Carol B. Pantuck

Effects of Cyclosporine on Anesthetic Action

: The effects of a single dose of cyclosporine on anesthetic actions of pentobarbital and fentanyl were studied in mice. Mice given pentobarbital 2 hr after receiving cyclosporine, 60 mg/kg, slept a statistically significant 2.3 times longer than did controls. In a second study, each of two dose levels of cyclosporine was given before each of four dose levels of fentanyl. The analgesic effect of fentanyl, measured with the abdominal constriction test, was dose-dependent. Cyclosporine significantly increased the analgesia produced by fentanyl and did so in a dose-dependent manner. Cyclosporine by itself did not produce analgesia. Plasma levels of fentanyl and binding of fentanyl by plasma proteins were unchanged by cyclosporine treatment. The results show that a single dose of cyclosporine can increase pentobarbital hypnosis and fentanyl analgesia in mice but do not establish the mechanism of these interactions.

Persistent Alterations of the Autonomic Nervous System after Noncardiac Surgery

Background Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both [Greek small letter beta]‐adrenergic receptor ([Greek small letter beta] AR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation. Methods The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine beta AR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals. Results After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol‐stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol‐stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery. Conclusions Persistent downregulation and desensitization of the lymphocyte beta AR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at‐risk period after major surgery appears to be about 1 week or more.

Antipyrine metabolism during the menstrual cycle

Two studies were initiated to determine the effect of the menstrual cycle on antipyrine metabolism. In the first study a relatively large oral dose of antipyrine (15 mg/kg) was given on days 3, 5, 10, 14, 16, 20, and 25 after the onset of menstruation. Salivary antipyrine half‐lifes (t½s) declined progressively, suggesting that the long‐term administration of this dose had stimulated antipyrine metabolism. To minimize this possible induction, in the second study a much smaller dose of antipyrine (1 mg/kg) was given on the same days of the cycle as in the first study. There was no induction. In both experiments, the menstrual cycle had little or no effect on the mean salivary t½, mean metabolic clearance rate, or apparent volume of distribution of antipyrine. In the second, men served as controls. The mean kinetic parameters for the men did not differ from those for the women. Although individuals of each sex varied from day to day in each kinetic parameter, the magnitude of the intraindividual variability in antipyrine metabolism was the same for both. The mean intraindividual coefficient of variation for antipyrine t½s was 14.4 ± 1.6% (SE) in women and 12.4 ± 1.3% (SE) in men. No consistent pattern for either sex was observed in the day‐to‐day variations in the means of the kinetic parameters investigated. Several women in whom the t½ rose or fell at midcycle were found to have a different pattern when reexamined 6 mo later.

Epidural patient-controlled analgesia after cesarean section: buprenorphine-0.015% bupivacaine with epinephrine versus fentanyl-0.015% bupivacaine with and without epinephrine.

We compared the analgesia, side effects, and plasma concentrations of buprenorphine and fentanyl in a double-blind study of 78 parturients receiving one of these drugs by patient-controlled epidural infusion after elective cesarean section with epidural anesthesia. Patients were randomized to three epidural infusion groups: group 1 (n = 26), 3 micrograms/mL buprenorphine with 0.015% bupivacaine and 1 microgram/mL epinephrine; group 2 (n = 26), 3 micrograms/mL fentanyl with 0.015% bupivacaine and 1 microgram/mL epinephrine; and group 3 (n = 26), 3 micrograms/mL fentanyl with 0.015% bupivacaine. Plasma for determination of opioid concentrations was obtained in some subjects in each group at intervals up to 48 h during the infusion and in some subjects from each group at intervals after the infusion was stopped. Pain relief was similar and satisfactory in all three groups. The median overall satisfaction scores were high for all three groups. Pruritus was more common in the fentanyl groups (P less than 0.05). However, vomiting was more disturbing to the patients and seen only with buprenorphine. No patient had a respiratory rate less than 12 breaths/min. Epinephrine use was associated with a slower infusion rate (P less than 0.05, group 2 vs 3). All patients were able to ambulate without difficulty. Mean opioid plasma concentrations did not exceed 1.5 ng/mL. Thus, epidural patient-controlled analgesia in all three groups provided excellent analgesia, permitted ambulation, and was without serious side effects. Epidural buprenorphine offered no advantages over epidural fentanyl.

