Individualized dosing with anesthetic agents.

The development of fundamental pharmacokinetics and pharmacodynamics concepts has enabled anesthesiologists to choose and dose anesthetic agents on a rational basis. The application of these concepts to a variety of clinical scenarios and patient populations makes it possible to individualize the dose, thereby decreasing the risk of complications. As more knowledge is gained about the sometimes profound differences in drug response, empirical dosing such as in milligrams per kilogram of total body weight is disappearing from the anesthesia specialty.

Dose adjustment of anaesthetics in the morbidly obese.

Anaesthesiologists must be prepared to deal with pharmacokinetic and pharmacodynamic (PD) differences in morbidly obese individuals. As drug administration based on total body weight can result in overdose, weight-based dosing scalars must be considered. Conversely, administration of drugs based on ideal body weight can result in a sub-therapeutic dose. Changes in cardiac output and alterations in body composition affect the distribution of numerous anaesthetic drugs. With the exception of neuromuscular antagonists, lean body weight is the optimal dosing scalar for most drugs used in anaesthesia including opioids and anaesthetic induction agents. The increased incidence of obstructive sleep apnoea and fat deposition in the pharynx and chest wall places the morbidly obese at increased risk for adverse respiratory events secondary to anaesthetic agents, thus altering the PD properties of these drugs. Awareness of the pharmacology of the commonly used anaesthetic agents including induction agents, opioids, inhalation agents and neuromuscular blockers is necessary for safe and effective care of morbidly obese patients.

The analgesic and antihyperalgesic effects of transcranial electrostimulation with combined direct and alternating current in healthy volunteers.

BACKGROUND: Transcranial electrostimulation (TES) has been reported to produce clinically significant analgesia, but randomized and double-blind studies are lacking. We investigated the analgesic and antihyperalgesic effects of TES in validated human experimental pain models. METHODS: In 20 healthy male subjects we evaluated the analgesic and antihyperalgesic effects of TES(60Hz) and TES(100Hz) to heat and mechanical pain in experimentally induced ultraviolet B skin sunburns and in normal skin. Previous animal studies in our laboratory predicted that TES(60Hz) would provide significant analgesia, and TES(100Hz) was a suitable active control. The study was conducted in a double-blind, randomized, 2-way cross-over fashion. TES was administered for 35 minutes. Quantitative sensory testing evaluating heat and mechanical pain thresholds was conducted before TES, during TES, and 45 minutes after TES. RESULTS: TES (TES(60Hz) > TES(100Hz)) evoked rapidly developing, significant thermal and mechanical antihyperalgesic effects in the ultraviolet B lesion, and attenuated thermal pain in unimpaired skin. No long-lasting analgesic and antihyperalgesic effects of a single TES treatment were demonstrated in this study. CONCLUSIONS: TES produces significant, frequency-dependent antihyperalgesic and analgesic effects in humans. The characteristics of the TES effects indicate a high likelihood of its ability to modulate both peripheral sensitization of nociceptors and central hyperexcitability.

The history of anesthesia for thoracic surgery.

Today, thoracic surgeons routinely perform complex operations on even the most complicated patient. However, just 75 years ago the ability to operate within the chest was strictly limited to only the simplest and quickest procedures. The dramatic advances in the specialty of thoracic surgery have closely paralleled the introduction of new anesthetic practices, equipment and drugs. This review will identify major events in the history of anesthesia for thoracic surgery.

The haemodilution enhanced onset of coagulation as measured by the thrombelastogram is transient.

BACKGROUND AND OBJECTIVE: Crystalloid haemodilution has been widely found to enhance coagulation onset, but the duration of this effect has never been documented. METHODS: Twelve healthy, consenting volunteers had a rapid infusion of 14 mL kg-1 of normal (0.9%) saline. Blood samples were taken, prior to (control), and immediately after (30 min) the rapid saline infusion was completed (30 min). They were then repeated at regular intervals up to 120 min. Haematocrit/platelet counts were taken to determine the degree of dilution and thrombelastograms, with and without platelet antagonists (ReoPro, Abciximab), were measured in all samples. Antithrombin levels were selectively measured. RESULTS: The haematocrit and platelet count showed a rapid dilutional decrease at 30 min (mean of -12.2% and -14.4%, respectively), with values returning towards baseline within 15 min after finishing the infusion. There was a significantly faster onset of coagulation (decrease in r-time) in the post-infusion sample (30 min) compared to control (P<0.05), again returning towards normal as the dilution effect was reversed. Similar thrombelastograms findings were evident in the plasma factor only group (platelets inhibited by ReoPro). Antithrombin levels changed in keeping with the haemodilution effect (P<0.0001). There was a linear relationship between antithrombin and thrombelastograms r-time (P=0.012). CONCLUSION: The faster onset of coagulation brought on by haemodilution return towards normal as the dilutional effect is reversed. This effect is mediated through plasma clotting factors. Of interest is the significant inverse correlation of the onset of coagulation increasing as the antithrombin levels decreased with dilution.

