Ken B. Johnson

Opioid-volatile anesthetic synergy : A response surface model with remifentanil and sevoflurane as prototypes

Background:Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane. Methods:Sixteen adult volunteers received a target-controlled infusion of remifentanil (0–15 ng/ml) and inhaled sevoflurane (0–6 vol%) at various target concentration pairs. After reaching pseudo–steady state drug levels, the Observers Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observers Assessment of Alertness/Sedation score ≥ 4) for anesthetics lasting 30–900 min. Results:Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil. Conclusion:Response surface analyses demonstrate a synergistic interaction between remifentanil and sevoflurane for sedation and all analgesic endpoints.

The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis.

Background Propofol is a common sedative hypnotic for the induction and maintenance of anesthesia. Clinicians typically moderate the dose of propofol or choose a different sedative hypnotic in the setting of severe intravascular volume depletion. Previous work has established that hemorrhagic shock influences both the pharmacokinetics and pharmacodynamics of propofol in the rat. To investigate this further, the authors studied the influence of hemorrhagic shock on the pharmacology of propofol in a swine isobaric hemorrhage model. Methods After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock groups. The shock group was bled to a mean arterial blood pressure of 50 mmHg over a 20-min period and held there by further blood removal until 30 ml/kg of blood was removed. Propofol 200 &mgr;g · kg−1 · min−1 was infused for 10 min to both groups. Arterial samples (15 from each animal) were collected at frequent intervals until 180 min after the infusion began and analyzed to determine drug concentration. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. Results The raw data demonstrated higher plasma propofol levels in the shock group. The pharmacokinetic analysis revealed slower intercompartmental clearances in the shock group. Hemorrhagic shock shifted the concentration effect relationship to the left, demonstrating a 2.7-fold decrease in the effect site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. Conclusions Hemorrhagic shock altered the pharmacokinetics and pharmacodynamics of propofol. Changes in intercompartmental clearances and an increase in the potency of propofol suggest that less propofol would be required to achieve a desired drug effect during hemorrhagic shock.

Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: a pharmacokinetic and pharmacodynamic analysis.

Background: Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol. Methods: After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer’s solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 &mgr;g·kg−1·min−1) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. Results: The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. Conclusions: Hemorrhagic shock followed by resuscitation with lactated Ringer’s solution did not alter the pharmacokinetics but did increase the potency of propofol. These results demonstrate that alterations in propofol pharmacokinetics observed in moderate to severe blood loss can be reversed with resuscitation. These results suggest that a modest reduction in propofol is prudent to achieve a desired drug effect after resuscitation from severe hemorrhagic shock.

When is a bispectral index of 60 too low?: Rational processed electroencephalographic targets are dependent on the sedative-opioid ratio.

Background: Opioids are commonly used in conjunction with sedative drugs to provide anesthesia. Previous studies have shown that opioids reduce the clinical requirements of sedatives needed to provide adequate anesthesia. Processed electroencephalographic parameters, such as the Bispectral Index (BIS; Aspect Medical Systems, Newton, MA) and Auditory Evoked Potential Index (AAI; Alaris Medical Systems, San Diego, CA), can be used intraoperatively to assess the depth of sedation. The aim of this study was to characterize how the addition of opioids sufficient to change the clinical level of sedation influenced the BIS and AAI. Methods: Twenty-four adult volunteers received a target-controlled infusion of remifentanil (0–15 ng/ml) and inhaled sevoflurane (0–6 vol%) at various target concentration pairs. After reaching pseudo–steady state drug levels, the modified Observer’s Assessment of Alertness/Sedation score, BIS, and AAI were measured at each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for each pharmacodynamic endpoint. Results: Response surface models adequately characterized all pharmacodynamic endpoints. Despite the fact that sevoflurane–remifentanil interactions were strongly synergistic for clinical sedation, BIS and AAI were minimally affected by the addition of remifentanil to sevoflurane anesthetics. Conclusion: Although clinical sedation increases significantly even with the addition of a small to moderate dose of remifentanil to a sevoflurane anesthetic, the BIS and AAI are insensitive to this change in clinical state. Therefore, during “opioid-heavy” sevoflurane–remifentanil anesthetics, targeting a BIS less than 60 or an AAI less than 30 may result in an unnecessarily deep anesthetic state.

