Andrew R. Bjorksten

Mild Hypothermia Alters Propofol Pharmacokinetics and Increases the Duration of Action of Atracurium

Mild intraoperative hypothermia is common.We therefore studied the effects of mild hypothermia on propofol pharmacokinetics, hepatic blood flow, and atracurium duration of action in healthy volunteers. Six young volunteers were studied on two randomly assigned days, at either 34 degrees C or 37 degrees C. Anesthesia was induced with thiopental, 3 mg/kg, and maintained with 70% N2 O and 0.6% isoflurane. Core hypothermia was induced by conductive and convective cooling. On the other study day, normothermia was maintained by a Bair Hugger Registered Trademark (Augustine Medical, Inc., Eden Prairie, MN) forced-air warmer. Propofol, 1 mg/kg lean body mass (LBM), then was given, followed by a 4-h infusion at 5 mg centered dot kg-1 centered dot h-1. After 2 h, atracurium 0.5 mg/kg was administered as an intravenous bolus. Indocyanine green was administered for estimation of hepatic blood flow. Arterial blood was assayed for propofol and indocyanine green concentration. Pharmacokinetic analysis was performed using NONMEM. Results are reported as means +/- SEM. Propofol blood concentrations averaged approximate equals 28% more at 34 degrees C than at 37 degrees C (P < 0.05). Hepatic blood flow decreased 23% +/- 11% in normothermic volunteers during the propofol infusion, and 33% +/- 11% in hypothermic volunteers (P = not significant). A three-compartment mamillary model fitted the data best. Inclusion of hepatic blood flow change from the prepropofol baseline as a covariate for total body clearance significantly improved the fit. The intercompartmental clearances were decreased in the presence of hypothermia. Core hypothermia prolonged the time to recovery of the first twitch in the train-of-four to 10% of its control value (T1 = 10%) after atracurium administration by approximate equals 60% (P < 0.05), from 44 +/- 4 min to 68 +/- 7 min. In contrast, T1 = 25%-75% remained unchanged. We conclude that 3 degrees C of core hypothermia increased propofol blood concentrations and prolonged atracurium duration of action. Hepatic blood flow was decreased during propofol administration, and this change was a significant predictor of propofol clearance, indicating that the effect of propofol on hepatic blood flow impairs the clearance of propofol itself. (Anesth Analg 1995;80:1007-14)

Propofol Linearly Reduces the Vasoconstriction and Shivering Thresholds

BackgroundSkin temperature is best kept constant when determining response thresholds because both skin and core temperatures contribute to thermoregulatory control. In practice, however, it is difficult to evaluate both warm and cold thresholds while maintaining constant cutaneous temperature. A re

N‐acetylcysteine attenuates the decline in muscle Na+,K+‐pump activity and delays fatigue during prolonged exercise in humans

Reactive oxygen species (ROS) have been linked with both depressed Na+,K+‐pump activity and skeletal muscle fatigue. This study investigated N‐acetylcysteine (NAC) effects on muscle Na+,K+‐pump activity and potassium (K+) regulation during prolonged, submaximal endurance exercise. Eight well‐trained subjects participated in a double‐blind, randomised, crossover design, receiving either NAC or saline (CON) intravenous infusion at 125 mg kg−1 h−1 for 15 min, then 25 mg kg−1 h−1 for 20 min prior to and throughout exercise. Subjects cycled for 45 min at 71%, then continued at 92% until fatigue. Vastus lateralis muscle biopsies were taken before exercise, at 45 min and fatigue and analysed for maximal in vitro Na+,K+‐pump activity (K+‐stimulated 3‐O‐methyfluorescein phosphatase; 3‐O‐MFPase). Arterialized venous blood was sampled throughout exercise and analysed for plasma K+ and other electrolytes. Time to fatigue at 92% was reproducible in preliminary trials (c.v. 5.6 ± 0.6%) and was prolonged with NAC by 23.8 ± 8.3% (NAC 6.3 ± 0.5 versus CON 5.2 ± 0.6 min, P < 0.05). Maximal 3‐O‐MFPase activity decreased from rest by 21.6 ± 2.8% at 45 min and by 23.9 ± 2.3% at fatigue (P < 0.05). NAC attenuated the percentage decline in maximal 3‐O‐MFPase activity (%Δactivity) at 45 min (P < 0.05) but not at fatigue. When expressed relative to work done, the %Δactivity‐to‐work ratio was attenuated by NAC at 45 min and fatigue (P < 0.005). The rise in plasma [K+] during exercise and the Δ[K+]‐to‐work ratio at fatigue were attenuated by NAC (P < 0.05). These results confirm that the antioxidant NAC attenuates muscle fatigue, in part via improved K+ regulation, and point to a role for ROS in muscle fatigue.

Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold

Background: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration‐dependent reduction in the shivering than vasoconstriction threshold. Methods: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 micro gram/ml (40 mg/h); and 3) a target concentration of 1.8 micro gram/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core‐temperature thresholds (at a designated skin temperature of 34 degrees Celsius) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose‐dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/‐ SDs. Results: The unbound meperidine fraction was [nearly equal] 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/‐ 0.8 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2 = 0.51 +/‐ 0.37) and markedly decreased the vasoconstriction threshold (‐3.3 +/‐ 1.5 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r sup 2 = 0.92 +/‐ 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (‐6.1 +/‐ 3.0 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2 = 0.97 +/‐ 0.05; P = 0.001). Conclusions: The special antishivering efficacy of meperidine results at least in part from an uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of thermoregulatory impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably.

Buspirone and meperidine synergistically reduce the shivering threshold

Mild hypothermia (i.e., 34°C) may prove therapeutic for patients with stroke, but it usually provokes shivering. We tested the hypothesis that the combination of buspirone (a serotonin 1A partial agonist) and meperidine synergistically reduces the shivering threshold (triggering tympanic membrane temperature) to at least 34°C while producing little sedation or respiratory depression. Eight volunteers each participated on four randomly-assigned days: 1) large-dose oral buspirone (60 mg); 2) large-dose IV meperidine (target plasma concentration of 0.8 &mgr;g/mL); 3) the combination of buspirone (30 mg) and meperidine (0.4 &mgr;g/mL); and 4) a control day without drugs. Core hypothermia was induced by infusion of lactated Ringer’s solution at 4°C. The control shivering threshold was 35.7°C ± 0.2°C. The threshold was 35.0°C ± 0.8°C during large-dose buspirone and 33.4°C ± 0.3°C during large-dose meperidine. The threshold during the combination of the two drugs was 33.4°C ± 0.7°C. There was minimal sedation on the buspirone and combination days and mild sedation on the large-dose meperidine day. End-tidal Pco2 increased ≈10 mm Hg with meperidine alone. Buspirone alone slightly reduced the shivering threshold. The combination of small-dose buspirone and small-dose meperidine acted synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity.

Alfentanil Slightly Increases the Sweating Threshold and Markedly Reduces the Vasoconstriction and Shivering Thresholds

Background Hypothermia is common in surgical patients and victims of major trauma; it also results from environmental exposure and drug abuse. In most cases, hypothermia results largely from drug-induced inhibition of normal thermoregulatory control. Although opioids are given to a variety of patients, the thermoregulatory effects of opioids in humans remain unknown. Accordingly, the hypothesis that opioid administration impairs thermoregulatory control was tested.

Dexmedetomidine and Meperidine Additively Reduce the Shivering Threshold in Humans

Background and Purpose— Hypothermia might prove to be therapeutically beneficial in stroke victims; however, even mild hypothermia provokes vigorous shivering. Meperidine and dexmedetomidine each linearly reduce the shivering threshold (triggering core temperature) with minimal sedation. We tested the hypothesis that meperidine and dexmedetomidine synergistically reduce the shivering threshold without producing substantial sedation or respiratory depression. Methods— We studied 10 healthy male volunteers (18 to 40 years) on 4 days: (1) control (no drug); (2) meperidine (target plasma level 0.3 &mgr;g/mL); (3) dexmedetomidine (target plasma level 0.4 ng/mL); and (4) meperidine plus dexmedetomidine (target plasma levels of 0.3 &mgr;g/mL and 0.4 ng/mL, respectively). Lactated Ringer’s solution (≈4°C) was infused through a central venous catheter to decrease tympanic membrane temperature by ≈2.5°C/h; mean skin temperature was maintained at 31°C. An increase in oxygen consumption >25% of baseline identified the shivering threshold. Sedation was evaluated by using the Observer’s Assessment of Sedation/Alertness scale. Two-way repeated-measures ANOVA was used to identify interactions between drugs. Data are presented as mean±SD;P <0.05 was statistically significant. Results— The shivering thresholds on the study days were as follows: control, 36.7±0.3°C; dexmedetomidine, 36.0±0.5°C (P <0.001 from control); meperidine, 35.5±0.6°C (P <0.001); and meperidine plus dexmedetomidine, 34.7±0.6°C (P <0.001). Although meperidine and dexmedetomidine each reduced the shivering threshold, their interaction was not synergistic but additive (P =0.19). There was trivial sedation with either drug alone or in combination. Respiratory rate and end-tidal Pco2 were well preserved on all days. Conclusions— Dexmedetomidine and meperidine additively reduce the shivering threshold; in the small doses tested, the combination produced only mild sedation and no respiratory toxicity.

Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block

BACKGROUND The transversus abdominis plane block is a novel technique involving injection of local anaesthetic between the internal oblique and the transversus abdominis muscles of the abdominal wall. It is possible that injection of a large dose of local anaesthetic into a relatively vascular plane may result in toxic concentrations. One previously published study examined plasma lidocaine concentrations after transversus abdominus plane block and showed potentially toxic plasma concentrations. Although ropivacaine is most commonly used for this technique, plasma concentrations of ropivacaine after this block have not been reported previously. METHODS Adult female patients undergoing elective open gynaecological surgery received bilateral ultrasound-guided transverse abdominal plane blocks before surgical incision (3 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood was collected each 15 min for the first hour, each 30 min for the second hour, and then at 3, 4, 12, and 24 h post-block. RESULTS Twenty-eight patients were recruited. The mean (sd) peak total ropivacaine concentration occurred 30 min post-injection and was 2.54 (sd 0.75) µg ml(-1). The highest measured concentration was 4.00 µg ml(-1), also 30 min post-injection. Mean total concentrations remained above 2.20 µg ml(-1) for up to 90 min post-injection. The mean unbound peak venous concentration was 0.14 (0.05) µg ml(-1), and the peak was 0.25 µg ml(-1). CONCLUSIONS Transversus abdominus plane block using 3 mg kg(-1) of ropivacaine produces venous plasma concentrations that are potentially neurotoxic, although broadly consistent with plasma levels found after injection at other comparable sites.

Induction speed is not a determinant of propofol pharmacodynamics.

Background:Evidence suggests that the rate at which intravenous anesthetics are infused may influence their plasma-effect site equilibration. The authors used five different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. The authors concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration. Methods:With Human Studies Committee approval, 18 healthy volunteers received five consecutive target-controlled propofol infusions. During each infusion, the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 &mgr;g · ml−1 · min−1. The Bispectral Index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM. Results:When the correct rate of plasma-effect site equilibration was determined for each individual (plasma-effect site equilibration = 0.17 min−1, time to peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of increase of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness. Conclusions:Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM seems useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system.

Midazolam minimally impairs thermoregulatory control

Perioperative hypothermia usually results largely from pharmacologic inhibition of normal thermoregulatory control.Midazolam is a commonly used sedative and anesthetic adjuvant whose thermoregulatory effects are unknown. We therefore tested the hypothesis that midazolam administration impairs thermoregulatory control. Eight volunteers were studied on 2 days each, once without drug and once at a target total plasma midazolam concentration of 0.3 micro gram/mL (corresponding to administration of approximate equals 40 mg over approximate equals 4 h). Each day, skin and core temperatures were increased sufficiently to provoke sweating, and then reduced to elicit peripheral vasoconstriction and shivering. We mathematically compensated for changes in skin temperature using the established linear cutaneous contributions to control of each response. From these calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C), we determined the thermoregulatory effects of midazolam. The sweating threshold was decreased approximate equals 0.3 degrees C by midazolam administration: 37.3 +/- 0.2 degrees C vs 37.0 +/- 0.3 degrees C (P = 0.0004, paired t-test). Midazolam decreased the core temperature that triggered vasoconstriction somewhat more: 37.1 +/- 0.2 degrees C vs 36.3 +/- 0.5 degrees C (P = 0.0002). Similarly, midazolam decreased the shivering threshold: 35.9 +/- 0.3 degrees C vs 35.3 +/- 0.6 degrees C (P = 0.03). The sweating-to-vasoconstriction (interthreshold) range, therefore, increased from 0.2 +/- 0.1 degrees C to 0.7 +/- 0.3 degrees C (P = 0.002). Although statistically significant, this relatively small increase contrasts markedly with the 3-5 degrees C interthreshold ranges produced by clinical doses of volatile anesthetics, propofol, and opioids. Thus, plasma concentrations of midazolam far exceeding those used routinely produce relatively little impairment of thermoregulatory control. (Anesth Analg 1995;81:393-8)