| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
© 1999 International Anesthesia Research Society
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
We assessed the sedative potential of continuous infusions of remifentanil with a validated composite alertness scale in 160 patients (ASA physical status I or II) undergoing hip replacement surgery with spinal block (n = 61) or hand surgery using brachial plexus block (n = 93). They were randomized to receive one of the following initial dose regimens in double-blinded fashion: placebo or 0.04, 0.07, or 0.1 µg · kg-1 · min-1 remifentanil subsequently titrated to effect. Additional midazolam IV was allowed for adequate sedation as required. The combined analysis of both surgery groups revealed a dose-related increase in achievement of sedation level
2 within 15 min of the start of the study drug infusion; all remifentanil dose comparisons with placebo reached significance (P < 0.001). The remifentanil 50% effective dose for a composite sedation level 2 within 15 min of the start of drug infusion was estimated as 0.043 µg · kg-1 · min-1 (95% confidence interval 0.01, 0.059). The requirement for midazolam decreased with increasing remifentanil dose compared with placebo (P < 0.001). The median time to return to alertness after the end of infusion was 10–12 min in the remifentanil groups and 5 min in the placebo group. Significant incidences of nausea, pruritus, sweating, and respiratory depression were reported during remifentanil infusions compared with placebo. The data suggest that remifentanil may be useful for supplementation of regional anesthesia, provided that ventilation is carefully monitored. Implications: In this dose-finding, placebo-controlled study, remifentanil infusions were used to provide sedation during spinal and brachial plexus regional anesthesia. The 50% effective dose for achievement of sedation was 0.043 µg · kg-1 · min-1. Return to alertness occurred after 10–12 min (median time). Remifentanil infusions can be used to supplement regional anesthesia, but this requires careful monitoring of ventilation.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Regional anesthesia techniques may require additional supplementation with sedatives or analgesics. Anxiety, apprehension, and fear can greatly enhance the severity of the pain or the discomfort experienced during locoregional blocks. Sedatives (propofol, midazolam) are considered benign and preferable to opioids when sedation is required in patients to control their emotional distress and to inhibit the associated sympathetic arousal. The benzodiazepines can reduce pain levels that have been increased by the presence of anxiety. Most of the benzodiazepines have fairly prolonged activity, and accumulation of the drug or its metabolites can occur, particularly in the elderly. Amnesic effects and daytime sedation may be disturbing for some patients. Hypnotics such as propofol produce better sedation than midazolam, but both drugs may lower blood pressure. There are particular risks of sedatives/hypnotics use in locoregional techniques, as they may destabilize precarious hemodynamic compensation. Both drugs have significant effects on respiratory function by shifting CO2 responsiveness and depression of the hypoxic respiratory drive (1–5).
The narcotic-type analgesics produce sedation and drowsiness. These effects may be useful in certain clinical situations. Sedation is characteristic of potent µ-receptor opioid drugs and is probably mediated through µ1-receptor effects on acetylcholine release in the medial pontine reticular formation (6). In the brain, the highest concentrations of opioid receptors are found in the limbic system, most particularly the amygdala, and in the frontal and temporal cortex and the hippocampus (7). These areas are primarily involved with affect, rather than with analgesia. Their activation reduces the behavioral perception of pain. These properties of opioids and their supraspinal and spinal antinociception may be useful during regional anesthesia, in which local anesthetics induce somatosensory analgesia and sympathetic block.
Opioid administration may relieve pain and discomfort from injection or from traction on deep structures, electrocautery, or posture, or may augment the local block when surgery is more extensive or the block is diminishing (8). Severe pain or discomfort in regional anesthesia requires that the patients be made comfortable as soon as possible. Titration to effect should take only minutes. Remifentanil, a selective esterase-metabolized µ-opioid receptor agonist with potent analgesic activity, has pharmacokinetic/pharmacodynamic properties that facilitate rapid titration (9) and control of clinical end points.