Bupivacaine 0.01% and/or Epinephrine 0.5 [micro sign]g/ml Improve Epidural Fentanyl Analgesia after Cesarean Section

Background The authors studied the addition of bupivacaine and epinephrine, separately and together, to epidural fentayl to determine whether this improved postcesarean analgesia and reduced the incidence of side effects. Methods After elective cesarean section, 100 parturient patients who received fentanyl (3 [micro sign]g/ml) epidurally for 48 h were allocated randomly in a double‐blinded manner to four groups to receive, in addition to the study solution, 0.01% bupivacaine, 0.5 [micro sign]g/ml epinephrine, both, or neither. A neurologic assessment of breast‐fed neonates was made at 2 and 48 h of life. Plasma fentanyl concentrations were determined in a subset of patients at intervals after treatment. Results Patients receiving fentanyl alone made more attempts at patient‐controlled analgesia (P < 0.01), required a greater total dose of fentanyl (P < 0.01), reported more pain (P < 0.003) and less satisfaction (P < 0.003), and had more nausea and urinary retention (P < 0.05) than all other groups. Patients who received bupivacaine with or without epinephrine had better overall satisfaction scores than those who did not receive bupivacaine (P < 0.001), and they required less fentanyl (P < 0.02) than patients who received fentanyl with only epinephrine. Motor blockade or orthostatic hypotension did not develop in any patient, and all patients could ambulate without difficulty. Neurobehavioral scores, which were similar among all neonates, were within the normal range. Plasma concentrations of fentanyl increased after epinephrine‐containing solutions were discontinued. Conclusions During the conditions of this study, the addition of epinephrine and bupivacaine to a 3‐[micro sign]g/ml epidural fentanyl solution for postcesarean section pain relief provided superior analgesia compared with fentanyl alone or fentanyl with epinephrine. Whether increasing the concentration of fentanyl alone might improve the efficacy of fentanyl remains unclear.

Postcesarean delivery epidural patient-controlled analgesia. Fentanyl or sufentanil?

BackgroundThe highly lipid-soluble opioids, fentanyl and sufentanil, frequently are used in combination with local anesthetic agents and/or epinephrine to provide postoperative epidural analgesia. The authors compared the incidence of side effects and patient satisfaction during prolonged epidural patient-controlled analgesia (PCA) infusions of these opioids in combination with bupivacalne and eplnephrine. MethodsUsing a double-blind study design, 250 patients scheduled for elective cesarean delivery were, on arrival in the postanesthesia care unit, randomized into two epidural PCA infusion groups: group I (n = 125) received fentanyl 2 μg/ml with bupivacalne 0.01% and epinephrine 0.5 μg/ml and group II (n = 125) received sufentanil 0.8 μg/ml with bupi-vacaine 0.01% and epinephrine 0.5 μg/ml. The Initial Infusionrate was 16 ml/h with self-administered 3-ml boluses every 15 min by PCA as desired. At Intervals after discontinuation of the infusion, plasma samples were obtained to determine opioid concentrations. ResultsThe median overall satisfaction scores were 9.0 for group I and 10.0 for group II (difference not significant). Pain relief was satisfactory and comparable in both groups, and all patients could ambulate easily. The total number of times PCA requests were made was greater (P < 0.05, by Wilcoxon rank-sum test) for group I than for group II (106.7 ± 312 vs. 70.8 ± 138). There were no differences between the groups with respect to incidence of pruritus, sedation, and nausea; however, vomiting occurred more frequently with sufentanil than with fentanyl (12% vs. 4.8%, respectively; P < 0.05). At approximately 1–2 h after discontinuation of the infusion, 1 patient receiving fentanyl and 42 patients receiving sufentanil complained of lightheadedness and dizziness (P < 0.0001). ConclusionsEpidural PCA in both groups had no serious side effects and achieved a high level of patient satisfaction. Those receiving sufentanil made fewer PCA requests but had a significantly greater incidence of vomiting during the infusion and dizziness after the termination of the infusion. Epidural sufentanil offered no advantages over epidural fentanyl.

Effects of Parenteral Nutritional Regimens on Oxidative Drug Metabolism

To determine whether the caloric source of intravenous nutrition can influence oxidative drug metabolizing capacity, antipyrine metabolism was studied in six healthy volunteers, who were taking no food or liquid by mouth, after they had been administered an intravenous nutritional regimen of 5% dextrose, 440 kcal/day, for 4 days and after they had been switched to an essentially isocaloric intravenous nutritional regimen of amino acids ( Aminosyn 3.5%) for 1 day. The change in intravenous nutritional regimen resulted in a 21% decrease in mean half-life (range: 3-32%), a 20% decrease in mean area under the concentration-time curve (range: 4-42%), and a 24% increase in mean metabolic clearance rate (range: 2-71%) for antipyrine. These results show that the change from intravenous dextrose to intravenous amino acids for only 1 day produced in all subjects an increase in antipyrine metabolism. Interestingly, there was marked variability in the responsiveness of the different subjects to the change in intravenous caloric source.

