Scott McJames

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.

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.

Buccal Absorption of Fentanyl Is pH-Dependent in Dogs

Background Analgesia and sedation have been achieved noninvasively by fentanyl administration through the oral and nasal mucosa. In theory, the transmucosal bioavailability and absorption of fentanyl could be improved by converting more fentanyl to the unionized form by adjusting the surrounding pH. The authors tested this hypothesis in dogs. Methods Under general anesthesia, each of six mongrel dogs was given fentanyl on repeated occasions, first intravenously (once), then by application to the buccal mucosa (six times). Buccal fentanyl administration was accomplished by placement of a pH‐buffered solution of fentanyl into a specially constructed cell, which was clamped to the dogs buccal mucosa for 60 min. Fentanyl solutions with pHs of 6.6, 7.2, and 7.7 were studied to span a tenfold difference in the unionized fraction of fentanyl. Femoral arterial blood samples were sampled frequently and analyzed for fentanyl using a radioimmunoassay. Peak plasma concentration and the time of its occurrence for each buccal study were noted from the plasma concentration verses time profile. Terminal elimination half‐life, bioavailability, and permeability coefficients were calculated using standard pharmacokinetic techniques. Results The variables peak plasma concentration, bioavailability, and permeability coefficient increased three‐to fivefold as the pH of the fentanyl buccal solution increased and more fentanyl molecules became unionized. There was no difference in terminal elimination half‐life after intravenous fentanyl (244 plus/minus 68 min) or buccal fentanyl administration (pH 7.7, 205 plus/minus 89 min; pH 7.2, 205 plus/minus 65 min; pH 6.6, 196 plus/minus 48 min). In all buccal studies regardless of pH, time to peak plasma concentration occurred within 10 min of removal of the fentanyl solutions from the buccal mucosa. Conclusions The buccal absorption, bioavailability, and permeability of fentanyl are markedly increased as the pH of the fentanyl solution becomes more basic. More likely, this is because of an increase in the fraction of unionized fentanyl.

Fentanyl pharmacokinetics in hemorrhagic shock: a porcine model.

BACKGROUND It is common clinical practice to administer reduced doses of opioid to patients suffering from hemorrhagic shock to minimize adverse hemodynamic consequences and to prevent prolonged opioid effect However, the scientific foundation supporting this practice is not well established. The aim of this study was to test the hypothesis that hemorrhagic shock alters both the distribution and clearance of opioids using fentanyl in a porcine isobaric hemorrhage model. METHODS Eighteen pigs were randomized to shock or control groups. The animals in the shock group were subjected to hemorrhage using an isobaric method. Pigs in both groups received fentanyl (50 microg/kg) intravenously over 5 min. Frequent arterial blood samples were obtained for radioimmunoassay. Each animals pharmacokinetic parameters were estimated by fitting a three-compartment model to the concentration versus time data Nonlinear mixed-effects population pharmacokinetic models examining the influence of mean arterial pressure and cardiac index were also constructed. Clinical simulations using the final population model were performed. RESULTS The shock cohort reached substantially higher fentanyl concentrations. The shock groups central clearance and central- and second-compartment distribution volumes were significantly reduced. The most useful population model scaled all pharmacokinetic parameters to mean arterial pressure. The simulations illustrated that hemorrhagic shock results in higher fentanyl concentrations for any given dosage scheme. CONCLUSION The essential finding of the study is that fentanyl pharmacokinetics are substantially altered by hemorrhagic shock. The reduced opioid requirement commonly observed during hemorrhagic shock is at least partially attributable to pharmacokinetic mechanisms.

The effect of prior dural puncture on cisternal cerebrospinal fluid morphine concentrations in sheep after administration of lumbar epidural morphine

Combined spinal epidural anesthesia has become increasingly popular as a method of providing rapid onset of analgesia or surgical block with access for further administration of analgesics or anesthetics.No in vivo studies have evaluated the relationship between dural puncture and drug transfer from the epidural space to the cerebrospinal fluid (CSF). To determine whether morphine administered in the epidural space adjacent to a dural puncture results in increased CSF concentrations at the cisterna magna (CM), 12 adult ewes were studied. Each animal was assigned to one of three groups. Animals in Group 1 served as a control and received no dural puncture. Animals in Group 2 received a dural puncture with a 25-gauge (G) Whitacre needle, while Group 3 animals received a dural puncture with an 18-G Tuohy needle. One hour after dural puncture, each animal was given epidural morphine, 0.2 mg/kg. Six hours after the administration of epidural morphine, CSF from the CM was sampled and analyzed by gas chromatographymass spectrometry for morphine concentration. The mean morphine concentration at the CM for Group 1 (control) was 22 +/- 12 ng/mL, whereas animals with 25-G and 18-G dural punctures had concentrations of 154 +/- 32 ng/mL and 405 +/- 53 ng/mL, respectively (P = 0.0005). These data demonstrate that a significant increase in CSF morphine concentration at the brainstem will occur when lumbar epidural morphine is administered adjacent to a dural puncture. Furthermore, the increase in CSF morphine concentration is positively correlated with the size of the needle producing the dural puncture. These findings highlight the potential for delayed respiratory depression when epidural opiate administration follows a dural puncture. (Anesth Analg 1996;83:523-5)

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 effect of distance from injection site to the brainstem using spinal sufentanil.