Quantifying alertness/sedation is highly subjective. Commonly, five-point categorical scales and visual analog scales are used (10,11), but these have not been validated. The Observer's Assessment of Alertness/Sedation (OAA/S) scale seems to be a more objective measure of the level of alertness in sedated subjects (12). The composite sedation score from the scale takes into account several separate variables considered important in assessing sedation, such as responsiveness, speech, facial expression, and degrees of ptosis.
The main purposes of this study were to estimate the remifentanil 50% and 90% effective doses (ED50 and ED90, respectively) for achievement of a composite sedation level 2 within 15 min of initiating the study drug infusion and to assess the safety of remifentanil throughout the regional anesthesia procedure.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A central ethics committee nominated for this study and the local ethics committees of the participating centers approved it. Written, informed consent was obtained from each patient. One hundred sixty male and female patients, ASA physical status I or II, aged 18–75 yr and weighing within 50% of their ideal body weight, who were undergoing routine hip replacement under spinal anesthesia or hand surgery under brachial plexus block via the axillary route participated. Women who were pregnant or breast-feeding or who had a positive pregnancy test on the day of treatment were excluded from the study, as were patients who had chronically used oral opioids or had received parenteral opioids or other anesthetics within 4 wk of the study day.
In an initial pilot study, six patients received either 0.04 or 0.1 µg · kg-1 · min-1 remifentanil infusions. In the double-blinded phase, patients were randomly allocated to receive one of the following initial dose regimens: 0.04, 0.07, or 0.10 µg · kg-1 · min-1 remifentanil or placebo (saline). The randomization was stratified by center. No premedication was administered. The study included three separate periods: an initial sedation phase, the regional block phase, and the operative phase. Respiratory rate (RR), percentage oxygen saturation (SpO2), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and the OAA/S score were assessed before and at 5-min intervals after the start of the infusion. The OAA/S five-point scale was used to assess sedation by measuring four component categories, and the composite score was assigned according to the highest component score given at a specified time (12). A composite score 2 indicated at least one component category 2. Patient comfort and anxiety scores were measured at baseline, after regional block placement, and 4 h postoperatively. Both were assessed with separate five-point scales grading the patient from "completely comfortable" to "extremely uncomfortable" and from "completely calm" to "extremely anxious." The investigators rated their impression on the result of treatment using a five-point scale as "completely satisfied," "slightly satisfied," "neutral," "somewhat unsatisfied," and "completely unsatisfied."
After baseline evaluation, patients received an IV infusion of the study drug fixed at 12 mL/h for the first 15 min of the procedure unless a safety end point was reached. In this case, the infusion rate was reduced by 50% or discontinued. Specific safety end points were defined as follows: the infusion rate would be halved if respiratory depression occurred (RR <8 breaths/min for >30 s or SpO2 decreased to <94% while oxygen was administered). This infusion was stopped if RR decreased to <6 breaths/min or if SpO2 decreased <90% while oxygen was administered. In patients with bradycardia (HR <55 bpm) or any clinically significant HR decrease that was unresponsive to atropine treatment, the infusion was halved or discontinued as necessary. If the study drug was stopped, patients were considered withdrawn from the study, and any further efficacy assessments for that patient were treated as missing data.
Study drug infusion rates could be increased in steps of 6 mL/h at 5-min intervals as required to achieve a composite sedation level 2. If patients were not adequately sedated 10 min after the third infusion increment (30 mL/h), they could be given supplemental midazolam 0.5 mg IV at 3-min intervals as required to achieve adequate sedation before placement of the regional block and thereafter.
The regional block phase commenced with the placement of the block according to a standardized procedure. Adequacy of the regional block and investigator satisfaction were assessed at 10 and 20 min in the hip and hand surgical groups, respectively, while the infusion was kept constant. Vital signs and sedation were assessed every 5 min. In the event of a failed regional block, as defined by the investigator, the study drug was discontinued, and the patient was withdrawn from the study. During the operative phase, adequate sedation was maintained with a continuous infusion of the study drug and supplemental midazolam if required.
