Haruhiko Hiraoka

Changes in Drug Plasma Concentrations of an Extensively Bound and Highly Extracted Drug, Propofol, in Response to Altered Plasma Binding

Cardiopulmonary bypass is known to result in a reduction in the plasma binding of drugs. The resulting effect on the hepatic clearance of drugs with low extraction is well understood. However, the situation with those that are highly extracted is less clear. Studies were, therefore, undertaken with one such drug, propofol, for which plasma binding was changed during cardiac surgery with cardiopulmonary bypass.

Diabetic Patients Have an Impaired Cerebral Vasodilatory Response to Hypercapnia Under Propofol Anesthesia

Background and Purpose— The purpose of this study was to examine the effects of diabetes mellitus and its severity on the cerebral vasodilatory response to hypercapnia. Methods— Thirty diabetic patients consecutively scheduled for elective major surgery were studied. After induction of anesthesia, a 2.5-MHz pulsed transcranial Doppler probe was attached to the patient’s head at the right temporal window, and mean blood flow velocity of the middle cerebral artery (Vmca) was measured continuously. After the baseline Vmca, arterial blood gases, and cardiovascular hemodynamic values were measured, end-tidal CO2 was increased by reducing ventilatory frequency by 2 to 5 breaths per minute. Measurements were repeated when end-tidal CO2 increased and remained stable for 5 to 10 minutes. Results— Significant differences were observed in absolute and relative CO2 reactivity between the diabetes and control groups (absolute CO2 reactivity: control, 2.8±0.7; diabetes mellitus, 2.1±1.3; P <0.01; relative CO2 reactivity: control, 6.3±1.4; diabetes mellitus, 4.5±2.7; P <0.01, Mann-Whitney U test). Significant differences were also found between diabetic patients with retinopathy and those without retinopathy in absolute (P =0.002) and relative (P =0.002) CO2 reactivity, glycosylated hemoglobin (P =0.0034), and fasting blood sugar (P =0.01) (Scheffé’s test, Mann-Whitney U test). There was an inverse correlation between absolute CO2 reactivity and glycosylated hemoglobin (r =0.69, P <0.001). Conclusions— Insulin-dependent diabetic patients have an impaired vasodilatory response to hypercapnia compared with that of the control group, and the present findings suggest that their degree of impairment is related to the severity of diabetes mellitus.

Human Kidneys Play an Important Role in the Elimination of Propofol

Background:Extrahepatic clearance of propofol has been suggested because its total body clearance exceeds hepatic blood flow. However, it remains uncertain which organs are involved in the extrahepatic clearance of propofol. In vitro studies suggest that the kidneys contribute to the clearance of this drug. The purpose of this study was to confirm whether human kidneys participate in propofol disposition in vivo. Methods:Ten patients scheduled to undergo nephrectomy were enrolled in this study. Renal blood flow was measured using para-aminohippurate. Anesthesia was induced with vecuronium (0.1 mg/kg) and propofol (2 mg/kg) and then maintained with nitrous oxide (60%), sevoflurane (1∼2%) in oxygen, and an infusion of propofol (2 mg · kg−1 · h−1). Radial arterial blood for propofol and para-aminohippurate analysis was collected from a cannula inserted in the radial artery. The renal venous sample and the radial arterial sample were obtained at the same time after the steady state of propofol was established. Results:The renal extraction ratio of propofol was 0.58 ± 0.15 (mean ± SD). The renal clearance of propofol was 0.41 ± 0.15 l/min (mean ± SD), or 27 ± 9.9% (mean ± SD) of total body clearance. Conclusion:Human kidneys play an important role in the elimination of propofol.

Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver

ObjectivePropofol is commonly used for anesthesia and sedation in intensive care units. Approximately 53% of injected propofol is excreted in the urine as the glucuronide and 38% as hydroxylated metabolites. Liver, kidneys and intestine are suspected as clearance tissues. We investigated the contribution of the liver and kidneys to propofol metabolism in humans using an in vitro–in vivo scale up approach.MethodsRenal tissue was obtained from five patients who received nephrectomies. Each renal hydroxylation and glucuronidation enzymatic activities in microsomal fractions from patients were performed discretely and their estimation based on the decrease of propofol concentration. Hepatic hydroxylation and glucuronidation activities were also performed separately using human liver microsomes. This estimation is based on the decrease of propofol concentration, assuming that the contribution of hydroxylation activity without NADPH-generating system and glucuronidation activity without UDPGA in each microsomal fraction are negligible. Both renal and hepatic clearances were estimated assuming a well-stirred model.ResultsEnzymatic activity of propofol oxidation in renal microsomes was negligible. Although glucuronidation activity in microsomes from kidneys was comparable to that from liver, the hepatic intrinsic clearance predicted from in vitro study was higher than that in kidneys due to the larger tissue volume and higher protein concentration. However, glucuronidation clearance in kidney is relatively similar to that in liver because of blood flow limitation of clearance in both tissues.ConclusionThe high degree of hydroxylation activity in liver microsomes is consistent with the blood flow-limited hepatic clearance of propofol. Although the activity of propofol glucuronidation in liver is higher, glucuronidation in kidney may be a substantial contributor.

A dopamine infusion decreases propofol concentration during epidural blockade under general anesthesia.

PurposeIt is common clinical practice to use dopamine to manage the reduction in blood pressure accompanying epidural blockade. As propofol is a high-clearance drug, propofol concentrations can be influenced by cardiac output (CO). The purpose of the present study was to investigate the effects of dopamine infusions on propofol concentrations administered by a target-controlled infusion system during epidural block under general anesthesia.Methods12 patients undergoing abdominal surgery were enrolled in this study. Anesthesia was induced with propofol and vecuronium 0.1 mg·kg-1, and maintained using 67% nitrous oxide, sevoflurane in oxygen and constant infusion of propofol. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 6.0 μg·mL-1 at intubation and 2.0 μg·mL-1 after intubation. Before and after the administration of 10 mL of 1.5% mepivacaine from the epidural catheter and dopamine infusion at 5 μg·kg-1·min-1, CO and effective liver blood flow (LBF) were measured using indocyanine green. Blood propofol concentration was also determined using high-performance liquid chromatography.ResultsAt one hour after epidural block and dopamine infusion, CO was significantly increased from 4.30 ± 1.07 L·min-1 to 5.82 ± 0.98 L·min-1 (P < 0.0001), and effective LBF was increased 0.75 ± 0.17 L·min-1 to 0.96 ± 0.18 L·min-1 (P < 0.0001). Propofol concentration was significantly decreased from 2.13 ± 0.24 μg·mL-1 to 1.59 ± 0.29 μg·mL-1 (P < 0.0001). Conclusions: Propofol concentrations decrease with an increase in CO, suggesting the possibility of inadequate anesthetic depth following catecholamine infusion during propofol anesthesia.RésuméObjectifII est courant d’utiliser la dopamine pour traiter la baisse de tension artérielle qui accompagne le bloc péridural. Comme le propofol est un médicament à clairance élevée, sa concentration peut être influencée par le débit cardiaque (DC). Nous avons vérifié les effets de perfusions de dopamine sur les concentrations de propofol administrées par un système de perfusion à concentration cible pendant le bloc péridural sous anesthésie générale.MéthodeDouze patients devant subir une intervention chirurgicale abdominale ont participé à notre étude. L’anesthésie, induite avec du propofol et 0,1 mg·kg-1de vécuronium, a été maintenue avec du protoxyde d’azote à 67 %, du sévoflurane dans de l’oxygène et une perfusion constante de propofol. Le propofol a été administré à tous les sujets par une perfusion à concentration cible pour atteindre 6,0 μg·mL-1 de propofol au moment de l’intubation et 2,0 μg·mL-1 après l’intubation. Avant et après l’administration de 10 mL de mépivacaïne à 1,5 % par le cathéter péridural et la perfusion de dopamine à 5 μg·kg-1·min-1, le CO et le débit sanguin hépatique (DSH) ont été mesurés avec le vert d’indocyanine. La concentration sanguine de propofol a aussi été déterminée par chromatographie liquide haute performance.RésultatsUne heure après le bloc péridural et la perfusion de dopamine, le CO s’était significativement élevé de 4,30 ± 1,07 L·min-1 à 5,82 ± 0,98 L·min-1 (P < 0,0001) et le DSH efficace était accru de 0,75 ± 0,17 L·min-1 à 0,96 ± 0,18 L·min-1 (P < 0,0001). La concentration de propofol a significativement baissé de 2,13 ± 0,24 μg·mL-1 à 1,59 ± 0,29 μg·mL-1 (P < 0,0001).ConclusionLes concentrations de propofol ont diminué avec l’augmentation de CO, ce qui soulève la possibilité d’un niveau anesthésique inadéquat après la perfusion de catécholamine pendant l’anesthésie au propofol.