Large volume N2O uptake alone does not explain the second gas effect of N2O on sevoflurane during constant inspired ventilation.

BACKGROUND: The second gas effect (SGE) is considered to be significant only during periods of large volume N(2)O uptake (VN(2)O); however, the SGE of small VN(2)O has not been studied. We hypothesized that the SGE of N(2)O on sevoflurane would become less pronounced when sevoflurane administration is started 60 min after the start of N(2)O administration when VN(2)O has decreased to approximately 125 ml min(-1), and that the kinetics of sevoflurane under these circumstances would become indistinguishable from those when sevoflurane is administered in O(2). METHODS: Seventy-two physical status ASA I-II patients were randomly assigned to one of six groups (n=12 each). In the first four groups, sevoflurane (1.8% vaporizer setting) administration was started 0, 2, 5 and 60 min after starting 2 litre min(-1) O(2) and 4 litre min(-1) N(2)O, respectively. In the last two groups, sevoflurane (1.8 or 3.6% vaporizer setting) was administered in 6 litre min(-1) O(2). The ratios of the alveolar fraction of sevoflurane (Fa) over the inspired fraction (Fi), or Fa/Fi, were compared between the groups. RESULTS: Sevoflurane Fa/Fi was larger in the N(2)O groups than in the O(2) groups, and it was identical in all four N(2)O groups. CONCLUSIONS: We confirmed the existence of a SGE of N(2)O. Surprisingly, when using an Fa of 65% N(2)O, the magnitude of the SGE was the same with large or small VN(2)O. The classical model and the graphical representation of the SGE alone should not be used to explain the magnitude of the SGE. We speculate that changes in ventilation/perfusion inhomogeneity in the lungs during general anaesthesia result in a SGE at levels of VN(2)O previously considered by most to be too small to exert a SGE.

Stroke volume equation for impedance cardiography.

The study's goal was to determine if cardiac output (CO), obtained by impedance cardiography (ICG), would be improved by a new equation N, implementing a square root transformation for dZ/dtmax/Z0, and a variable magnitude, mass-based volume conductor Vc. Pulmonary artery catheterisation was performed on 106 cardiac surgery patients pre-operatively. Post-operatively, thermodilution cardiac output (TDCO) was simultaneously compared with ICG CO. dZ/dtmax/Z0 and Z0 were obtained from a proprietary bioimpedance device. The impedance variables, in addition to left ventricular ejection time TLVE and patient height and weight, were input using four stroke volume (SV) equations: Kubicek (K), Sramek (S), Sramek-Bernstein (SB), and a new equation N. CO was calculated as SV x heart rate. Data are presented as mean +/- SD. One way repeated measures of ANOVA followed by the Tukey test were used for inter-group comparisons. Bland-Altman methods were used to assess bias, precision and limits of agreement. P< 0.05 was considered statistically significant. CO implementing N (6.06 +/- 1.48 l min(-1)) was not different from TDCO (5.97 +/- 1.41 l min(-1)). By contrast, CO calculated using K (3.70 +/- 1.53 l min(-1)), S (4.16 +/- 1.83 l min(-1)) and SB (4.37 +/- 1.82 l min(-1)) was significantly less than TDCO. Bland-Altman analysis showed poor agreement between TDCO and K, S and SB, but not between TDCO and N. Compared with TDCO, equation N, using a square-root transformation for dZ/dtmax/Z0, and a mass-based Vc, was superior to existing transthoracic impedance techniques for SV and CO determination.

Nitrous oxide and laparoscopic bariatric surgery.

BACKGROUND: Nitrous oxide (N2O) is frequently used to supplement more potent anesthetic agents. One side-effect of N2O is its ability to expand an air-containing space. We investigated if N2O adversely affected operating conditions by distending normal bowel during laparoscopic bariatric procedures. METHODS: 50 morbidly obese patients were divided into 2 study groups. Group 1 patients were ventilated with a halogenated anesthetic/oxygen/air mixture, while Group 2 received a halogenated anesthetic/oxygen/N2O mixture. At 30, 60, and 90 min intervals during the operation, the surgeon was asked if N2O was being used. RESULTS: The surgeons responded correctly only 42% (30 min), 50% (60 min), and 48% (90 min) of the time. In Group 2 (N2O) patients, they incorrectly answered that N2O was not being used 88% (30 min), 68% (60 min), and 68% (90 min); and in Group 1 (air) patients, they incorrectly answered that N2O was being used 28% (30 min), 32% (60 min), and 36% (90 min) of the time. CONCLUSION: We found that using N2O did not cause noticeable bowel distention during laparoscopic bariatric procedures of relatively short duration.