After drug infusion at the end of surgery (last suture), postoperative vital signs and sedation levels were assessed at 5-min intervals for 30 min; thereafter at 30-min intervals for up to 4 h, at which time the investigator satisfaction score was also recorded; and thereafter at 4-h intervals until 24 h. The time to return of alertness was noted. All adverse events during the study were recorded.
The primary efficacy variable was achievement of an OAA/S score 2 within 15 min of starting the drug infusion. Secondary end points included the requirement for midazolam, investigator satisfaction scores, patient comfort, and anxiety scores. Safety assessments included the incidence of adverse events and vital sign measurements throughout the study.
The sample size was based on an estimate of 80% of patients at the largest remifentanil dose achieving a sedation level 2 compared with 20% of patients receiving placebo treatment. The safety population was defined as all patients who received the study drug. The intent-to-treat population was defined as all randomized patients who received at least one dose of the study drug and who had at least one postdose efficacy measurement. All tests of significance were two-sided and were performed at the 5% level. The primary efficacy variable and the dose-response curves for estimation of the ED50 and the ED90 were analyzed using logistic regression (13). The effect of surgery type, center, age, gender, weight, and ASA physical status, combined with all pairwise interactions with treatment, were investigated. Time to return of alertness was analyzed by using Cox's proportional hazards model (14). The proportion of patients who required midazolam was analyzed by using logistic regression, and investigator satisfaction scores were analyzed by using the Wilcoxon rank-sum test with pairwise comparison of each remifentanil group versus placebo (13). Analysis of vital signs was performed by using analysis of covariance allowing for treatment, surgery type, and center within surgery type with prestudy drug baseline as covariate.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The hip surgery group was older than the hand surgery group, but all other demographic factors were relatively well balanced across surgery and treatment groups (Table 1). Thirteen patients, all from the remifentanil groups, were withdrawn during the study because of adverse events; eight were due to respiratory depression and/or oxygen desaturation (SpO2 <90%). Regional anesthesia was considered incomplete in 7%–19% of patients belonging to the remifentanil subgroups in hip surgery and in 30%–35% of patients in all subgroups in hand surgery.
|
Because the treatment effects were consistent across the hand and hip surgery groups, the data from both groups were analyzed together. The ED50 for achievement of a composite sedation level
2 within 15 min was estimated as 0.043 µg · kg-1 · min-1 (95% confidence interval 0.01, 0.059), but an accurate estimate of the ED90 could not be obtained because the estimate was outside the studied dose range. Compared with placebo, all remifentanil groups manifested a significant dose-related increase in achievement of a composite sedation level 2: 8% on placebo compared with 49%, 62%, and 77% on initial infusion rates of 0.04, 0.07, and 0.1 µg · kg-1 · min-1 remifentanil, respectively (P < 0.05) (Fig. 1). There was no significant interaction with treatment or actual effect on response for surgery type, study center, age, gender, weight, and ASA physical status.
|
Requirement for supplemental midazolam decreased across treatment groups, from 95% in the placebo group to 18% in the 0.1 µg · kg-1 · min-1 remifentanil group (Fig. 2, Table 1). All pairwise comparisons of remifentanil versus placebo were significant (P < 0.001).
|
Investigator satisfaction scores were significantly better in both surgery groups for all comparisons of remifentanil with placebo during the regional block phase and 4 h postinfusion (P < 0.01). Patient comfort and anxiety scores were similar among all groups during the regional block phase, although patient comfort was significantly better in the 0.1 µg · kg-1 · min-1 remifentanil group compared with placebo (P < 0.03) in the hand surgery subgroup.