Down-regulation and desensitization of the beta-adrenergic receptor system of human lymphocytes after cardiac surgery.

We used the beta-adrenergic receptor (beta AR) system of human lymphocytes as a model to examine perioperative adrenergic regulation in 12 patients undergoing coronary artery bypass grafting and 12 patients undergoing mitral or aortic valve replacement. beta AR function was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol and prostaglandin E1. Receptor number and dissociation constant (KD) were assessed with [125I]iodopindolol. In the valve surgery patients, basal, isoproterenol-stimulated, and prostaglandin E1-stimulated cAMP production were significantly decreased postoperatively, by 39%, 55%, and 24%, respectively. beta AR number decreased from a mean of 1333 +/- 143 sites/cell to 897 +/- 56 sites/cell postoperatively, whereas the KD increased from 12.9 +/- 1.1 pM to 37.0 +/- 7.3 pM. In the coronary artery bypass graft patients, there were no significant alterations in cAMP production or receptor number, but the KD increased from 19.8 +/- 2.9 pM to 57.5 +/- 11.8 pM. These findings suggest that cardiac surgery and/or cardiopulmonary bypass may result in significant down-regulation and desensitization of the beta AR system of lymphocytes, which may parallel alterations in other organ systems.

The primary action of epidural fentanyl after cesarean delivery is via a spinal mechanism.

We tested the hypotheses that the primary mechanism of action of epidural fentanyl after cesarean delivery is spinal and that very small dose epidural bupivacaine with epinephrine enhances this effect. After elective cesarean delivery, 100 parturients were randomized in a double-blinded design to four groups. Group I and II patients received a continuous 12 mL/h epidural infusion of bupivacaine 0.015% with epinephrine 1 &mgr;g/mL for 48 h and Groups III and IV received a 12 mL/h saline epidural infusion instead. Fentanyl 20 &mgr;g/mL was administered via a patient-controlled analgesia device either into the epidural infusion (Groups I and IV) or IV (Groups II and III). When compared to patients receiving epidural fentanyl, those receiving IV fentanyl required larger mean infused and total dose of fentanyl (P < 0.0001), reported more pain (P < 0.001), and had a more frequent incidence of excessive sedation (P < 0.01), nausea (P < 0.01), and vomiting (P < 0.01). Plasma concentrations of fentanyl were larger for Group II and III than for Groups I and IV (P < 0.001) at 24 and 48 h. Our results support the hypothesis that the primary mechanism of analgesia of epidural fentanyl after cesarean delivery is spinal. Our data also show that the total required dose of epidural, but not IV, fentanyl is reduced by very small dose epidural bupivacaine and epinephrine (Group I versus Group IV, P < 0.02 and Group II vs Group III, not significant).

Alterations of the beta-adrenergic receptor system after thoracic and abdominal surgery.

We studied perioperative regulation of the beta-adrenergic receptor (beta AR) in lymphocytes obtained from 12 patients undergoing noncardiac thoracic surgery and 12 patients undergoing abdominal surgery. beta AR number (Bmax) and dissociation constant (KD) were determined from [125I]iodopindolol saturation binding curves. Function of the beta AR/adenylyl cyclase system was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol (ISO) and prostaglandin E1 (PGE1). In thoracic surgery patients, basal and ISO-stimulated cAMP production were significantly decreased postoperatively, by 44% and 45%, respectively, with no change in PGE1-stimulated cAMP. Bmax decreased from 1369 +/- 138 (mean +/- SE) sites/cell to 891 +/- 82 sites/cell postoperatively, while the KD increased from 26.7 +/- 5.6 pM to 37.8 +/- 5.1 pM. In the abdominal surgery patients, there were no significant alterations in cAMP production, but Bmax decreased, from 1235 +/- 146 sites/cell preoperatively to 888 +/- 65 sites/cell postoperatively, while the KD increased from 18.8 +/- 3.6 pM to 58.1 +/- 12.5 pM. The beta AR and its associated effector system are altered during the perioperative period of abdominal and thoracic surgery.