A model of the ventilatory depressant potency of remifentanil in the non-steady state

BACKGROUND: The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil. METHODS: Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration. RESULTS: The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25. CONCLUSION: Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.     

Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics

BACKGROUND: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. METHODS: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. RESULTS: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. CONCLUSIONS: Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.     

Two-stage vs mixed-effect approach to pharmacodynamic modeling of propofol in children using state entropy

Objectives: To compare the population pharmacodynamic (PD) models of propofol in children derived using two‐stage and mixed‐effect modeling approaches. Methods: Fifty‐two ASA 1 and 2 children aged 6–15 years presenting for gastrointestinal endoscopy were administered a loading dose of 4 mg·kg^?1 of propofol intravenously at an infusion rate determined by a randomization schedule. Using the plasma concentration predicted by the Paedfusor pharmacokinetic (PK) model, the propofol effect on state entropy (SE) was modeled using the two‐stage and the mixed‐effect modeling approaches, and the final population PD models were compared with each other in terms of their prediction performance, using median percentage and absolute percentage errors as well as mean absolute weighted error as metrics. The effects of age and body weight as prospective covariates were examined. Results: The final population models were comparable with each other; the two‐stage and the mixed‐effect approaches resulted in a k_e0 of 2.38 and 2.66 min^?1, γ of 5.29 and 5.68, and EC₅₀ of 4.73 and 4.84 μg·ml^?1, respectively. The bootstrap estimates of the PD parameters were mean (sd ) k_e0 = 2.38 (0.10), γ = 5.30 (0.30), and EC₅₀ = 4.73 (0.14). The PD parameters did not exhibit dependence on age and body weight. The parameters reported in this study in children were different from their adult counterparts reported in previous studies. Conclusions: Models derived using different mathematical approaches produced consistent model parameters. By virtue of its relative computational efficiency, the two‐stage approach can serve as an attractive alternative to the mixed‐effect approach in situations where data are not sparse.     

Total intravenous anesthesia with propofol augments the potency of mivacurium

BACKGROUND: Little is known about the potentiating effect of propofol on neuromuscular blocking drugs. However, some animal studies indicate a dose-dependent increase of the potency of neuromuscular blocking drugs by propofol. This study compared mivacurium potency after five minutes and after 20 min of total intravenous anesthesia with propofol (TIVA propofol). METHODS: Twenty-eight patients were randomized into two groups, after approval of the Ethics Committee and written consent. Anesthesia was induced, in all patients, using remifentanil 0.5 microg.kg(-1).min(-1) for two minutes, after which: 3 mg.kg(-1) of propofol was injected; a laryngeal mask airway was inserted; and intermittent, positive pressure ventilation was initiated. Anesthesia was maintained using TIVA propofol (titrated using bispectral index monitoring to 40-45). Neuromuscular monitoring consisted of phonomyography at the adductor pollicis muscle. In Groups 5 min and 20 min, a tetanic stimulation of the ulnar nerve commenced after four minutes and after 19 min of TIVA, respectively, followed by controlled, single twitch stimulation at 1 Hz for one minute. Boli of 60, 30, 30, and 30 microg.kg(-1) mivacurium, respectively, were administered (each drug increment was administered after the effect of the previous dose had caused a stable response), and single twitch stimulation continued at 0.1 Hz. The dose-response curve was determined for both groups; potency was calculated using log-probit analysis. Data were presented as mean (SD) and were compared using two-sided analysis of variance, P < 0.05. RESULTS: Patient characteristics were similar in the two groups. The corresponding ED(50) and ED(95) values were greater, at 76.7 +/- 12.4 microg.kg(-1) and 146.6 +/- 27.6 microg.kg(-1) for Group 5 min, vs 46.7 +/- 12.2 microg.kg(-1) and 101.1 +/- 20.2 microg.kg(-1) for Group 20 min, respectively. CONCLUSIONS: After 20 min of TIVA propofol, the potency of mivacurium is approximately 50% greater than after five minutes of TIVA propofol. For clinical purposes, it is important, therefore, to consider the duration of TIVA propofol before determining the dose of neuromuscular blocking drug.     

Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of alfentanil.

