Pharmacokinetic and pharmacodynamic drug display and simulation systems in anesthesia practice.

PURPOSE OF REVIEW: This review explores the use of tools and displays based on pharmacokinetic and pharmacodynamic (PK/PD) modelling of drugs used in anesthesia. The primary focus is on those tools designed to illustrate the interactions between two or more drugs, or classes of drugs, and in particular, their use in a real-time clinical support role. Off-line, educational tools are also explored. RECENT FINDINGS: Despite initial promise and encouraging supporting data, the use of real-time display of PK/PD is not common except in target-controlled infusion (TCI) pumps. SUMMARY: PK/PD simulation is a useful tool for exposition of the relationship between drug dosing and effect. The initial promise of real-time tools has yet to be realized in routine clinical practice.

Carbon Dioxide Absorption During Inhalation Anesthesia: A Modern Practice.

CO2 absorbents were introduced into anesthesia practice in 1924 and are essential when using a circle system to minimize waste by reducing fresh gas flow to allow exhaled anesthetic agents to be rebreathed. For many years, absorbent formulations consisted of calcium hydroxide combined with strong bases like sodium and potassium hydroxide. When Sevoflurane and Desflurane were introduced, the potential for toxicity (compound A and CO, respectively) due to the interaction of these agents with absorbents became apparent. Studies demonstrated that strong bases added to calcium hydroxide were the cause of the toxicity, but that by eliminating potassium hydroxide and reducing the concentration of sodium hydroxide to <2%, compound A and CO production is no longer a concern. As a result, CO2 absorbents have been developed that contain little or no sodium hydroxide. These CO2 absorbent formulations can be used safely to minimize anesthetic waste by reducing fresh gas flow to approach closed-circuit conditions. Although absorbent formulations have been improved, practices persist that result in unnecessary waste of both anesthetic agents and absorbents. While CO2 absorbents may seem like a commodity item, differences in CO2 absorbent formulations can translate into significant performance differences, and the choice of absorbent should not be based on unit price alone. A modern practice of inhalation anesthesia utilizing a circle system to greatest effect requires reducing fresh gas flow to approach closed-circuit conditions, thoughtful selection of CO2 absorbent, and changing absorbents based on inspired CO2.

The effect of isocapnic hyperventilation on early recovery after remifentanil/sevoflurane anesthesia in O2 /air: A randomized trial.

BACKGROUND: Isocapnic hyperventilation (ICHV) may hasten emergence from general anesthesia but remains inadequately studied. We prospectively determined emergence time after sevoflurane anesthesia of variable duration with and without ICHV. METHODS: In 25 ASA I-II patients, general anesthesia was maintained with one age-adjusted MAC sevoflurane in O2 /air and target-controlled remifentanil delivery. At the start of skin closure, the remifentanil effect-site concentration was reduced to 1.5 ng/mL, any residual neuromuscular block reversed, and once the remifentanil effect-site concentration had decreased to 1.5 ng/mL, remifentanil and sevoflurane administration was stopped, and the fresh gas flow increased above minute ventilation. Patients randomly received either normoventilation (n = 13) or ICHV (doubling minute ventilation while titrating CO2 into the inspiratory limb to maintain isocapnia [n = 12]). Three early recovery end points were determined: time to proper response to verbal command; time to extubation; and time to stating one's name. RESULTS: Demographics were the same in both groups. Recovery end points were reached faster in the ICHV group compared to the normoventilation group: time to proper response to verbal command was 7.6 ± 2.2 vs 9.9 ± 2.9 min (P = 0.03); time to extubation was 7.6 ± 2.6 vs 11.0 ± 2.4 min (P = 0.002); and time to stating one's name was 8.9 ± 2.8 vs 12.5 ± 2.6 min (P = 0.003). Within each group, duration of anesthesia only marginally affected the times to reach these recovery end points. CONCLUSION: Isocapnic hyperventilation only had a small effect on emergence times after anesthesia, suggesting that isocapnic hyperventilation may have limited clinical benefits with modern potent inhaled anesthetics.

Kinetics of anesthetic onset measured with a direct index of neural activity.

BACKGROUND: Previous modeling of the kinetics of uptake and elimination of anesthetic drugs from the site of action has used measures derived from the electroencephalogram. Such measures lag the current brain activity because of the time needed to acquire a signal sample and derive the measure. With a direct measure of anesthetic activity, we could model brain uptake more exactly. METHODS: In volunteers, using a double-blind single-session design, we made repeated measurements using a well-known psychomotor test, the 2 target tapping test, during the washin and washout of 30% nitrous oxide. We also assessed maximal drug effect with a test of cognitive function, the digit symbol substitution test. Concentration at the site of action was modeled from end-tidal measurements, using a simple exponential washin and washout function, with half-times between 0.5 and 3 minutes. Comparisons were made within subjects, using 0 and 5% nitrous oxide. RESULTS: We studied 20 subjects. Nitrous oxide, at 30%, consistently reduced performance of the digit symbol substitution test. Tapping frequency was also reduced, but the effect was less consistent, and only 9 of 20 subjects showed a significant individual reduction in tapping frequency. In these subjects, the relationship between the modeled brain concentration and drug effect was better with a half-time set at 2 minutes, compared with 1.5 or 3 minutes. CONCLUSIONS: Given in subanesthetic concentrations, nitrous oxide has rapid onset and offset, consistent with a half-time of 2 minutes. This value is less than the values expected from studies during anesthesia using processed electroencephalogram, but consistent with measures of blood flow to active cerebral tissue in conscious subjects. Studies of performance in conscious subjects may aid further studies of anesthetic kinetics.

Observational audit of sevoflurane consumption during paediatric anaesthesia.