Isosulfan blue affects pulse oximetry.

BACKGROUND: Certain vital dyes are known to cause pulse oximetry (Spo2) desaturation. The authors studied the effect of isosulfan blue (IB) on Spo2. METHODS: Thirty-three women, aged 34-81 yr, who were undergoing surgery for breast cancer were studied. IB, 5 ml (50 mg), was injected intraparenchymally around the tumor area by the surgeon. A pulse oximeter was used to continuously record Spo2 values up to 130 min after IB injection. Friedman repeated-measures analysis of ranks was used to analyze the baseline Spo2 and values at 5, 10, 20, 30, 40, 50, and 60 min. RESULTS: Spo2 values were significantly different from baseline values at 5, 10, 20, 30, 40, 50, and 60 min (P < 0.05). In a typical patient, a maximum Spo2 decrease of 3% can be anticipated 25 min after injection of IB. CONCLUSIONS: After peritumoral administration of IB, 50 mg, a significant interference with Spo2 will occur.

Rapacuronium recovery characteristics and infusion requirements during inhalation versus propofol-based anaesthesia.

We examined the effect of four maintenance anaesthetics on the neuromuscular blocking activity and spontaneous recovery characteristics after a short-term infusion of rapacuronium. Eighty ASA I-III adult patients undergoing elective surgery were studied at four centres. Anaesthesia was induced with propofol 1.5-2.5 mg kg-1 and fentanyl 1-2 micrograms kg-1, followed by a bolus of rapacuronium 1.5 mg kg-1. The patients were randomized to receive either desflurane (2-4% end-tidal, ET), sevoflurane (0.75-1.5% ET), isoflurane (0.4-0.8% ET), or a propofol infusion (75-150 micrograms kg-1 min-1) for maintenance of anaesthesia in combination with nitrous oxide (60-70%) in oxygen. When the first twitch (T1) of a train-of-four stimulus (using the TOF Guard accelerometer) returned to 5%, an infusion of rapacuronium was started at 3 mg kg-1 h-1 and adjusted to maintain T1/T0 at 10%. The duration of infusion lasted between 45 and 60 min, and the average infusion rates of rapacuronium were similar in all groups, ranging from 1.6 to 2.5 mg kg-1 h-1. There were no significant differences among the groups in the times for T1/T0 to return to 25%, 75% or 90%, or for T4/T1 to return to 70% and 80% upon discontinuation of the infusion. When potent inhalation anaesthetics are used in clinically relevant concentrations for maintenance of anaesthesia, the neuromuscular recovery profile of rapacuronium administered as a variable-rate infusion for up to 1 h is similar to that found with a propofol-based anaesthetic technique.

Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery.

BACKGROUND: Remifentanil blood concentrations necessary for adequate intraoperative anesthesia have not been defined. The goal of this study was to determine the blood concentrations of remifentanil needed for anesthesia with 66% nitrous oxide during intraabdominal surgery. In addition, the pharmacokinetics of remifentanil and the effects of covariates on both the pharmacodynamics and the pharmacokinetics were determined. METHODS: Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and remifentanil. Remifentanil was administered by a computer-controlled infusion pump that rapidly attained, and then maintained, constant remifentanil blood concentrations. If the patient showed signs of inadequate anesthesia (autonomic or somatic response), the target concentration was increased by 1 or 2 ng/ml. If no response occurred during a 15-min period, the concentration was decreased by 1 or 2 ng/ml. Remifentanil pharmacodynamics and pharmacokinetics were estimated using NONMEM. RESULTS: The remifentanil blood concentration for which there is a 50% probability of adequate anesthesia during abdominal surgery (Cb50) with 66% nitrous oxide was 4.1 ng/ml in men and 7.5 ng/ml in women. The Cb50 values for prostatectomy, nephrectomy, and other abdominal procedures were 3.8, 5.6, and 7.5 ng/ml, respectively. Remifentanil pharmacokinetics were best described by a two-compartment model with lean body mass as a significant covariate, where V1 = 0.129(lean body mass-50) + 3.79 l, V2 = 6.87 l, CL1 = 0.0389(lean body mass-50) + 2.34 l/min and CL2 = 1.14 l/min. CONCLUSIONS: The Cb50 differed according to patient gender. However, because surgery type was not specified for each man or woman, this may reflect a difference in surgical procedure.