BACKGROUND: Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. METHODS: After institutional approval approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 microg x kg(-1) x min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2 = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 microg/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PE(CO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO2). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing PaCO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. RESULTS: The indirect response model adequately described the time course of the PaCO2. The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 microg/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4(28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO2 in maintaining alveolar ventilation in the presence of opioid. CONCLUSIONS: The model described the data for the entire opioid-PaCo2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.     

肝硬化对大鼠异丙酚镇静效力的影响

目的 探讨肝硬化对大鼠异丙酚镇静效力的影响.方法 健康雄性SD大鼠58只,体重180～220 g,随机分为3组,正常对照组(C组,n=18)、轻度肝硬化组(M1组,n=20)和重度肝硬化组(M2组,n=20).M1组和M2组采用四因素法制备大鼠轻度肝硬化和重度肝硬化模型.模型制备成功后,静脉注射异丙酚,第1只大鼠的剂量为5.912 mg/kg,应用序贯法确定下一只大鼠的剂量,相邻剂量比为0.85,以翻正反射消失作为判断异丙酚镇静起效的标准.采用序贯法计算异丙酚镇静效应的半数有效剂量(ED50).结果 与C组比较,M1组及M2组异丙酚镇静效应的ED50降低(P＜0.05或0.01);与M1组比较,M2组异丙酚镇静效应的ED50降低(P＜0.05).结论 肝硬化可强化大鼠异丙酚的镇静效力.     

Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics

To establish anesthesia with minimal respiratory and cardiovascular depression using propofol, the effects of varying the rate of delivery on anesthetic induction dose requirements and hemodynamic changes were studied in four groups of 20 patients each undergoing body surface surgery. All patients were premedicated with temazepam and received 1.5 micrograms/kg fentanyl 5 min before induction. Propofol was delivered at 50, 100, or 200 mg/min by the Ohmeda 9000 infusion pump (groups 1, 2, and 3, respectively) or by bolus of 2 mg/kg (group 4) until loss of verbal contact. Anesthesia was maintained thereafter with propofol infused at 6 mg.kg-1.h-1. Using slower infusion rates, induction took significantly longer (124, 92, 62, and 32 s in groups 1, 2, 3, and 4, respectively) and was achieved with significantly smaller doses of propofol (1.40, 1.96, 2.61, and 2.15 mg/kg in groups 1, 2, 3, and 4, respectively). Slow infusion (groups 1 and 2) caused less depression of systolic and diastolic blood pressure than rapid infusion (groups 3 and 4), but the differences were not statistically significant. Patients in groups 3 and 4 had significantly greater decreases in pulse rate and a greater incidence of apnea than did patients in group 1. There was no correlation between the size of the induction dose and subsequent maintenance requirements of propofol. The finding that the sleep dose of propofol is reduced at slower infusion rates has important practical and theoretical implications when considering the relative potencies of intravenous anesthetics.     

Time course of ventilatory depression following induction doses of propofol and thiopental.

To improve our understanding of the respiratory pharmacology of intravenous induction agents, the authors compared the acute effects of intravenous (iv) propofol 2.5 mg.kg-1 and iv thiopental 4.0 mg.kg-1 on the ventilatory response to CO2 (VeRCO2) of eight healthy volunteers. The slope of VeRCO2 decreased from 1.75 +/- 0.23 to a minimum of 0.77 +/- 0.14 1.min-1.mmHg-1 (mean +/- standard error) 90 s after propofol; similarly, the slope of VeRCO2 decreased from 1.79 +/- 0.22 to a minimum of 0.78 +/- 0.23 l.min-1.mmHg-1 30 s after thiopental. For both drugs, the slope was less than control in the 0.5-5-min period after injection (P less than 0.05). The slope returned to baseline within 6 min after thiopental; in contrast, after propofol, the slope remained less than control for the entire 20-min follow-up period (P less than 0.05 at 6-10, 11-15, and 16-20 min after injection). Also, from 6-10, 11-15, and 16-20 min after injection, the slope was less after propofol than at corresponding times after thiopental (P less than 0.05). Recovery of consciousness was approximately 4 min slower after propofol than after thiopental; nonetheless, awareness scores returned to baseline within 14 min after both drugs. The authors conclude that propofol 2.5 mg.kg-1 iv produces longer-lasting depression of VeRCO2 than a 4.0 mg.kg-1 iv dose of thiopental; after propofol, ventilatory depression may persist despite apparently complete recovery of consciousness.     

