Brian Ginsberg

The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the bispectral index

The Bispectral Index (BIS) correlates well with the level of consciousness with single anesthetic drugs.We studied the effect of the interaction of propofol with alfentanil on propofol concentration and BIS associated with 50% probability of loss of consciousness and lack of recall (Cp50 and BIS50,

Pharmacokinetics of Remifentanil in Anesthetized Pediatric Patients Undergoing Elective Surgery or Diagnostic Procedures

Remifentanil hydrochloride is an ultra-short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases. We aimed to characterize the pharmacokinetics and determine the hemodynamic profile of remifentanil after a single-bolus dose in children aged 0 to 18 yr. Forty-two children undergoing elective surgical procedures received remifentanil 5 &mgr;g/kg infused over 1 min. Patients were divided into age groups as follows: young infants (≤2 mo), older infants (>2 mo to <2 yr), young children (2 to <7 yr), older children (7 to <13 yr), adolescents (13 to <16 yr), and young adults (16 to <18 yr). Arterial blood samples were collected and analyzed by mass spectroscopy to determine remifentanil pharmacokinetic profiles. Hemodynamic measurements for remifentanil’s effect were made after the infusion. Methods of statistical analysis included analysis of variance and linear regression, with significance at P ≤ 0.05. Complete remifentanil pharmacokinetic data were obtained from 34 patients. The volume of distribution was largest in the infants <2 mo (mean, 452 mL/kg) and decreased to means of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants <2 mo of age (90 mL · kg−1 · min−1) and infants 2 mo to 2 yr (92 mL · kg−1 · min−1) than in the other groups (means, 46 to 76 mL · kg−1 · min−1). The half-life was similar in all age groups, with means of 3.4 to 5.7 min. Seven subjects (17%) developed hypotension related to the remifentanil bolus. Remifentanil showed an extremely rapid elimination similar to that in adults. The fast clearance rates observed in neonates and infants, as well as the lack of age-related changes in half-life, are in sharp contrast to the pharmacokinetic profile of other opioids. Remifentanil in a bolus dose of 5 &mgr;g/kg may cause hypotension in anesthetized children.

Opioid-sparing Effects of a Low-dose Infusion of Naloxone in Patient-administered Morphine Sulfate

Background: A naloxone infusion is effective in reducing epidural and intrathecal opioid‐related side effects. The use of naloxone infusion concomitant with intravenous morphine patient‐controlled analgesia (PCA) has not been evaluated, probably because of an expected direct antagonism of the systemic opioid effect. The authors compared the incidence of morphine‐related side effects and the quality of analgesia from two small doses of naloxone infusion. Methods: Sixty patients classified as American Society of Anesthesiologists physical status 1, 2, or 3 who were scheduled for total abdominal hysterectomies were enrolled in the study. Patients received a standardized general anesthetic. In the postanesthetic care unit, patients received morphine as a PCA. They were randomized to receive either 0.25 micro gram [center dot] kg sup ‐1 [center dot] h sup ‐1 naloxone (low dose), 1 micro gram [center dot] kg sup ‐1 [center dot] h sup ‐1 (high dose), or saline (placebo) as a continuous infusion. Verbal rating scores for pain, nausea, vomiting, and pruritus; sedation scores; requests for antiemetic; and morphine use were recorded for 24 h. Blood pressure, respiratory rate, and oxyhemoglobin saturation were also monitored. Results: Sixty patients completed the study. Both naloxone doses were equally effective in reducing the incidence of nausea, vomiting, and pruritus compared with placebo (P < 0.05 by the chi‐squared test). There was no difference in the verbal rating scores for pain between the groups. The cumulative morphine use was the lowest in the low‐dose group (42.3 +/‐ 24.1 mg; means +/‐ SD) compared with the placebo (59.1 +/‐ 27.4 mg) and high‐dose groups (64.7 +/‐ 33.0 mg) at 24 h (P < 0.05 by analysis of variance). There was no incidence of respiratory depression (< 8 breaths/min) and no difference in sedation scores, antiemetic use, respiratory rate, and hemodynamic parameters among the groups. Conclusions: Naloxone is effective in preventing PCA opioid‐related side effects. Naloxone infusion at 0.25 micro gram [center dot] kg sup ‐1 [center dot] h sup ‐1 not only attenuates these side effects but appears to reduce postoperative (beyond 4–8 h) opioid requirements. This dosing regimen can be prepared with 400 micro gram naloxone in 1,000 ml crystalloid given in 24 h to a patient weighing 70 kg.