Determination of the distribution volume that can be used to calculate the intravenous loading dose.

An intravenous loading dose is given to rapidly achieve a desired drug concentration in the blood. A loading dose calculated with the volume of distribution (Vd) at steady state will result in high peak concentrations and possibly serious adverse effects. A loading dose based on the central compartment Vd (Vc) followed by a maintenance infusion may also miss the target drug concentration and cause serious adverse effects. The Vd can be viewed as a time-dependent variable that expands from the Vc immediately after injection, to eventually include the steady-state Vd. If the loading dose is calculated from a Vd determined after the time of peak effect (tmax), then the actual concentration will exceed the target concentration at the tmax. If a loading dose is calculated from a Vd before the peak effect occurs, the actual concentration will be insufficient to achieve the target concentration at tmax. A loading dose based on the Vd at the tmax will accurately achieve the concentration at the tmax without unexpected adverse effects. To determine the Vd at peak effect, it is necessary that an effect can be measured, the peak effect can be detected and the plasma concentrations are sampled frequently enough to quantify the plasma concentrations at the tmax. For drugs that attain an ultra-fast effect (1 to 2 minutes), arterial samples need to be measured. If the onset of effect is intermediate or slow, venous blood can be sampled as the arterial and venous concentrations may be similar at the tmax.

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

BACKGROUND: Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. METHODS: Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. RESULTS: The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively. CONCLUSIONS: This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.

Pharmacokinetic-pharmacodynamic relationships for opioids in balanced anaesthesia.

The pure mu-receptor opioid agonists fentanyl, sufentanil and alfentanil are commonly used to provide the specific anti-nociceptive component of a balanced anaesthesia technique. Trefentanil and remifentanil are new opioids with a very short duration of action. Remifentanil has an ester structure and is very rapidly metabolised by blood and tissue esterases. Different perioperative stimuli require different plasma concentrations to suppress responses of the patient. The ability of the anaesthesiologist to select a precise dosage scheme for the individual patient is impeded by the large interindividual pharmacokinetic and pharmacodynamic variability. In addition, the combination of opioids and other drugs used to produce the desired components of balanced anaesthesia may exert additive, synergistic or antagonistic effects. Knowledge of factors influencing the pharmacokinetics and pharmacodynamics is still fragmentary and often controversial. Consequently, the opioid dose needs to be adjusted according to the responses of the patient during surgery to ensure adequate anaesthesia and rapid recovery. The duration of action is not predicted by the elimination half-life alone. The decline in effect-site concentration is dependent on the complex entity of infusion duration, and pharmacokinetic and pharmacodynamic parameters. Computer simulations of infusions of varying duration have been extremely useful when selecting an opioid for a specific clinical scenario on a rational basis. Traditionally, opioids are still administered by intermittent bolus injections. A disadvantage of this method of administration is that plasma concentrations fluctuate above and below the level required for adequate anaesthesia. Computer-assisted infusion pumps make it possible to target a particular drug concentration in plasma and to maintain or change this concentration as needed. This technique provides more stable anaesthesia and a more rapid recovery of the patient.

Pharmacokinetic/dynamic assessment in drug development: application to the investigational opioid mirfentanil.

The safety, pharmacokinetics, and pharmacodynamics of the investigational partial opioid agonist, mirfentanil, were determined in a dose-escalating, Phase 1 study in healthy male volunteers. Hemodynamic, central nervous system, and respiratory monitoring were used for safety assessment. The electroencephalogram (EEG) was evaluated as a surrogate measure of drug effect. Butorphanol was chosen as the control drug. In the mirfentanil group (n = 8) the dose was increased in sequential subjects from 25 micrograms.kg-1.min-1 for 30 min to 450 micrograms.kg-1.min-1 for 15 min, and in the butorphanol group (n = 10) from 2 micrograms.kg-1.min-1 for 30 min to 25 micrograms.kg-1.min-1 for 15 min. In the mirfentanil group, serious side effects were observed at plasma concentrations more than 2000 ng/mL: heart rates exceeded 130 bpm (n = 2), epileptiform EEG potentials (n = 2), and a convulsion (n = 1). The clearance of mirfentanil was high (5.8-7.2 L/min), and the volume of distribution large (247-348 L). The EEG of the subjects receiving mirfentanil showed no changes typical for opioids. Butorphanol however, caused intermittent slowing in the delta and theta ranges. The results of our study define the upper limit of safe plasma concentrations in future mirfentanil studies.