RR before and during the regional block phase was significantly slower in all remifentanil groups, with a difference of 3–4 breaths/min compared with placebo (P < 0.001) (Fig. 3). SBP, DBP, HR, and SpO2 values in these intervals did not differ significantly among treatment groups. Across surgery groups, the weighted mean infusion rates were similar. The mean final remifentanil infusion rates during the operative period varied between 0.05 and 0.1 µg · kg-1 · min-1 (Table 2). The time to return to alertness (i.e., composite sedation level 1) was faster in the placebo group (median 5 min) than in the remifentanil groups (median 10–12 min), although this was only significant for the 0.07 µg · kg-1 · min-1 group (P < 0.05).
|
= 0.04 µg · kg-1 · min-1 remifentanil, 
= 0.07 µg · kg-1 · min-1 remifentanil, 
= 0.10 µg · kg-1 · min-1 remifentanil. Mean values ± SEM.
|
Incidences of O2 desaturation were seen during remifentanil infusions and occurred in 12% of the patients receiving 0.1 µg · kg-1 · min-1 remifentanil (Table 3). The most commonly reported adverse events during drug infusion were sweating, hypotension, bradycardia, nausea, respiratory depression, and pruritus. The incidence of respiratory depression, pruritis, and sweating was significantly higher in patients who received doses of remifentanil
0.07 µg · kg-1 · min-1 than in patients who received placebo (P < 0.05). Postoperatively, nausea and vomiting were reported in all patient groups, with no statistically significant differences in the incidence of these adverse events.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We assessed the sedative potential of remifentanil during regional anesthesia using OAA/S scoring system (12). The patients were maintained between composite sedation levels 2 and 3 for most of the case by rapid titration of a remifentanil infusion. An accurate estimate of the ED90 could not be obtained from the combined dose-response data, but the ED50 was estimated as 0.043 µg · kg-1 · min-1. No significant effect of either surgery type or age on the overall attainment of sedation level
2 was seen. Combined analysis of surgery groups showed that, even at the lowest infusion rate (0.04 µg · kg-1 · min-1), significantly more patients attained adequate sedation compared with placebo treatment. This suggests that the scoringsystem was an objective and sensitive measure for sedation, the primary end point. Regional anesthetic techniques often produce inadequate surgical anesthesia (15). Benzodiazepines and small amounts of opioids are widely used to improve patient cooperation by their anxiolytic, amnestic, and sedative properties (16) and to provide additional analgesia. In this study, incomplete anesthesia was present in many patients in both surgery groups. The titrated remifentanil infusions appropriately supplemented the incomplete somatosensory analgesia of the regional block, as shown by the similar patient sedation, comfort, and anxiety scores within all treatment groups during the operative phase. In the placebo group, this effect was achieved through the greater use of midazolam, whereas there was a lesser requirement for supplemental midazolam in the remifentanil groups. This finding supports the hypothesis of a synergistic interaction between remifentanil and midazolam (17) similar to that documented for other opioids (18,19).
The remifentanil infusions had no effect on the hemodynamic variables and only affected the RR. The mean final infusion rate of 0.05–0.1 µg · kg-1 · min-1 was within the range documented for anesthetic procedures with spontaneous ventilation (20–22). There was no clear dose-related trend in the incidence of respiratory depression due to the ability to titrate the remifentanil infusion according to response. Thus, the overall incidence of respiratory depression/hypoxia requiring the patient be withdrawn from the study was low (5%). Opioid antagonists were not required in any of these patients. The administration of supplemental doses of midazolam may have contributed to the respiratory effects (17). Indeed, synergistic effects of benzodiazepines and opioids on the respiratory system have been reported (23).
Time to alertness was faster in the placebo group (median 5 min) despite the larger amounts of midazolam administered. This was not unexpected, as the sedative effects of midazolam at doses used in this study disappear within 3 h with recovery of psychomotor functions (24). The extensive metabolic clearance of remifentanil, its lack of accumulation, and its short pharmacokinetic context-sensitive half-time of 2–5 min would lead one to predict a rapid return to alertness across all remifentanil treatment groups when the infusion was discontinued. In all remifentanil groups, the median time to alertness was 10–12 min. This corresponds closely to the reported measured pharmacodynamic context-sensitive half-time of 2–8 min (25).