The anaesthetic potency of propofol in the rat is reduced by simultaneous intravenous administration of lignocaine.

Lignocaine added to the anaesthetic preparation Diprivan reduces propofol induced pain on injection. This effect is due to a drop in pH which decreases the content of propofol in the aqueous phase of the soya bean emulsion. This in turn changes the electrostatic forces in the emulsion and destabilization occurs. The effect of lignocaine on the anaesthetic potency of propofol was validated in a randomized blind study in the rat. The induction dose of 1% propofol mixed with 1% lignocaine (10 + 1) was significantly higher when compared with the induction dose of propofol 1% given after a separate injection of 1% lignocaine (9.4 +/- 5.5 vs. 5.6 +/- 5.2 mg; P < 0.05). The duration of sleep was shorter in rats injected with propofol 1% mixed with lignocaine 1% (10 + 1) compared with those given 1% lignocaine and 1% propofol in separate injections (160 +/- 181 vs. 375 +/- 202 s; P < 0.05). The anaesthetic potency of propofol was not significantly changed by the addition of either saline or hydrochloric acid. The anaesthesia inducing effect was not time-dependent. A similar lower potency was observed for a solution stored for 4 h compared with one freshly prepared, although sleeping time was longer (9.2 +/- 6.8 mg; 428 +/- 110 s) as compared with the 4 h mixture. The results indicate that lignocaine altered the propofol preparation. The reduced anaesthetic potency of propofol after addition of lignocaine is not due to the resultant drop in pH, which is known to occur.     

The general anesthetic potency of propofol and its dependence on hydrostatic pressure.

Although plasma concentrations of propofol during anesthesia are well known, the free concentration remains unknown because of uncertainties regarding plasma protein binding, interaction with other protein-bound substances, the level of binding to its lipid carrier, and the use of adjuvants. At elevated surrounding pressure, all general anesthetics require higher concentrations to reach adequate levels of anesthesia. To determine the anesthetic potency of propofol at equilibrium conditions and to study the effects of pressure on propofol-induced anesthesia, Rana pipiens tadpoles were exposed to different concentrations of pure, not emulsified, propofol in aqueous solution. Anesthesia was defined as loss of the righting reflex. Ten animals per concentration were used, and each experiment was conducted twice. Pressure experiments were performed with nonanesthetized tadpoles and urethane-anesthetized tadpoles as control groups. Propofol concentrations were measured spectrophotometrically. At 1 atmosphere absolute (atm abs), a semilogarithmic sigmoidal concentration-response curve was obtained with a half-maximal effect of propofol at 2.2 +/- 0.22 microM (EC50; mean +/- SE). Increased pressure shifted the concentration-response curve to the right. The EC50 increased linearly with increasing pressure up to 121 atm abs (EC50 at 121 atm abs = 4.1 +/- 0.41 microM). For pressure greater than 121 atm abs, an increased excitability of the tadpoles made it difficult to distinguish the righting reflex from involuntary movements. The saturated solubility of propofol in aqueous solution was found to be 1.0 +/- 0.02 mM (mean +/- SD), and the octanol/water partition coefficient was 4,300 +/- 280. Propofol adhered to the correlation between anesthetic potency and octanol/water partition coefficient exhibited by other general anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of hemorrhage on propofol pseudo-steady state concentration

BACKGROUND: A small induction dose has been recommended in cases of hemorrhagic shock. However, the influence of hemorrhage on the amplitude of plasma propofol concentration has not yet been fully investigated during continuous propofol infusion. The authors hypothesized that the effect of hemorrhage on plasma propofol concentration is variously influenced by the different stages of shock. METHODS: After 120 min of steady state infusion of propofol at a rate of 2 mg x kg(-1) x h(-1), nine instrumented immature swine were studied using a stepwise increasing hemorrhagic model (200 ml of blood every 30 min until 1 h, then additional stepwise bleeding of 100 ml every 30 min thereafter, to the point of circulatory collapse). Hemodynamic parameters and plasma propofol concentration were recorded at every step. RESULTS: Before total circulatory collapse, it was possible to drain 976 +/- 166 ml (mean +/- SD) of blood. Hemorrhage of less than 600 ml (19 ml/kg) was not accompanied by a significant change in plasma propofol concentration. At individual peak systemic vascular resistance, when cardiac output and mean arterial pressure decreased by 31% and 14%, respectively, plasma propofol concentration increased by 19% of its prehemorrhagic value. At maximum heart rate, when cardiac output and mean arterial pressure decreased by 46% and 28%, respectively, plasma propofol concentration increased by 38%. In uncompensated shock, it increased to 3.75 times its prehemorrhagic value. CONCLUSIONS: During continuous propofol infusion, plasma propofol concentration increased by less than 20% during compensated shock. However, it increased 3.75 times its prehemorrhagic concentration during uncompensated shock.     