There is a recognition of the contribution to global warming from emissions of anaesthetic gases into the atmosphere. We audited sevoflurane use to help guide future initiatives to reduce consumption. We observed sevoflurane use during paediatric anaesthesia in a single operating theatre over eight weeks. We recorded demographics, timing of induction and maintenance of anaesthesia, type of circuit used and amount of liquid sevoflurane used (in mL). Ninety-four cases were available for analysis. Of these, 65 had gas inductions and 29 had intravenous (IV) inductions. The median sevoflurane use was 19 mL (interquartile range, IQR 13­24 mL). The median duration of cases was 50.5 min (IQR 35­78 min). The median sevoflurane consumption for cases with a gas induction was 22 mL (IQR 16­26 mL) and for those with an IV induction was 11 mL (IQR 7­17 mL; P < 0.00001). The duration of cases for the gas and IV induction cohorts were similar. During maintenance of anaesthesia, there was no difference between the IV and gas induction cohorts. There was little difference in sevoflurane use between the T-piece and circle system groups. Cases performed with gas inductions consumed twice the sevoflurane as those with IV inductions. Future interventions to reduce sevoflurane consumption should focus on this period.

Changing patterns in anesthetic fresh gas flow rates over 5 years in a teaching hospital.

BACKGROUND: Reducing anesthetic fresh gas flows can reduce volatile anesthetic consumption without affecting drug delivery to the patient. Delivery systems with electronic flow transducers permit the simple and accurate collection of fresh gas flow information. In a 2001 audit of fresh gas flow, we found little response to interventions designed to foster more efficient use of fresh gas. We compared current practice with our earlier results. METHODS: Flow data were collected in areas with a mix of general and acute surgery in March and November 2001, and again during 2006, by recording directly from the Datex ADU to a computer every 10 s. We extracted the distribution of flow rates when a volatile anesthetic was being administered. Data collection in March 2001 and 2006 was not advertised. RESULTS: In 2001, the mean flow rates were 1.95 and 2.1 L/min with a median flow of 1.5 L/min. In 2006, the mean was 1.27 and the median in the range 0.5-1.0 L/min. Isoflurane use decreased from 47% in 2001 to 4% in 2006. CONCLUSIONS: Fresh gas flows used in our department have decreased by 35% over 4 years. Although the absolute change in flow rate is not large, this represents potential annual savings of more than $US130,000. This occurred without specific initiatives, suggesting an evolution in practice towards lower fresh gas flow. Improvements in equipment and monitoring, including a locally developed system, which displays forward predictions of end-tidal and effect-site vapor concentrations, may be factors in this change.

The effect of using different values for the effect-site equilibrium half-time on the prediction of effect-site sevoflurane concentration: a simulation study.

UNLABELLED: We have developed a predictive display that allows effect-site concentration (Ceff) to be used as a target for administration of inhaled anesthesia. Ceff is dependent on the half-time for plasma effect-site equilibrium [t 1/2 1/2(ke0)]. The t 1/2(ke0) used in the predictive display is fixed and may differ from that in the patient. We wished to explore the effect of this difference on predictions of Ceff. In a computer simulation, fresh gas flow and vaporizer settings required to achieve a predefined time profile for Ceff were determined for t 1/2(ke0) of 2.5, 3.5, and 5 min. The end-tidal values for each simulation were used to recalculate Ceff with each t 1/2(ke0). The maximal deviation at predetermined points, measures of global fit, and the delay in "recovery" were calculated. With a predictive display t 1/2(ke0) of 3.5 min, the maximal error in Ceff was 0.18 vol%, occurring during the wash-in phase and disappearing within 2-3 min. The difference in time for Ceff to decrease from 1.0 to 0.7 vol% was 1.3 min. Results with a display t 1/2(ke0) of 2.5 min or 5 min and simulated patient t 1/2(ke0) of 5 min or 2.5 min were approximately twice as large. These results suggest that Ceff is relatively insensitive to large (50%-100%) variations in t 1/2(ke0). IMPLICATIONS: A model-based predictive display to guide effect site targeting of volatile anesthesia is described. The effect of using different values for the rate of transfer of sevoflurane between central and effect site compartments is explored. The results suggest effect site concentration is relatively insensitive to 50-100% variations in half-time for plasma effect-site equilibrium.

The effect of the interval between blood pressure determinations on the delay in the detection of changes: a computer simulation.

UNLABELLED: The frequency of automated noninvasive blood pressure (NIBP) measurements during routine anesthesia is a balance between potentially deleterious effects of frequent cycling and a delay in detecting changes caused by a long cycle time. A computer model generated systolic blood pressures that changed to a new, random value after a period of stability. We sampled these data at intervals between 1 and 10 min to simulate NIBP measurements. A separate algorithm, based on Trigg's Tracking Variable, indicated when a change had been detected. For each set of variables, the simulation was repeated 1000 times, and the average time to detect a change was recorded. The mean time to detect a change was 8.0 min with a 1-min cycle, 8.9 min with a 2-min cycle, 10.8 min with a 5-min cycle, and 13.0 min with a 10-min cycle. As the cycle time increased, the delay in detecting changes increased but only by approximately half the increase in the cycle time. The optimum variables for the trend detection algorithm also changed as the NIBP interval increased. Provided that abrupt changes in blood pressure are not anticipated, a 1- or 2-min cycle time for NIBP offers little advantage over a longer period. IMPLICATIONS: We used a computer model to study the effect of increasing noninvasive blood pressure (NIBP) sampling interval on the detection of blood pressure changes. The detection time increased only 50% of the increase in the sampling interval. This information may help optimize NIBP intervals in different circumstances.