No clear dose-related increase in any of the most commonly reported events was found despite their increased incidence during the remifentanil infusions compared with placebo. The incidence of nausea, sweating, and respiratory depression was significantly higher in all remifentanil groups compared with placebo. These incidences are similar to those reported during monitored anesthesia care (17) and regional anesthesia (21,22). Nausea and vomiting occurred with similar incidences in the placebo and remifentanil groups during the postoperative period.
In conclusion, a continuous infusion of remifentanil achieved a composite sedation level 2 within 15 min compared with placebo and produced a dose-related decrease in the requirement for midazolam. Titration of a remifentanil infusion allowed control and maintenance of the degree of sedation, as would be expected from its rapid pharmacokinetics/pharma-codynamics, but time to alertness was longer in all the remifentanil groups compared with the placebo group. The potent respiratory depressant effect of remifentanil emphasizes the need to carefully monitor ventilation during its infusion.
|
Acknowledgments |
|---|
This work was supported by a grant from Glaxo Wellcome Research and Development Ltd.
The following anesthetists contributed to this study as members of the International Study Team investigating remifentanil adjunct to regional anesthesia: C. Vanlersberghe, Belgium; A. Helle, D. Krohn, A. Stubhaug, E. Lien, Norway; O. Nyström, B. Lantz, N. Wasberg, M. Hessel, Sweden; K. Eggers, M. J. Evans, I. Power, T. Asai, United Kingdom; and J. Viby-Mogensen, T. Mogensen, Denmark.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Gross JB, Zebrowski ME, Carel WD, et al. Time course of ventilatory depression after thiopental and midazolam in normal subjects and in patients with chronic obstructive pulmonary disease. Anesthesiology 1983;58:540–4.[Web of Science][Medline]
-
Foster A, Morel D, Bachman M, et al. Respiratory depressant effects of different doses of midazolam and lack of reversal with naloxone A double-blind randomized study. Anesth Analg 1983;62:920–4.
[Abstract/Free Full Text] -
Alexander CM, Gross JB. Sedative doses of midazolam depress hypoxic ventilatory responses in humans. Anesth Analg 1988;67:377–82.
[Abstract/Free Full Text] - Rosa G, Conti G, Orsi P, et al. Effects of low-dose propofol administration on central respiratory drive, gas exchanges and respiratory pattern. Acta Anaesthesiol Scand 1992;36:128–31.[Medline]
- Blouin RT, Seifert HA, Babenco HD, et al. Propofol depresses the hypoxic ventilatory response during conscious sedation and isohypercapnia. Anesthesiology 1993;79:1177–82.[Medline]
- Lydic R, Keifer JC, Baghdoyan HA, et al. Microdialysis of the pontine reticular formation reveals inhibition of acetylcholine release by morphine. Anesthesiology 1993;79:1003–12.[Web of Science][Medline]
- Kuhar MJ, Pert CB, Snyder SH. Regional distribution of opiate receptor binding in monkey and human brain. Nature 1973;245:447–51.[Medline]
- Smith I, Taylor E. Monitored anesthesia care. In: White PF, ed. International Anesthesiology Clinics: Anesthesia for ambulatory surgery. Boston:Little Brown Co, 1994:99–112.
- Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short acting opioid remifentanil (GI 87084B) in healthy adult volunteers. Anesthesiology 1993;79:881–92.[Web of Science][Medline]
-
Samra SK, Bradshaw EG, Pandit SK, et al. The relation between lorazepam-induced auditory amnesia and auditory evoked potentials. Anesth Analg 1988;67:526–33.
[Abstract/Free Full Text] -
Taub HA, Eisenberg L. An evaluation of memory under regional anesthesia with iv lorazepam as premedicant. Anesth Analg 1976;55:368–73.
[Abstract/Free Full Text] - Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51.[Web of Science][Medline]
- Peace KE. Biopharmaceutical statistics for drug development. New York:Marcel Dekker Inc, 1988:403–53.
