 +/- 23 min) compared with the nocturnal period (group 1: 94 +/- 23 min and group 4: 91 +/- 23 min) (P < 0.01). The largest intraday variation of analgesia duration among groups reached 28%. CONCLUSIONS: Epidural analgesia duration exhibits a temporal pattern with important differences among diurnal and nocturnal phases. The authors emphasize that the lack of consideration of the chronobiologic conditions in epidural analgesia studies may create significant statistical bias. Future studies dealing with epidural local anesthetics should consider the time of drug administration.

Alveolar and serum procalcitonin: diagnostic and prognostic value in ventilator-associated pneumonia.

BACKGROUND: The potential role of serum and alveolar procalcitonin as early markers of ventilator-associated pneumonia (VAP) and its prognostic value were investigated. METHODS: Ninety-six patients with a strong suspicion of VAP were prospectively enrolled. VAP diagnosis was based on a positive quantitative culture obtained via a mini-bronchoalveolar lavage of 103 colony-forming units/ml or more. Blood and alveolar samples were collected for procalcitonin measurement and analyzed for diagnostic and prognostic evaluation on days 0, 3, and 6. Sensitivity, specificity, positive likelihood ratio, and receiver-operating characteristic curves were analyzed to define ideal cutoff values and approach the decision analysis. RESULTS: Serum procalcitonin was significantly increased in the VAP group (n = 44) compared with the non-VAP group (n = 52): 11.5 ng/ml (95% confidence interval, 5.9-17.0) versus 1.5 ng/ml (1.1-1.9). A serum procalcitonin concentration greater than 3.9 ng/ml (best cutoff value) was considered positive for the VAP diagnosis (sensitivity, 41%; specificity, 100%). Serum procalcitonin was significantly increased in the non-survivors compared with the survivors for the VAP group: 16.5 ng/ml (95% confidence interval, 8.1-24.9) versus 2.9 ng/ml (1.2-4.7). The best cutoff value for serum procalcitonin of the nonsurvivors in the VAP group was 2.6 ng/ml (sensitivity, 74%; specificity, 75%; positive likelihood ratio, 2.96). Regarding VAP diagnosis and prognosis, no significant differences were found for alveolar procalcitonin in all groups. CONCLUSIONS: Serum but not alveolar procalcitonin seems to be a helpful parameter in the early VAP diagnosis and an appropriate marker for predicting mortality.