Background and Objectives Intrathecal (IT) sufentanil is commonly used in parturients to provide rapid onset of labor analgesia without motor block. This practice, although widely used, has been associated with severe respiratory depression in some patients. The mechanism of this respiratory depression is unclear, however, rapid cephalad movement and interaction with parenteral opioids are 2 frequently cited explanations for this complication. Because this complication has occurred only in women with heights between 150 and 157 cm, we elected to study the effect of the distance from injection site to the cisterna magna (CM) on peak brainstem cerebrospinal fluid (CSF) concentrations. Methods Ten adult ewes were injected with IT sufentanil (0.3 μg/kg) at a mean distance of either 71 cm (65 to 78 cm) from the brainstem (pelvic group) or 37 cm (34 to 42 cm) from the brainstem (thoracic group). CSF was then sampled at 5-minute intervals from the CM. Results Measurable CM concentrations of sufentanil were noted in the brainstem at 20 and 25 minutes, respectively, for the thoracic and the pelvic groups. Peak sufentanil concentrations from the thoracic group were nearly 10-fold higher (0.553 ± 0.43 ng/mL) compared with the pelvic group (0.064 ± 0.002 ng/mL) when measured in the CM (P = .023). Conclusions Our results suggest that sufentanil migrates relatively large distances in the IT space. Injection site (distance from the brainstem) appears to be a prominent factor in determining brainstem concentrations and subsequent respiratory depression after spinal administration.

Compartmental modeling of technetium-99m-labeled teboroxime with dynamic single-photon emission computed tomography: comparison with static thallium-201 in a canine model.

Di Bella EVR, Ross SG, Kadrmas DJ, et al. Compartmental modeling of technetium-99m–labeled teboroxime with dynamic single-photon emission computed tomography: Comparison with static thallium-201 in a canine model. Invest Radiol 2001;36:178–185. rationale and objectives. A compartmental modeling approach to deriving kinetic parameters from a time series of single-photon emission computed tomography (SPECT) images of technetium-99m–labeled (99mTc-) teboroxime may have value for semiquantitative assessment of myocardial perfusion. This study investigated the value of the kinetic parameters derived from a two-compartment model of 99mTc-teboroxime for measuring myocardial perfusion and compared it with static thallium-201 (201Tl) uptake and microsphere-measured blood flow in dogs. methods.Experiments were successfully conducted in 9 of 11 open-chest dogs. During adenosine stress, a single complete set of projections of 201Tl uptake was acquired. 99mTc-teboroxime was then injected during adenosine stress, and a complete set of projections was acquired every 5.7 seconds for 17 minutes. Resting studies were performed on 4 of the animals. All of the projection sets were reconstructed with an iterative algorithm and incorporated corrections for attenuation and the geometric response of the collimators. Regional kinetic parameters (washin and washout) were determined semiautomatically from the time series of reconstructed 99mTc-teboroxime images and registered with microsphere data. Regional washin estimates were compared with 201Tl intensities and myocardial blood flows determined from microspheres. results.Optimally scaled 99mTc-teboroxime washin parameters and 201Tl uptakes were correlated with microsphere-determined blood flows (r = 0.91, y = 0. 99 x + 0.01, and r = 0.92, y = 0.88 x + 0.28, respectively). In six of the studies, the left anterior descending coronary artery was occluded, and stress occluded-to-normal (O/N) ratios were calculated. The O/N ratios were 0.32 ± 0.17 as determined from microspheres injected with 201Tl and 0.38 ± 0.29 from microspheres injected with 99mTc-teboroxime (P = NS). The O/N ratios were 0.48 ± 0.16 for static 201Tl uptake and 0.27 ± 0.21 for 99mTc-teboroxime washin (P < 0.05). conclusions.Both 201Tl uptake and 99mTc-teboroxime kinetic parameters were well correlated with flow. The 99mTc-teboroxime washin parameters offer semiquantitative flow values and provide greater defect contrast than can be obtained with 201Tl uptake values.

Is fentanyl an anesthetic in the dog

The authors used the absence of vocalization and movement during application of a hemostat clamped to the first ratchet at the base of the tail as an indication of anesthesia for evaluation of the anesthetic properties of fentanyl in the dog. Eighty-six unpremedicated, unrestrained, untrained mongrel dogs were given one of eight doses of fentanyl citrate (125, 250, 500, 750, 1000, 1500, 2000, and 3000 μg/kg) as a single intravenous bolus injection. Dogs breathed spontaneously without oxygen supplementation. Anesthesia was assessed every 5 min until absence of anesthesia was recorded for two consecutive evaluations. Venous plasma samples were obtained in two or three dogs receiving each of the doses of fentanyl 5 min after fentanyl injection and again when application of the tail clamp elicited either vocalization or movement (positive response). Fentanyl resulted in re-cumbency in all animals except two receiving 125 Although all doses of fentanyl produced anesthesia in at least one animal 5 min after injection, the duration of anesthesia was short, responses unpredictable, and anesthesia achieved in all animals only with a dose of 3000 μg/kg. Increasing doses of fentanyl resulted in higher plasma fentanyl concentrations 5 min after injection and at the time of the first positive response to tail clamp but there was great variability. All doses of fentanyl caused statistically significant decreases in heart and respiratory rates but none produced apnea or a PaCO2 higher than 67 mm Hg. All dogs survived without sequelae. The data demonstrate that fentanyl can produce anesthesia in the dog but that requirements vary enormously and are extremely high in some animals and duration is short.