Allison M. Martinez

Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration.

UNLABELLED Indicator dilution theory predicts that the first-pass pulmonary and systemic arterial concentrations of a drug will be inversely related to the cardiac output. For high-clearance drugs, these first-pass concentrations may contribute significantly to the measured arterial concentrations, which would therefore also be inversely related to cardiac output. We examined the cardiac output dependence of the initial kinetics of propofol in two separate studies using chronically instrumented sheep in which propofol (100 mg) was infused IV over 2 min. In the first study, steady-state periods of low, medium, and high cardiac output were achieved by altering carbon dioxide tension in six halothane-anesthetized sheep. The initial area under the curve and peak value of the pulmonary artery propofol concentrations were inversely related to cardiac output (R2 = 0.57 and 0.66, respectively). For the systemic arterial concentrations, these R2 values were 0.68 and 0.71, respectively. In our second study, transient reductions in cardiac output were achieved in five conscious sheep by administering a short infusion of metaraminol concurrently with propofol. Cardiac output was lowered by 2.2 L/min, and the area under the curve to 10 min of the arterial concentrations increased to 143% of control. IMPLICATIONS The initial arterial concentrations of propofol after IV administration were shown to be inversely related to cardiac output. This implies that cardiac output may be a determinant of the induction of anesthesia with propofol.

The Influence of the Bolus Injection Rate of Propofol on Its Cardiovascular Effects and Peak Blood Concentrations in Sheep

The influence of the bolus injection rate of propofol on its cardiovascular effects has not been extensively studied.We therefore examined the influence of the injection rate of IV bolus doses of propofol on its acute cardiovascular effects and peak blood concentrations in seven chronically instrumented sheep. Each received IV propofol (200 mg) over 2 min (slow injection) and 0.5 min (rapid injection) on separate occasions in random order. The rapid injection was associated with more profound decreases in mean arterial blood pressure than slow injection (35.7% vs 23.7% maximal reductions from baseline, respectively; P = 0.02). There were no significant differences between the injection rates for peak reductions in myocardial contractility, increases in heart rate, or degree of respiratory depression. Concurrently, the rapid injections were associated with significantly higher arterial (26.9 vs 11.9 mg/L) propofol concentrations in a manner consistent with indicator dilution principles. There were no differences in the peak coronary sinus concentrations between the injection rates. We conclude that the rapid injection of propofol in the context of the induction of anesthesia produced significantly higher peak arterial propofol concentrations and suggest that it is these higher concentrations that produced relatively greater reductions in arterial blood pressure from rapid injections. Implications: Propofol is injected into a vein to initiate anesthesia. It can cause a rapid decrease in blood pressure, which may be dangerous to the patient. We examined the effect of rapid and slow injection rates of propofol in sheep and found that rapid injection caused a greater decrease in blood pressure. This was because rapid injection caused higher concentrations of propofol in the blood immediately after the injection. We believe that if the same processes occur in humans, there may be little advantage in injecting propofol rapidly. (Anesth Analg 1998;86:1109-15)

Comparison of the sedative properties of CNS 7056, midazolam, and propofol in sheep

BACKGROUND CNS 7056 is an esterase-metabolized benzodiazepine sedative currently under development. Its short duration of action would suggest a clinical role similar to midazolam or propofol. METHODS The effect of a range of doses of CNS 7056, midazolam, and propofol on depth of sedation, the respiratory system, and the cardiovascular system was studied in chronically instrumented sheep (n=5 or 6). The low, medium, and high doses of CNS 7056, midazolam, and propofol were 0.37, 0.74, and 1.47 mg kg(-1); 0.05, 0.1, and 0.2 mg kg(-1); and 1, 2, and 4 mg kg(-1), respectively. RESULTS CNS 7056 produced substantial sedation with rapid onset and offset for all doses, with duration rather than depth of sedation increasing with the dose. The lower doses of midazolam had minimal sedative effect; increasing the dose produced variable but longer term sedation. Sedation from propofol was comparable with that of CNS 7056 for the medium and high doses only. The high doses produced approximately 20 min of sedation. All three drugs produced dose-dependent respiratory (e.g. reductions in arterial oxygen tension) and cardiovascular depression (e.g. reductions in mean arterial pressure). For CNS 7056, midazolam, and propofol, the magnitude of the cardiovascular and respiratory depression was proportional to the depth of sedation achieved for any given drug or dose. For all three drugs, the respiratory and cardiovascular depression was not of sufficient magnitude to endanger the animals. CONCLUSIONS CNS 7056 is a powerful and short-acting anaesthetic in sheep with respiratory and cardiovascular effects consistent with its sedative/anaesthetic qualities.

Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep

BACKGROUND CNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. METHODS The stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg(-1) (2 min infusion) of CNS 7056 in alternating order on separate days. RESULTS CNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min(-1) and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min(-1), and inter-compartmental clearances of 2.85 and 1.44 litre min(-1), while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t(1/2,)(k)(e0) for sedation was 1.78 min, and the EC(50) was 0.10 µg ml(-1). CONCLUSIONS CNS 7056 has PK-PD properties compatible with its potential human use as a short-acting i.v. sedative.

A dose escalation study in sheep of the effects of the benzodiazepine CNS 7056 on sedation, the EEG and the respiratory and cardiovascular systems

CNS 7056 is a new, rapidly metabolized benzodiazepine. The effects of escalating doses of CNS 7056 on sedation, and respiratory and cardiovascular function, were examined in conscious, chronically instrumented sheep for the first time.

Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model

The pharmacokinetics and time course of blood–brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg−1 BUP or 0.6 mg kg−1 norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min−1) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min−1) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood–brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 ± 0.08 and 1.18 ± 0.04 (mean ± SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.

Prolonged dysequilibrium between blood and brain concentrations of propofol during infusions in sheep

Background: Previous work had shown dysequilibrium between the arterial blood and brain concentrations of the intravenous anaesthetic agent propofol following its rapid administration over 2 min to sheep. The extent of dysequilibrium was examined following slower administration as a constant rate 45‐min infusion (10 mg/min).

Development and validation of a recirculatory physiological model of the myocardial concentrations of lignocaine after intravenous administration in sheep.

A recirculatory physiological model of the determinants of the myocardial concentrations of lignocaine after intravenous administration was developed in sheep and validated with the intention of analysing and predicting the outcome of altered dose regimens and various pathophysiological states on the initial myocardial concentrations of lignocaine.

PHARMACOKINETICS AND PHARMACODYNAMICS OF INDOMETHACIN: EFFECTS ON CEREBRAL BLOOD FLOW IN ANAESTHETIZED SHEEP

1 Indomethacin has been used to manage raised intracranial pressure (ICP) in humans during neuroanaesthesia and neurosurgery. Indomethacin causes cerebral vasoconstriction and reduces cerebral blood flow (CBF) and, therefore, ICP. 2 The systemic kinetics, cerebral kinetics and cerebral dynamics of indomethacin (0.2 mg/kg) were measured and modelled using a population approach. Data were collected using an instrumented sheep preparation with raised ICP and under either isoflurane or propofol anaesthesia to parallel the clinical use of indomethacin in neurosurgery. 3 The systemic kinetics of indomethacin could be described by a two‐compartment model, with small distribution volumes and a clearance of 0.68 L/min. The cerebral kinetics of indomethacin could be described using a model with a cerebral distribution volume between 5 and 8 mL and a loss term of 3.3 mL/min, the latter probably representing slow diffusion across the blood–brain barrier. 4 The changes in CBF lagged behind the blood concentrations of indomethacin. Indirect response models with turnover times of 1.70–4.08 min were generally better able to describe the effect of indomethacin on CBF than effect compartment models. 5 There was a non‐linear concentration–effect relationship, with the maximum possible reduction in CBF being to 73–74% of baseline. 6 The data and model support the concept of indomethacin having limited uptake into the brain, with its effect on CBF being the result of its action on the endothelium, where it indirectly modifies the turnover of a compound regulating vascular tone.

The effects of indomethacin on intracranial pressure and cerebral hemodynamics during isoflurane or propofol anesthesia in sheep with intracranial hypertension.

The effect of indomethacin in reducing intracranial pressure (ICP) may be dependent on the choice of anesthetic regimen. We studied the effects of indomethacin on ICP and cerebral blood flow (CBF) during isoflurane or propofol anesthesia in a sheep model of intracranial hypertension. A crossover design was applied in which six sheep were anesthetized with isoflurane and propofol in a random order. Anesthetic depth was measured with response and state entropy. Changes in CBF, ICP, mean arterial blood pressure, arterio-venous oxygen difference, and Paco2 were measured at specific times before and after an IV indomethacin bolus (0.2 mg/kg). Response and state entropy values during anesthesia were similar in both groups. Isoflurane and propofol reduced CBF by 11% and 34%, respectively. Indomethacin caused a reduction in ICP within 15 s during both anesthetic regimens, with the decrease in ICP being significantly more pronounced during isoflurane (P = 0.009). In both anesthetic groups, indomethacin caused a simultaneous increase in mean arterial blood pressure and a further 17% versus 14% decrease in CBF from predrug values for isoflurane and propofol, respectively. The reduction in CBF was significantly more pronounced for propofol (P = 0.02). The effect on ICP, however, was most pronounced during isoflurane anesthesia. We suggest that the effect of indomethacin is partly mediated by an autoregulatory response.