Use of patient-controlled analgesia to compare the efficacy of epidural to intravenous fentanyl administration.

Fentanyl, unlike morphine, is highly lipophilic and rapidly diffuses out of the epidural space. Respiratory depression is, therefore, unlikely when fentanyl is given epidurally. However, much of fentanyls analgesic effect is mediated by systemic rather than spinal receptor binding. To test this hypothesis, we performed a prospective, double-blind, cross-over study comparing epidural and intravenous (IV) administration of fentanyl in 16 patients for the first 12 h after lower abdominal or lower extremity surgery. To allow direct comparison of these two routes of administration, patient-controlled analgesia was used so patients could self-titrate their analgesia. Patients were randomized to receive fentanyl initially by an epidural (group A, n = 8) or IV (group B, n = 8) catheter for 6 h, after which they were crossed-over to the alternate route by means of a hidden three-way stopcock. The degree of analgesia was subjectively evaluated by a visual analogue scale, and by an observer rating patients comfort and sedation. Cumulative dosage of fentanyl was recorded, and plasma fentanyl concentrations were measured. The onset of analgesia and increase in plasma fentanyl concentrations were more rapid with intravenous fentanyl. However, after 60 min, analgesia (visual analogue scale 2-4 cm) or plasma fentanyl concentrations (0.3-0.7 ng/mL) did not differ between the two routes of administration. There were also no significant differences in the cumulative dosage of fentanyl within each group (epidural vs IV) or between the groups. Thus, the analgesic effects of epidural fentanyl appear largely mediated by systemic absorption. Intravenous fentanyl achieves a similar degree of analgesia and a more rapid onset of effect without the need for epidural catheterization.

Meperidine: a critical review.

Meperidine was initially synthesized as an anticholinergic agent but was soon discovered to have analgesic properties. Although meperidines anticholinergic effects were demonstrated in vivo, the anticholinergic effects on the biliary and renal tracts have not been demonstrated in vivo. Studies have clearly demonstrated that meperidine is no more efficacious in treating biliary or renal tract spasm than comparative mu opioids. The initial studies demonstrating the analgesic efficacy of meperidine were mostly case reports and not double-blind, randomized, controlled trials in specific populations. Subsequent comparative studies failed to demonstrate any advantages of meperidine over comparable doses of other analgesics. Meperidine was portrayed in practice and teaching as having unique clinical advantages. The analgesic effects of meperidine are not pronounced, and, in addition, meperidine use is complicated by unique side effects including serotonergic crisis and normeperidine toxicity. Meperidines poor efficacy, toxicity, and multiple drug interactions have resulted in a movement to replace meperidine with more efficacious and less toxic opioid analgesics.

Double-blind, randomized comparison of ondansetron and intraoperative propofol to prevent postoperative nausea and vomiting.