Hepatosplanchnic oxygenation is better preserved during mild hypothermic than during normothermic cardiopulmonary bypass.

PurposeTo assess and compare the effects of normothermic and mild hypothermic cardiopulmonary bypass (CPB) on hepatosplanchnic oxygenation.MethodsWe studied 14 patients scheduled for elective coronary artery bypass graft surgery who underwent normothermic (> 35°C; group I,n = 7) or mild hypothermie (32°C; group II,n = 7) CPB. After induction of anesthesia, a hepatic venous catheter was inserted into the right hepatic vein to monitor hepatic venous oxygen saturation (ShvO2) and hepatosplanchnic blood flow by a constant infusion technique that uses indocyanine green.ResultsThe ShvO2 decreased from a baseline value in both groups during CPB and was significantly lower at ten minutes and 60 min after the onset of CPB in group I (39.5 ± 16.2% and 40.1 ± 9.8%, respectively) than in group II (61.1 ± 16.2% and 6.0 ±17.9%, respectively;P < 0.05). During CPB, the hepatosplanchnic oxygen extraction ratio was significantly higher in group I than in group II (44.0 ± 7.2%vs 28.7 ±13.1%;P < 0.05).ConclusionHepatosplanchnic oxygenation was better preserved during mild hypothermie CPB than during normothermic CPB.RésuméObjectifÉvaluer et comparer les effets de la circulation extracorporelle (CEC), sous normothermie ou hypothermie légère, sur l’oxygénation hépatosplanchnlque.MéthodeNous avons étudié 14 patients devant subir un pontage aortocoronarien avec CEC sous normothermie (> 35 °C; groupe I, n = 7) ou hypothermie légère (32 °C; groupe II, n = 7). Après l’induction de l’anesthésle, un cathéter a été inséré dans la veine hépatique droite pour permettre de vérifier la saturation en oxygène du sang veineux hépatique (SO2vh) et le débit sanguin hépatosplanchnlque par une perfusion constante utilisant le vert d’indocyanlne.RésultatsLa SO2vh a diminué de sa valeur de base dans les deux groupes et a été significativement plus basse à 10 minutes et à 60 min après le début de la CEC dans le groupe I (39,5 ± 16,2 % et 40,1 ± 9,8 %, respectivement) que dans le groupe II (61,1 ± 16,2 % et 61,0 ± 17,9 %, respectivement; P < 0,05). Le taux déxtraction d’oxygène hépatosplanchnlque pendant la CEC a été significativement plus élevé dans le groupe I que dans le groupe II (44,0 ± 7,2 % vs 28,7 ± 13,1 %; P < 0,05).ConclusionLoxygénation hépatosplanchnlque a été mieux préservée pendant la CEC sous hypothermie légère que sous normothermie.