Determination of the potency of remifentanil compared with alfentanil using ventilatory depression as the measure of opioid effect.

BACKGROUND: Remifentanil is a new opioid with properties similar to other mu-specific agonists. To establish its pharmacologic profile relative to other known opioids, it is important to determine its potency. This study investigated the relative potency of remifentanil compared with alfentanil. METHODS: Thirty young healthy males were administered double-blind remifentanil or alfentanil intravenously for 180 min using a computer-assisted continuous infusion device. Depression of ventilation was assessed by the minute ventilatory response to 7.5% CO2 administered via a "bag in the box" system. The target concentration of the study drug was adjusted to obtain 40-70% depression of baseline minute ventilation. Multiple blood samples were obtained during and following the infusion. The concentration-effect relationship of each drug was modeled, and the concentration needed to provide a 50% depression of ventilation (EC50) was determined. RESULTS: Only 11 subjects in each drug group completed the study; however, there were sufficient data in 28 volunteers to model their EC50 values. The EC50 (mean and 95% confidence interval) for depression of minute ventilation with remifentanil was 1.17 (0.85-1.49) ng/ml and the EC50 for alfentanil was 49.4 (32.4-66.5) ng/ml. CONCLUSION: Based on depression of the minute ventilatory response to 7.5% CO2, remifentanil is approximately 40 (26-65) times more potent than alfentanil when remifentanil and alfentanil whole-blood concentrations are compared. As alfentanil is usually measured as a plasma concentration, remifentanil is approximately 70 (41-104) times more potent than alfentanil when remifentanil whole-blood concentration is compared with alfentanil plasma concentration. This information should be used when performing comparative studies between remifentanil and other opioids.     

Comparison of the effects of sub-hypnotic concentrations of propofol and halothane on the acute ventilatory response to hypoxia

To compare the effects of sub-anaesthetic concentrations of propofol and halothane on the respiratory control system, we have studied the acute ventilatory response to isocapnic hypoxia (AHVR) in 12 adults with and without three different concentrations of propofol and halothane. Target doses for propofol were 0, 0.05, 0.1 and 0.2 of the effective plasma concentration (EC50 = 8.1 micrograms ml-1). Target doses for halothane were 0, 0.05, 0.1 and 0.2 minimum alveolar concentration (MAC = 0.77%). The doses achieved experimentally were 0.01, 0.06, 0.13 and 0.26 of the EC50 for propofol and 0, 0.05, 0.11 and 0.20 MAC for halothane. During the experiment subjects breathed via a mouthpiece from an end-tidal forcing system. End-tidal PO2 (PE'O2) was held at 13.3 kPa for 5 min, and then at 6.7 kPa for 5 min. End- tidal PCO2 (PE'CO2) was held constant at 0.13-0.27 kPa greater than the subject's natural level throughout. The mean values for AHVR with propofol were: 12.8 (SEM 2.4) litre min-1 (0.01 EC50), 10.0 (1.9) litre min-1 (0.06 EC50), 9.8 (2.3) litre min-1 (0.13 EC50) and 4.9 (1.2) litre min-1 (0.26 EC50). The values for AHVR with halothane were: 11.9 (2.4) litre min-1 (0 MAC), 7.8 (1.6) litre min-1 (0.05 MAC), 5.9 (1.2) litre min-1 (0.11 MAC) and 3.2 (1.6) litre min-1 (0.2 MAC). The decline in AHVR with increasing dose for both drugs was statistically significant (ANOVA, P < 0.001); there was no significant difference between the two drugs with respect to this decline. Normoxic ventilation with propofol declined from 13.2 (1.6) litre min-1 (0.01 EC50) to 8.3 (0.9 litre min-1 (0.26 EC50), and with halothane declined from 13.5 (2.0) litre min-1 (0 MAC) to 11.8 (1.6) litre min-1 (0.2 MAC). This was significant for both drugs (ANOVA, P < 0.001).      