- Cox DR, Oakes D. Analysis of survival data. New York:Chapman and Hall, 1984:91–110.
- Schroeder LE, Horlocker TT, Schroeder DR. The efficacy of axillary block for surgical procedures about the elbow. Anesth Analg 1996;83:747–51.[Abstract]
- White PF, Negus JB. Sedative infusions during local and regional anesthesia a comparison of midazolam and propofol. J Clin Anesth 1993;3:32–9.
- Avramov M, Smith I, White PF. Interactions between midazolam and remifentanil during monitored anesthesia care. Anesthesiology 1996;85:1283–9.[Web of Science][Medline]
-
Kissin I, Vinik HR, Castillo R, et al. Alfentanil potentiates midazolam induced unconsciousness in subanalgesic doses. Analg 1990;71:65–9.
[Abstract/Free Full Text] - Short TG, Plummer JL, Chui PT. Interactions between propofol, alfentanil and midazolam. Anaesth 1992;69:162–7.
- Peacock JE, Luntley JB, O'Connor B, et al. Remifentanil in combination with propofol for spontaneous ventilation anaesthesia. Anaesth 1998;80:509–11.
- Lauwers MH, Vanlersberghe C, Camu F. Comparison of remifentanil and propofol infusions for sedation during regional anesthesia. Reg Anesth Pain Med 1998;23:64–70.[Web of Science][Medline]
- Mingus ML, Monk TG, Gold MI, et al. Remifentanil versus propofol as adjuncts to regional anesthesia. J Clin Anesth 1998;10:46–53.[Web of Science][Medline]
- Bailey PL, Pace NL, Ashburn MA, et al. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990;73:826–30.[Web of Science][Medline]
- Nuotto EJ, Korttila KT, Lichtor JL, et al. Sedation and recovery of psychomotor function after intravenous administration of various doses of midazolam and diazepam. Anesth Analg 1992;74:265–71.[Web of Science][Medline]
- Kapila A, Glass PSA, Jacobs JR, et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995;83:968–75.[Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  M. R. Rai, T. M. Parry, A. Dombrovskis, and O. J. Warner Remifentanil target-controlled infusion vs propofol target-controlled infusion for conscious sedation for awake fibreoptic intubation: a double-blinded randomized controlled trial Br. J. Anaesth., January 1, 2008; 100(1): 125 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Van de Velde, D. Van Schoubroeck, L. E. Lewi, M. A.E. Marcus, J. C. Jani, C. Missant, A. Teunkens, and J. A. Deprest Remifentanil for Fetal Immobilization and Maternal Sedation During Fetoscopic Surgery: A Randomized, Double-Blind Comparison with Diazepam Anesth. Analg., July 1, 2005; 101(1): 251 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-M. Machata, C. Gonano, A. Holzer, D. Andel, C. K. Spiss, M. Zimpfer, and U. M. Illievich Awake Nasotracheal Fiberoptic Intubation: Patient Comfort, Intubating Conditions, and Hemodynamic Stability During Conscious Sedation with Remifentanil Anesth. Analg., September 1, 2003; 97(3): 904 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Burmeister, T. G. Standl, M. Wintruff, P. Brauer, I. Blanc, and J. Schulte am Esch Dolasetron prophylaxis reduces nausea and postanaesthesia recovery time after remifentanil infusion during monitored anaesthesia care for extracorporeal shock wave lithotripsy Br. J. Anaesth., February 1, 2003; 90(2): 194 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Saidman and R. D. Miller Drug Company-Supported Symposia: What Should Be Disclosed? Response Anesth. Analg., August 1, 2000; 91(2): 495 - 496. [Full Text] [PDF]
|
|
|
|
|
|
G. K. Federolf and M. Lauwers Remifentanil for Regional Anesthesia • Response Anesth. Analg., August 1, 1999; 89(2): 535 - 535. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