Influence of hemorrhagic shock on remifentanil : A pharmacokinetic and pharmacodynamic analysis

BackgroundHemorrhagic shock is known to alter significantly the pharmacokinetics of fentanyl, an opioid that requires delivery to the liver for metabolism. The authors hypothesized that the pharmacokinetics and pharmacodynamics of remifentanil, an esterase metabolized opioid that does not require delivery to a metabolic organ, would be altered less by hemorrhagic shock that those of fentanyl. MethodsSixteen pigs were assigned randomly to control and shock groups. The shock group was bled using an isobaric hemorrhage model. Remifentanil 10 &mgr;g · kg−1 · min−1 was infused for 10 min to both groups. Arterial samples were collected for remifentanil concentration assay. Pharmacokinetic parameters were estimated using a three-compartment model. The electroencephalogram spectral edge was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. ResultsRemifentanil blood levels were higher in the shocked group. The central clearance was slower and the central compartment was smaller in shocked animals. No difference between groups was observed in the magnitude or time course of the remifentanil-induced decrease in spectral edge. ConclusionsHemorrhagic shock altered the pharmacokinetics of remifentanil, suggesting that less remifentanil would be required to maintain a target plasma concentration. However, because of its rapid metabolism, the impact of hemorrhagic shock on the concentration decline of remifentanil after termination of the infusion was minimal. Hemorrhagic shock did not alter the pharmacodynamics of remifentanil.

Remifentanil and propofol combination for awake craniotomy: case report with pharmacokinetic simulations.

Remifentanil and propofol infusions were used to provide neuroleptanalgesia during an awake craniotomy to resect a left frontoparietal glioblastoma near the motor speech center. This operation presented anesthetic requirements ranging from adequate analgesia during bone flap removal to an appropriate level of consciousness during cortical speech mapping. We performed pharmacokinetic simulations to estimate the effect site concentrations of propofol and remifentanil as the infusion rates were modulated to meet the dynamic sedation and analgesic needs of the operation. Simulations revealed that changes in infusion rates were quickly followed by changes in the effect site concentrations which corresponded well with the desired changes in patient sedation and analgesia. We propose that remifentanil and propofol in combination may be a useful technique for awake craniotomy.

An evaluation of remifentanil propofol response surfaces for loss of responsiveness, loss of response to surrogates of painful stimuli and laryngoscopy in patients undergoing elective surgery.

INTRODUCTION:In this study, we explored how a set of remifentanil-propofol response surface interaction models developed from data collected in volunteers would predict responses to events in patients undergoing elective surgery. Our hypotheses were that these models would predict a patient population’s loss and return of responsiveness and the presence or absence of a response to laryngoscopy and the response to pain after surgery. METHODS:Twenty-one patients were enrolled. Anesthesia consisted of remifentanil and propofol infusions and fentanyl boluses. Loss and return of responsiveness, responses to laryngoscopy, and responses to postoperative pain were assessed in each patient. Model predictions were compared with observed responses. RESULTS:The loss of responsiveness model predicted that patients would become unresponsive 2.4 ± 2.6 min earlier than observed. At the time of laryngoscopy, the laryngoscopy model predicted an 89% probability of no response to laryngoscopy and 81% did not respond. During emergence, the loss of responsiveness model predicted return of responsiveness 0.6 ± 5.1 min before responsiveness was observed. The mean probability of no response to pressure algometry was 23% ± 35% when patients required fentanyl for pain control. DISCUSSION:This preliminary assessment of a series of remifentanil-propofol interaction models demonstrated that these models predicted responses to selected pertinent events during elective surgery. However, significant model error was evident during rapid changes in predicted effect-site propofol-remifentanil concentration pairs.

The Influence of Hemorrhagic Shock on Etomidate: A Pharmacokinetic and Pharmacodynamic Analysis

We studied the influence of hemorrhagic shock on the pharmacology of etomidate in swine. Sixteen swine were randomly assigned to control and shock groups. The shock group was bled to a mean arterial blood pressure of 50 mm Hg and held there until 30 mL/kg blood was removed. Etomidate 300 &mgr;g · kg−1 · min−1 was infused for 10 min to both groups. Fifteen arterial samples were collected until 180 min after the infusion began to determine drug concentration. Pharmacokinetic variables for each group were estimated by using a three-compartment model. The bispectral index scale was used as a measure of drug effect. The pharmacodynamics were characterized by using a sigmoid inhibitory maximal effect model. The raw data revealed a 25% increase in the plasma etomidate concentration at the end of the 10-min infusion which resolved after termination of the infusion in the shock group. The pharmacokinetic analysis revealed subtle changes in the variable estimates between groups. The etomidate infusion produced a similar Bispectral Index Scale change in both groups. These results demonstrated that, unlike the influence of hemorrhagic shock on other sedative hypnotics and opioids, moderate hemorrhagic shock produced minimal changes in the pharmacokinetics and no change in the pharmacodynamics of etomidate.

