Masahiro Uraoka

Influence of Fluid Infusion Associated with High-volume Blood Loss on Plasma Propofol Concentrations

BackgroundIt is common clinical practice to use fluid infusion to manage high-volume blood loss until a blood transfusion is performed. The authors investigated the influence of fluid infusion associated with blood loss on the pseudo-steady state propofol concentration. MethodsTwenty-seven swine were assigned to a lactated Ringer’s solution group, a hydroxyethyl starch group, or a threefold lactated Ringer’s solution group (n = 9 in each group). After 180 min of steady state infusion of propofol at a rate of 2 mg · kg−1 · h−1, hemorrhage and infusion were induced by stepwise bleeding followed by fluid infusion every 30 min. In each of the first two steps, 400 ml blood was collected; thereafter, 200 ml was collected at each step. Just after each bleeding step, fluid infusion was rapidly performed using a volume of lactated Ringer’s solution or hydroxyethyl starch equivalent to the blood withdrawn, or a threefold volume of lactated Ringer’s solution. Hemodynamic parameters and the plasma propofol concentration were recorded at each step. ResultsAlthough the plasma propofol concentration in the lactated Ringer’s solution group increased with hemorrhage and infusion, it decreased in both the hydroxyethyl starch and the threefold lactated Ringer’s solution groups. The propofol concentration in the hydroxyethyl starch group could be expressed by the following equation: Plasma Propofol Concentration Decrease (%) = 0.80 × Hematocrit Decrease (%) (r2 = 0.83, P < 0.0001). ConclusionsWhen high-volume blood loss is managed by isovolemic hemodilution, the plasma propofol concentration during continuous propofol infusion decreases linearly with the hematocrit decrease.

Deterioration of myocardial injury due to dexmedetomidine administration after myocardial ischaemia.

AIM Dexmedetomidine is a highly selective α-2 adrenergic agonist used perioperatively. Dexmedetomidines cardioprotective effect after myocardial ischaemia remains unknown. In this study, we administered dexmedetomidine after ischaemia to investigate its ability to protect the cardiac muscle from ischaemia-reperfusion injury in isolated rat hearts. METHODS After a 30-min stop of perfusion, isolated rat hearts underwent reperfusion for 120 min. At the initiation of reperfusion, dexmedetomidine was administered for 25 min at concentrations of 0 nM (control group), 1 nM (Dex 1 group), and 10 nM (Dex 10 group). Yohimbine (an α-2 adrenergic antagonist) was administered in the manner as above in another group of isolated rat hearts at a concentration of 1 μM without dexmedetomidine (Yoh group) and at 1 μM with 10 nM dexmedetomidine (Yoh+Dex 10 group). The area of infarction was measured using 2,3,5-triphenyltetrazolium staining. RESULTS Dexmedetomidine administration did not influence haemodynamics or the coronary flow (CF), but did increase the myocardial infarct size. Neither concentration of dexmedetomidine affected the infarct size as the Dex 1 and Dex 10 groups had almost the same infarct size. The infarct size was 40.5±2.9% in the control group, 60.9±5.3% in the Dex 1 group, and 60.9±2.8% in the Dex 10 group. The infarct size was reduced in the yohimbine groups. The infarct size was 39.2±3.3% in the Yoh+Dex 10 group and 45.0±3.2% in the Yoh group. CONCLUSION Dexmedetomidine administration does not influence haemodynamics or CF, but does increase the cardiac infarct size. α-2 Adrenergic stimulation may induce this mechanism.

Landiolol, an ultra short-acting beta1-adrenoceptor antagonist, does not alter the minimum alveolar anesthetic concentration of isoflurane in a swine model.

BACKGROUND:We previously reported that landiolol, an ultra–short-acting β1-adrenoceptor antagonist, does not alter the electroencephalographic effect of isoflurane. Here, we investigated the influence of landiolol on the minimum alveolar anesthetic concentration (MAC) of isoflurane required to prevent movement in response to a noxious stimulus in 50% of subjects. METHODS:Ten swine (29.0 ± 3.4 kg) were anesthetized by inhalation of isoflurane. MAC was determined using the dewclaw clamp technique, in which movement in response to clamping is recorded. After determination of MAC in the baseline period, an infusion of landiolol (0.125 mg · kg−1 · min−1 for 1 min, then 0.04 mg · kg−1 · min−1) was started. After a 20-min stabilization period, MAC was again assessed (0.04 mg · kg−1 · min−1 landiolol). The infusion of landiolol was then increased from 0.04 to 0.2 mg · kg−1 · min−1, and after a 20-min stabilization period, MAC was again assessed (0.2 mg · kg−1 · min−1 landiolol). Finally, the infusion of landiolol was stopped, and after a 20-min stabilization period, MAC was assessed for a fourth time (Baseline 2). RESULTS:Landiolol clearly attenuated the increases in heart rate and mean arterial blood pressure that occurred in response to the dewclaw clamp, but did not alter the MAC of isoflurane. CONCLUSIONS:Landiolol does not alter the antinociceptive effect of isoflurane. This result, combined with that from our previous work, also suggests that landiolol does not influence the anesthetic potency of inhaled anesthetics.