Non-steady state analysis of the pharmacokinetic interaction between propofol and remifentanil

BACKGROUND: The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil. METHODS: Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term. RESULTS: The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol. CONCLUSIONS: Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.     

Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics

Background: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol.

Methods: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg [middle dot] kg-1 [middle dot] h-1 for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed.

Results: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model.     

Assessment of the intrinsic contractile state within an area of myocardium

Afterload independent, inotropic state sensitive indices of regional function were sought in 31 canine hearts instrumented with piezoelectric crystals to depict trapezoidal areas in the left anterior descending and circumflex arterial beds. Control and postinterventional end-systolic pressure versus regional length and area relationships and regional stroke work versus end-diastolic length and area relationships were inscribed during incremental volume loading on right heart bypass. Hearts were randomized to undergo afterload variation with phenylephrine infusion, contractility augmentation by calcium chloride, or 20 minutes of ischemia in the region of the left anterior descending artery with 30 minutes of reperfusion. All relationships were linear before and after each intervention (mean r = 0.726 to 0.974). The slopes of each correlation were interpreted to quantify intrinsic regional contractility, and all were afterload insensitive (unaffected by phenylephrine). Regional stroke work versus end-diastolic area and length relationships were depressed 55% and 62%, respectively, after ischemia (p less than 0.001 each), whereas neither end-systolic pressure versus regional area nor regional length was significantly altered. Calcium chloride increased regional stroke work versus area 45% in both arterial beds, but significantly increased the other indices only in the left anterior descending and not the left circumflex region. Unlike previous studies of global contractility, correlation of end-systolic events alone did not reliably discriminate perturbations in regional function. The superiority of regional stroke work versus end-diastolic area may be due to incorporating pressure-area changes during the entire cardiac cycle and obviating variability owing to crystal orientation inexactly parallel to fiber shortening.     

Bispectral index and state entropy of the electroencephalogram during propofol anaesthesia

Editor—We read with interest the study by Bonhomme andcolleagues,¹ in which some interesting differences from ourpublished data² have emerged. We agree that Bland–Altmananalysis appears to be the right statistical test to performin an attempt to determine the degree of agreement between twomeasurement techniques. The only two studies that used the Bland–Altmananalysis to compare BIS and SE have been published by Bonhommeand our group. We found a good comparability (mean difference0.1) between the two (the upper and lower limits of agreementwere –19.9 and 19.6). Bonhomme used the same type of analysison data pairs averaged over 1 min over the entire period andreported a mean difference of 2.5 and similar upper and lowerlimits of agreement (–19.5 and 24.6). We agree that thismay be     

Recirculatory spinal subarachnoid perfusions in dogs: a method for determining CSF dynamics under non-steady state conditions

Open-ended ventriculocisternal perfusion techniques for determining cerebrospinal fluid production and absorption rates are severely restricted by the absolute requirement that steady state conditions be present. A new closed recirculatory spinal perfusion technique is described. Because steady state equilibrium is not necessary, numerous determinations at multiple intracranial pressures or under varied experimental conditions are possible within relatively brief perfusion periods. Cerebrospinal fluid (CSF) and nondiffusible albumin tracer are rapidly recirculated through the spinal subarachnoid space in a cephalad direction. The concentration of fluorescein-tagged albumin is continuously monitored as the CSF is circulated through a fluorometric flow cell. Measured continuously, intracranial pressure (ICP) is regulated by changing the volume of the external perfusion circuit with a syringe pump connected in series to the recirculatory spinal perfusion. CSF formation and absorption rates are calculated from measurements of albumin concentration, concentration changes with time, ICP, syringe pump infusion rate, and the external perfusion circuit volume. In dogs, data can be collected after only 45 minutes for mixing; perfusions at four or five intracranial pressures in addition to normal resting pressure can be completed within 2 to 3 hours. The data from 15 perfusions in 14 dogs are presented. The method provides normal resting pressure values of CSF production and absorption consistent with those values in the literature determined by traditional ventriculocisternal perfusion techniques. Determinations at multiple intracranial pressures suggest a proportional relationship between absorption and ICP. No consistent acute change in CSF formation with pressures to 50 mm Hg can be inferred from these data.