The Evaluation of a Pulmonary Display to Detect Adverse Respiratory Events Using High Resolution Human Simulator

OBJECTIVE Authors developed a picture-graphics display for pulmonary function to present typical respiratory data used in perioperative and intensive care environments. The display utilizes color, shape and emergent alerting to highlight abnormal pulmonary physiology. The display serves as an adjunct to traditional operating room displays and monitors. DESIGN To evaluate the prototype, nineteen clinician volunteers each managed four adverse respiratory events and one normal event using a high-resolution patient simulator which included the new displays (intervention subjects) and traditional displays (control subjects). Between-group comparisons included (i) time to diagnosis and treatment for each adverse respiratory event; (ii) the number of unnecessary treatments during the normal scenario; and (iii) self-reported workload estimates while managing study events. MEASUREMENTS Two expert anesthesiologists reviewed video-taped transcriptions of the volunteers to determine time to treat and time to diagnosis. Time values were then compared between groups using a Mann-Whitney-U Test. Estimated workload for both groups was assessed using the NASA-TLX and compared between groups using an ANOVA. P-values < 0.05 were considered significant. RESULTS Clinician volunteers detected and treated obstructed endotracheal tubes and intrinsic PEEP problems faster with graphical rather than conventional displays (p < 0.05). During the normal scenario simulation, 3 clinicians using the graphical display, and 5 clinicians using the conventional display gave unnecessary treatments. Clinician-volunteers reported significantly lower subjective workloads using the graphical display for the obstructed endotracheal tube scenario (p < 0.001) and the intrinsic PEEP scenario (p < 0.03). CONCLUSION Authors conclude that the graphical pulmonary display may serve as a useful adjunct to traditional displays in identifying adverse respiratory events.

An exploration of remifentanil-propofol combinations that lead to a loss of response to esophageal instrumentation, a loss of responsiveness, and/or onset of intolerable ventilatory depression.

BACKGROUND: Remifentanil and propofol are increasingly used for short-duration procedures in spontaneously breathing patients. In this setting, it is preferable to block the response to moderate stimuli while avoiding loss of responsiveness (LOR) and intolerable ventilatory depression (IVD). In this study, we explored selected effects of combinations of remifentanil-propofol effect-site concentrations (Ces) that lead to a loss of response to esophageal instrumentation (EI), LOR, and/or onset of IVD. A secondary aim was to use these observations to create response surface models for each effect measure. We hypothesized that (1) in a large percentage of volunteers, selected remifentanil and propofol Ces would allow EI but avoid LOR and IVD, and (2) the drug interaction for these effects would be synergistic. METHODS: Twenty-four volunteers received escalating target-controlled remifentanil and propofol infusions over ranges of 0 to 6.4 ng · mL−1 and 0 to 4.3 &mgr;g · mL−1, respectively. At each set of target concentrations, responses to insertion of a blunt end bougie into the midesophagus (40 cm), level of responsiveness, and respiratory rate were recorded. From these data, response surface models of loss of response to EI and IVD were built and characterized as synergistic, additive, or antagonistic. A previously published model of LOR was used. RESULTS: Of the possible 384 assessments, volunteers were unresponsive to EI at 105 predicted remifentanil-propofol Ces; in 30 of these, volunteers had no IVD; in 30, volunteers had no LOR; and in 9, volunteers had no IVD or LOR. Many other assessments over the same concentration ranges, however, did have LOR and/or IVD. The combinations that allowed EI and avoided IVD and/or LOR primarily clustered around remifentanil-propofol Ces ranging from 0.8 to 1.6 ng · mL−1 and 1.5 to 2.7 &mgr;g · mL−1, respectively, and to a lesser extent approximately 3.0 to 4.0 ng · mL−1 and 0.0 to 1.1 &mgr;g · mL−1, respectively. Models of loss of response to EI and IVD both demonstrated a synergistic interaction between remifentanil and propofol. CONCLUSION: Selected remifentanil-propofol concentration pairs, especially higher propofol-lower remifentanil concentration pairs, can block the response to EI while avoiding IVD in spontaneously breathing volunteers. It is, however, difficult to block the response to EI and avoid both LOR and IVD. It may be necessary to accept some discomfort and blunt rather than block the response to EI to consistently avoid LOR and IVD.