The influence of hemorrhagic shock on the minimum alveolar anesthetic concentration of isoflurane in a swine model.

BACKGROUND:Although hemorrhagic shock decreases the minimum alveolar concentration (MAC) of inhaled anesthetics, it minimally alters the electroencephalographic (EEG) effect. Hemorrhagic shock also induces the release of endorphins, which are naturally occurring opioids. We tested whether the release of such opioids might explain the decrease in MAC. METHODS:Using the dew claw-clamp technique in 11 swine, we determined the isoflurane MAC before hemorrhage, after removal of 30% of the estimated blood volume (21 mL/kg of blood over 30 min), after fluid resuscitation using a volume of hydroxyethylstarch equivalent to the blood withdrawn, and after IV administration of 0.1 mg/kg of the &mgr;-opioid antagonist naloxone. RESULTS:Hemorrhagic shock decreased the isoflurane MAC from 2.05% ± 0.28% to 1.50% ± 0.51% (P = 0.0007). Fluid resuscitation did not reverse MAC (1.59% ± 0.53%), but additional administration of naloxone restored it to control levels (1.96% ± 0.26%). The MAC values decreased depending on the severity of the shock, but the alterations in hemodynamic variables and metabolic changes accompanying fluid resuscitation or naloxone administration did not explain the changes in MAC. CONCLUSIONS:Consistent with previous reports, we found that hemorrhagic shock decreases MAC. In addition, we found that naloxone administration reversed the effect on MAC, and we propose that activation of the endogenous opioid system accounts for the decrease in MAC during hemorrhagic shock. Such an activation would not be expected to materially alter the EEG, an expectation consistent with our previous finding that hemorrhagic shock minimally alters the EEG.

Influence of hypovolemia on the electroencephalographic effect of isoflurane in a swine model

Background: Hypovolemia alters the effect of several intravenous anesthetics by influencing pharmacokinetics and end-organ sensitivity. The authors investigated the influence of hypovolemia on the effect of an inhalation anesthetic, isoflurane, in a swine hemorrhage model. Methods: Eleven swine were studied. After animal preparation with inhalation of 2% isoflurane anesthesia, the inhalation concentration was decreased to 0.5% and maintained at this level for 25 min before being returned to 2% (control). After 25 min, hypovolemia was induced by removing 14 ml/kg of the initial blood volume via an arterial catheter. After a 25-min stabilization period, the inhalation concentration was decreased to 0.5%, maintained at this level for 25 min, and then returned to 2% (20% bleeding). After another 25 min, a further 7 ml/kg blood was collected, and the inhalation concentration was altered as before (30% bleeding). End-tidal isoflurane concentrations and an electroencephalogram were recorded throughout the study. Spectral edge frequency was used as a measure of the isoflurane effect, and pharmacodynamics were characterized using a sigmoidal inhibitory maximal effect model for the spectral edge frequency versus end-tidal concentration. Results: There was no significant difference in the effect of isoflurane among the conditions used. Hypovolemia did not shift the concentration–effect relation (the effect site concentration that produced 50% of the maximal effect was 1.2 ± 0.2% under control conditions, 1.2 ± 0.2% with 20% bleeding, and 1.1 ± 0.2% with 30% bleeding). Conclusions: Hypovolemia does not alter the electroencephalographic effect of isoflurane, in contrast to several intravenous anesthetics.

Influence of cardiac output on the pseudo-steady state remifentanil and propofol concentrations in swine.

The propofol concentration during constant infusion is affected by a change in cardiac output, but the effect of this change on remifentanil, which is frequently used in combination with propofol, is unclear.

The influence of hemorrhagic shock on the electroencephalographic and immobilizing effects of propofol in a swine model.

BACKGROUND: Hemorrhagic shock increases the hypnotic effect of propofol, but the influence of hemorrhagic shock on the immobilizing effect of propofol is not fully defined. METHODS: Twenty-four swine (30.3 ± 3.6 kg) were anesthetized by inhalation of isoflurane and randomly assigned to either a control (n = 12) or a hemorrhagic shock (n = 12) group. Animals in the shock group were bled to a mean arterial blood pressure of 50 mm Hg and maintained at this level for 60 min. After isoflurane inhalation was stopped, propofol was infused at 50 mg · kg−1 · h−1 until no movement was observed after application of a dewclaw clamp every 2 min. Arterial samples for measurement of the propofol concentration were collected just before each use of the dewclaw clamp and the Bispectral Index (BIS) was also recorded. Analysis of the pharmacodynamics was performed using a sigmoidal inhibitory maximal effect model for BIS versus effect-site concentration and a logistic regression analysis for the probability of movement versus effect-site concentration. RESULTS: The propofol doses needed to reach a 50% decrease from baseline BIS, and no movement after noxious stimuli were reduced by hemorrhagic shock by 54% and 38%, respectively. Hemorrhagic shock decreased the effect-site concentration that produced 50% of the maximal BIS effect from 11.6 ± 3.8 to 9.1 ± 1.7 μg/mL and that producing a 50% probability of movement from 26.8 ± 1.0 to 20.6 ± 1.0 μg/mL. CONCLUSIONS: The results show that hemorrhagic shock increases both the hypnotic and immobilizing effects of propofol due to pharmacokinetic and pharmacodynamic alterations, with the changes in pharmacodynamics occurring to a similar extent for both effects.

