Harry J. M. Lemmens

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

BackgroundPrevious 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 pharmacodyn

The Pharmacokinetics of the New Short-acting Opioid Remifentanil (gi87084b) in Healthy Adult Male Volunteers

BackgroundRemifentanil (GI87084B) is a new short-acting opioid with a unique ester structure. Metabolism of remifentanil by ester hydrolysis results in very rapid elimination. The aim of this study was to characterize in detail the pharmacokinetic profile of remifentanil in healthy male volunteers. MethodsTen healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 μg · kg-1 · min-1 for 20 min. Frequent arterial blood samples were drawn and analyzed by gas chromatographic mass spectroscopy to determine the remifentanil blood concentrations. The raw pharmacokinetic data were analyzed using three different parametric compartmental modeling methods (traditional two-stage, naive pooled data, and NONMEM). The raw pharmacokinetic data also were analyzed using numeric deconvolution and a nonparametric moment technique. A computer simulation using the pharmacokinetic parameters of the NONMEM compartmental model was performed to provide a more intuitively meaningful and clinically relevant description of the pharmacokinetics. The simulation estimated the time necessary to achieve a 50% decrease in remifentanil concentration after a variable-length infusion. ResultsFor each parametric method, a three-compartment mamillary model that accurately describes remifentanils concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 1/min, a volume of distribution at steady state of 32.8 1, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 1/min, a volume of distribution at steady state of 31.8 1, and a mean residence time of 10.9 min. The computer simulation revealed the strikingly unique pharmacokinetic profile of remifentanil compared to that of the currently available fentanyl family of opioids. ConclusionsRemifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.

Morbid Obesity and Tracheal Intubation

The tracheas of obese patients may be more difficult to intubate than those of normal-weight patients. We studied 100 morbidly obese patients (body mass index >40 kg/m2) to identify which factors complicate direct laryngoscopy and tracheal intubation. Preoperative measurements (height, weight, neck circumference, width of mouth opening, sternomental distance, and thyromental distance) and Mallampati score were recorded. The view during direct laryngoscopy was graded, and the number of attempts at tracheal intubation was recorded. Neither absolute obesity nor body mass index was associated with intubation difficulties. Large neck circumference and high Mallampati score were the only predictors of potential intubation problems. Because in all but one patient the trachea was intubated successfully by direct laryngoscopy, the neck circumference that requires an intervention such as fiberoptic bronchoscopy to establish an airway remains unknown. We conclude that obesity alone is not predictive of tracheal intubation difficulties.

Pharmacodynamics of Propofol in Female Patients

Although the clinical properties of propofol have been studied extensively, the pharmacodynamics have not yet been described fully. We studied the propofol concentration-effect relationships for loss of eyelash reflex, loss of consciousness, and hemodynamic changes in 18 female patients, ASA physical status 1, aged 20-49 yr. Propofol was given by computer-controlled infusion. The initial target concentration of 0.5-1 microgram/ml was increased every 12 min by 0.5-1 microgram/ml until the patients lost consciousness. Every 3 min, loss of eyelash reflex and loss of consciousness were tested and an arterial blood sample was taken for analysis of the blood propofol concentration. The concentration-response relationships for loss of eyelash reflex and loss of consciousness were defined by fitting a sigmoid Emax function (where Emax = the maximum effect that can be reached; i.e., 100% of the patients showing loss of eyelash reflex or loss of consciousness) to the response/no response data versus the propofol concentration, using nonlinear regression. The effect of propofol on hemodynamic parameters was analyzed by linear regression. The propofol concentrations at which 50% and 90% of the patients showed loss of eyelash reflex were 2.07 and 2.78 micrograms/ml, respectively. The corresponding values for loss of consciousness were 3.40 and 4.34 micrograms/ml. The systolic and diastolic blood pressure decreased with increasing blood propofol concentration. The correlation coefficients for the decrease in systolic and diastolic blood pressure versus the blood propofol concentration were r2 = -0.663 and r2 = -0.243, but heart rate did not change. In conclusion, propofol concentrations inducing loss of eyelash reflex are less than those inducing loss of consciousness.

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.

Left double-lumen tubes: clinical experience with 1,170 patients

MODERN DISPOSABLE plastic double-lumen tubes (DLTs) are generally safe and easy to use.1,2 However, a misplaced or improperly used DLT can jeopardize any procedure and even injure the patient. This article reviews considerations for the selection and placement of left-sided DLTs based on data collected from a large series of patients undergoing thoracic procedures requiring one-lung ventilation (OLV) at this institution. Although the information presented represents the authors’ experience at a single center, others can apply many of the lessons in their own practices. With the permission of the Human Subjects Committee at Stanford University Medical Center, over an 8-year period from 1993 and 2001, 1,170 consecutive patients undergoing anesthesia for noncardiac, general thoracic surgical procedures were studied. All patients were anesthetized by anesthesia residents under the supervision of one of the authors (JBB). At the time of operation, patient sex, height, weight, site, and type of surgical procedure were recorded. When the patient’s chest radiograph (CXR) was available the width of trachea, and in some patients the width of the left bronchus, were measured. The size of the DLT selected, the depth of placement of the DLT in the bronchus, and the volume of air used to inflate the bronchial cuff were recorded. Data are reported as the mean standard deviation unless indicated otherwise. Relationships between parameters were analyzed using regression analysis. Any difficulties encountered, complications, or changes in tube position during the procedure were also noted. Data for measured parameters were not complete for some patients.

Patient state index : titration of delivery and recovery from propofol, alfentanil, and nitrous oxide anesthesia

Background The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide–narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia. Methods Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol–alfentanil–nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery. Results No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 &mgr;g · kg−1 · min−1;P < 0.01) and historic control group (18.2 &mgr;g · kg−1 · min−1;P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3–3.8 min;P < 0.001) and standard practice control (1.4–1.5 min;P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found. Conclusions Patient State Index–directed titration of propofol delivery resulted in faster emergence and recovery from propofol–alfentanil–nitrous oxide anesthesia, with modest decrease in the amount of propofol delivered, without increasing the number of unwanted events.

The Dose of Succinylcholine in Morbid Obesity

The appropriate dose of succinylcholine (SCH) in morbidly obese patients is unknown. We studied 45 morbidly obese (body mass index >40 kg/m2) adults scheduled for gastric bypass surgery. The response to ulnar nerve stimulation of the adductor pollicis muscle at the wrist was recorded using the TOF-Watch SX® acceleromyograph. In a randomized double-blind fashion, patients were assigned to one of three study groups. In Group I, patients received SCH 1 mg/kg ideal body weight, in Group II 1 mg/kg lean body weight, and in Group III 1 mg/kg total body weight. After SCH administration, endotracheal intubating conditions were scored. The recovery from neuromuscular block was recorded for 20 min. There was no difference in the onset time of maximum neuromuscular blockade among groups, but maximum block was significantly less in Group I. The recovery intervals were significantly shorter in Groups I and II. In one third of the patients in Group I, intubating conditions were rated poor, whereas no patient in Group III had poor intubating conditions. Our study demonstrates that for complete neuromuscular paralysis and predictable laryngoscopy conditions, SCH 1 mg/kg total body weight is recommended.

Stroke volume equation for impedance cardiography

The studys 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 × 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.

Estimating Blood Volume in Obese and Morbidly Obese Patients

Preoperative assessment of blood volume (BV) is important for patients undergoing surgery. The mean value for indexed blood volume (InBV) in normal weight adults is 70 mL/kg. Since InBV decreases in a non-linear manner with increasing weight, this value cannot be used for obese and morbidly obese patients. We present an equation that allows estimation of InBV over the entire range of body weights.