Background Breast surgery is associated with a high incidence of postoperative nausea and vomiting. Propofol and prophylactic administration of ondansetron are associated with a lower incidence of postoperative nausea and vomiting. To date no comparison of these two drugs has been reported. A randomized study was done to compare the efficacy of ondansetron and intraoperative propofol given in various regimens. Methods Study participants included 89 women classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled for major breast surgery. Patients were randomly assigned to one of four groups. Group O received 4 mg ondansetron in 10 ml 0.9% saline and groups PI, PIP, and PP received 10 ml 0.9% saline before anesthesia induction. Group O received thiopental, isoflurane, nitrous oxide-oxygen, and fentanyl for anesthesia. Group PI received propofol, isoflurane, nitrous oxide-oxygen, and fentanyl. Group PIP received propofol, isoflurane, nitrous oxide-oxygen, and fentanyl. Thirty minutes before expected skin closure, isoflurane was discontinued and 50 to 150 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 propofol was given intravenously to maintain anesthesia. Group PP received propofol for induction and maintenance of anesthesia, nitrous oxide-oxygen, and fentanyl. Postoperative pain relief was provided with morphine administered by a patient-controlled analgesia pump. The incidence of nausea and vomiting, requests for rescue antiemetic and sedation, pain scores, and hemodynamic data were recorded for 24 h. Results Within 6 h of surgery, groups O and PP had a lower incidence of nausea compared with groups PI and PIP (P < 0.05). Fewer patients in group PP (19%) vomited during the 24-h period compared with groups O (48%), PI (64%), and PIP (52%) (P < 0.05). The incidence of antiemetic use was also less in group PP (P < 0.05). Patients in group PP had lower sedation scores at 30 min and at 1 h (P < 0.05). There were no differences among the groups in pain scores, blood pressure, heart rate, respiratory rate, and incidence of pruritus. Conclusions Propofol administered to induce and maintain anesthesia is more effective than ondansetron (with thiopental-isoflurane anesthesia) in preventing postoperative vomiting and is associated with fewer requests for rescue antiemetic and sedation in the early phase of recovery. It is equally effective in preventing postoperative nausea as ondansetron in the first 6 h after operation. Propofol used only as an induction agent or for induction and at the end of surgery were not as protective against postoperative nausea and vomiting.

Acute Post-Surgical Pain Management: A Critical Appraisal of Current Practice

The Acute Pain Summit 2005 was convened to critically examine the perceptions of physicians about current methods used to control postoperative pain and to compare those perceptions with the available scientific evidence. Clinicians with expertise in treatment of postsurgical pain were asked to evaluate 10 practice-based statements. The statements were written to reflect areas within the field of acute-pain management, where significant questions remain regarding everyday practice. Each statement made a specific claim about the usefulness of a specific therapy (eg, PCA or epidural analgesia) or the use of pain-control modalities in specific patient populations (eg, epidural analgesia after colon resection). Members of the American Society of Regional Anesthesia and Pain Medicine (ASRA) were asked, via a Web-based survey, to rate their degree of agreement with each of the 10 statements; 22.8% (n = 632) of members responded. In preparation for the pain summit, a panel member independently conducted a literature search and summarized the available evidence relevant to each statement. Summit participants convened in December 2005. The assigned panel member presented the available evidence, and workshop participants then assigned a category for the level of evidence and recommendation for each statement. All participants then voted about each statement by use of the same accept/reject scale used earlier by ASRA members. This manuscript details those opinions and presents a critical analysis of the existing evidence supporting new and emerging techniques used to control postsurgical pain.

The Successful Implementation of Pharmaceutical Practice Guidelines Analysis of Associated Outcomes and Cost Savings

Background: Although approximately 2,000 medical practice guidelines have been proposed, few have been successfully implemented and sustained. We hypothesized that we could develop and institute practice guidelines to promote more appropriate use of costly anesthetics, to generate and sustain widespread compliance from a large physician group, and to decrease costs without adversely affecting clinical outcomes. Methods: A prospective before and after comparison study was performed at a tertiary care medical center. Clinical outcomes data and times indicative of perioperative patient flow were collected on the first of two sets of patients 1 month before discussion of practice guidelines. Practice guidelines were developed by the physicians and their associated care team for the intraoperative use of anesthetic drugs. A drug distribution process was developed to aid compliance. Clinical outcomes data and times indicative of perioperative patient flow were collected on the second set of patients 1 month after institution of practice guidelines. Hospital drug costs and adherence to guidelines were noted throughout the study period and for each of the following 9 months by querying the database of an automated anesthesia record keeper. Results: A total of 1,744 patients were studied. Drug costs decreased from 56 dollars per case to 32 dollars per case as a result of adherence to practice guidelines. Perioperative patient flow was minimally affected. Time (mean +/‐ SD) from end of surgery to arrival in the post‐anesthesia care unit (PACU) increased from 11 +/‐ 7 min before the authors instituted practice guidelines to 14 +/‐ 8 min after practice guidelines (P < 0.0001). Admission of inpatients to the PACU receiving monitored anesthesia care increased from 6.5 to 12.9% (P <0.02). Perioperative patient flow and clinical outcomes were not otherwise adversely affected. Compliance and cost savings have been sustained. Conclusions: This study is an example of a successful physician‐directed program to promote more appropriate utilization of health care resources. Cost savings were obtained without any substantial changes in clinical outcomes. Institution of similar practice guidelines should result in pharmaceutical savings in the range of 50% at tertiary care centers around the country, with a slightly smaller degree of savings expected at institutions with more ambulatory surgery.