Influence of hemorrhagic shock and subsequent fluid resuscitation on the electroencephalographic effect of isoflurane in a swine model

Background:The authors have previously reported that hemorrhage does not alter the electroencephalographic effect of isoflurane under conditions of compensated hemorrhagic shock. Here, they have investigated the influence of decompensated hemorrhagic shock and subsequent fluid resuscitation on the electroencephalographic effect of isoflurane. Methods:Twelve swine were anesthetized through inhalation of 2% isoflurane. The inhalational concentration was then decreased to 0.5% and maintained for 25 min, before being returned to 2% and maintained for 25 min (control period). Hemorrhagic shock was then induced by removing 28 ml/kg blood over 30 min. After a 30-min stabilization period, the inhalational concentration was varied as in the control period. Finally, fluid infusion was performed over 30 min using a volume of hydroxyethyl starch equivalent to the blood withdrawn. After a 30-min stabilization period, the inhalational concentration was again varied as in the control period. End-tidal isoflurane concentrations and spectral edge frequency were recorded throughout the study. The pharmacodynamics were characterized using a sigmoidal inhibitory maximal effect model for spectral edge frequency versus effect site concentration. Results:Decompensated hemorrhagic shock slightly but significantly shifted the concentration–effect relation to the left, demonstrating a 1.12-fold decrease in the effect site concentration required to achieve 50% of the maximal effect in the spectral edge frequency. Fluid resuscitation reversed the onset of isoflurane, which was delayed by hemorrhage, but did not reverse the increase in end-organ sensitivity. Conclusions:Although decompensated hemorrhagic shock altered the electroencephalographic effect of isoflurane regardless of fluid resuscitation, the change seemed to be minimal, in contrast to several intravenous anesthetics.

Do the kidneys contribute to propofol elimination

BACKGROUND Propofol is mainly metabolized in the liver, but extrahepatic clearance may also be important since systemic propofol clearance exceeds hepatic clearance. Recent reports suggest that the kidneys contribute to propofol elimination in humans and here we investigated renal elimination of propofol in a controlled animal study. METHODS Seventeen swine were anaesthetized with 5% isoflurane induction and 2% isoflurane maintenance. After a left subcostal incision, the left kidney and renal pedicle were exposed by an approach via the retroperitoneum and the renal vein was identified for blood sampling. Propofol was then administered via the right jugular vein at a rate of 2 mg kg(-1) h(-1). After 120 min of pseudo-steady-state infusion of propofol (Baseline 1), cardiac output (CO) was increased by continuous infusion of dobutamine for 30 min (high-CO state). Thirty minutes after stopping dobutamine (Baseline 2), CO was decreased by bolus administration of propranolol (low-CO state). Blood samples were collected simultaneously from the renal vein (direct puncture) and the femoral artery at Baseline 1, in the high-CO state, at Baseline 2, and in the low-CO state. RESULTS There was no significant difference in propofol concentration between femoral arterial and renal venous blood in all states. The propofol concentration significantly decreased with increased CO, but renal extraction was not observed in any state. CONCLUSIONS The kidneys are a minor site of propofol elimination in a swine model.

Influence of haemorrhage on the pseudo-steady-state remifentanil concentration in a swine model: a comparison with propofol and the effect of haemorrhagic shock stage

BACKGROUND The increase in remifentanil concentration during haemorrhagic shock and the difference between this effect and that for propofol are not fully understood. We investigated the influence of haemorrhage on the pseudo-steady-state remifentanil concentration in a porcine model and compared the changes with those for propofol. METHODS After infusion of remifentanil (0.5 µg kg⁻¹ min⁻¹) and propofol (6 mg kg⁻¹ h⁻¹ after 2 mg kg⁻¹ bolus infusion) for 60 min, nine swine [mean (standard deviation) body weight=26.3 (1.3) kg] were studied using a stepwise haemorrhage model (10% of estimated blood volume removed every 30 min until 1.5 h, and stepwise removal of 5% every 30 min thereafter until circulatory collapse). Haemodynamic and metabolic variables and plasma remifentanil and propofol concentrations were measured at every step. RESULTS A mean volume of 913 (82) ml of blood was drained before reaching circulatory collapse. The increases in plasma concentrations from the prehaemorrhagic value fitted the following equations: % increase in remifentanil=2.1 × cumulative blood loss (% of initial blood volume) and % increase in propofol = 0.7 × cumulative blood loss during compensated shock; and % increase in remifentanil = 27.4 × cumulative blood loss-897 and % increase in propofol = 9.5 × cumulative blood loss-306 during uncompensated shock. Remifentanil concentrations were highly correlated with the reciprocal of cardiac output. CONCLUSIONS During haemorrhage, the plasma remifentanil concentration showed a three-fold greater increase than that of propofol in administration by continuous infusion.