Changes in the auditory evoked potentials and the bispectral index following propofol or propofol and alfentanil.

Background Midlatency auditory evoked potentials (MLAEP) show graded changes with increasing doses of hypnotics but little change with opioids. The effect of their combination on the MLAEP was evaluated. Also, the bispectral index (BIS) was compared with the ability of MLAEP to correlate with sedation and predict loss of consciousness. Methods Twenty healthy volunteers were randomly assigned to receive stepped increases in propofol concentration (10 subjects) or propofol plus alfentanil 100 ng/ml (10 subjects). At baseline and at each targeted effect site concentration the mean MLAEP, BIS, measures of sedation, and drug concentration were obtained. The relation among MLAEP, BIS, and sedation score was determined. The prediction probability (Pk) was calculated and compared for BIS and MLAEP. Results The BIS and MLAEP patterns showed significant changes (Pa and Nb decreased in amplitude and increased in latency) with increasing level of sedation (P < 0.0001). The BIS correlated better with sedation scores (0.884) than did the MLAEP (P < 0.05). Pa and Nb latencies showed the best correlation with sedation levels (0.685 and 0.658, respectively). The addition of alfentanil did not affect the relation between MLAEP and loss of consciousness (P > 0.15). The BIS (Pk = 0.952) was a better predictor of loss of consciousness than were Pa and Nb amplitude (P < 0.05) but were comparable to Pa and Nb latency (Pk = 0.869 and 0.873, respectively). Conclusion MLAEP changes, like the BIS, correlate well with increasing sedation produced by propofol, and these changes in the MLAEP are independent of the presence of an opioid. Among all the MLAEP parameters, Pa and Nb latencies are the best predictors of increasing sedation and loss of consciousness.

The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain.

UNLABELLED Pharmacokinetic studies have shown that oral transmucosal absorption of fentanyl is relatively rapid compared with gastrointestinal absorption, and it results in increased bioavailability. We designed this study to establish the relative potency of oral transmucosal fentanyl citrate (OTFC) compared with i.v. morphine in 133 postoperative patients. The morning after surgery, patients randomly received one dose of either OTFC (200 or 800 microg) and a placebo i.v. injection or i.v. morphine (2 or 10 mg) and an oral transmucosal placebo unit. Pain intensity, pain relief, time to meaningful pain relief, and time to remedication were recorded. Median time to onset of relief was approximately 5 min for all groups. Over the first hour, little difference among treatment groups was seen for pain intensity and pain relief. By 2 h after study drug administration, 800 microg of OTFC and 10 mg of i.v. morphine generally produced similar analgesia, which was better than the smaller doses. Duration of analgesia with the larger doses (800 microg of OTFC and 10 mg of morphine) was similar and longer that produced by the smaller doses. The larger doses of OTFC and morphine produced better and more sustained analgesia than 200 microg of OTFC or 2 mg of morphine. IMPLICATIONS The relative potency of oral transmucosal fentanyl citrate (OTFC) to i.v. morphine was 8-14:1. In this postoperative setting, OTFC produced rapid pain relief similar to that produced by i.v. morphine. The larger doses of OTFC (800 microg) and morphine (10 mg) produced better and more sustained analgesia than 200 microg of OTFC or 2 mg of morphine.