Benefits of the laryngeal mask for airway management during electroconvulsive therapy

Accumulation of carbon dioxide (CO2) can disturb systemic hemodynamics and increase the seizure threshold in patients receiving electroconvulsive therapy (ECT). The purpose of this study was to investigate the effects of the laryngeal mask on blood gas, hemodynamics, and seizure duration during ECT under propofol anesthesia. Ventilation was assisted using either a face mask (n = 23) or laryngeal mask (n = 23) and 100% oxygen. There was no significant difference in PaO2 between the two groups. PaCO2 was greater in the face mask group than the laryngeal mask group at 3 minutes (54 ± 11 mm Hg, 41 ± 8 mm Hg, respectively) and 5 minutes (52 ± 11 mm Hg, 43 ± 15 mm Hg, respectively) after electrical stimulation (p < 0.01). Mean blood pressure was higher than the corresponding preanesthesia value at 1 to 5 minutes after electrical stimulation in the face mask group and at 1 to 3 minutes after electrical stimulation in the laryngeal mask group. Mean seizure duration in the face mask group was significantly shorter than that in the laryngeal mask group (33 ± 11 seconds, 42 ± 10 seconds, respectively p < 0.01). The change in PaCO2 was minor in the laryngeal mask group compared with the face mask group and seizure duration was longer in the laryngeal mask group. Laryngeal mask may be suitable for airway management during ECT anesthesia, especially when fitting a face mask is difficult.

Propofol concentrations during the anhepatic phase of living-related donor liver transplantation.

o the Editor: Propofol is a short-acting anesthetic drug with a large olume of distribution and a high total body clearance, and s we recently reported in the Journal, the hepatic extraction atio of propofol is high. Urinary excretion of unchanged ropofol is minimal, and hepatic metabolism is considered to e the primary elimination pathway. Nevertheless, propofol is sed during liver transplantation because its metabolism is ot greatly affected by liver failure, since its metabolism epends on liver blood flow. However, the pharmacokinetics f propofol during liver transplantation has not been defined. he pharmacokinetics of propofol could be influenced by the bsence of hepatic metabolism when the liver is excluded rom the circulation. We have measured the changes in propool concentrations during living-related donor liver transplanation. After institutional ethical approval was given, informed onsent was obtained from 10 patients (10 men; age range, 0-60 years; weight range, 40-75 kg) undergoing liver translantation. Individuals were excluded from the study if they ad severe renal insufficiency or a known allergy to eggs or ropofol. Anesthesia was induced with 0.1 mg/kg vecuroium and 2 mg/kg propofol. Anesthesia was maintained by 0% air, 0.5% to 1.5% isoflurane in oxygen, 30 g/kg fentnyl, and an infusion of propofol at 2 mg · kg 1 · h . After njection of propofol, radial arterial blood was collected at 5, 0, 15, 30, 45, 60, 90, and 120 minutes and every 60 minutes uring the dissection phase and reperfusion phase. During the nhepatic phase, radial arterial samples were collected at 5, 0, 15, 20, 25, 30, 45, and 60 minutes and every 30 minutes ntil completion of the anhepatic phase. The propofol conentrations in whole blood were measured by use of HPLC as eported previously. The mean duration of the anhepatic phase was 151 36 inutes. Pseudo–steady state was established within 2 hours uring the anhepatic phase (Fig 1). Pseudo–steady-state conentrations increased from 1.05 0.34 g/mL to 1.78 0.40 g/mL after hepatic blood flow was stopped. In this study pseudo–steady state was established even uring the anhepatic phase because extrahepatic sites of meabolism in the lung, as well as the kidney and intestines, ave been postulated. To our knowledge, this is the first work o describe the pseudo–steady state of propofol during the nhepatic phase during living-related donor liver transplantaion in humans. Further investigations into the extrahepatic

Influence of the prone position on propofol pharmacokinetics

causes particular difficulty in maintaining normothermia as the standard warming blankets are only able to cover a limited area of the patient. The standard surgical access warming blanket is 90 · 240 cm. There is a rectangular gap of 33 · 53 cm approximately a third of the way along its length. This allows abdominal surgery to be performed in a supine patient whilst blowing warm air onto the chest and legs. We have modified the standard blanket by cutting longitudinally from the middle of the far edge up to the gap. The cut edges are then taped to prevent excessive escape of warmed air. The resulting limbs of the blanket can be wrapped around the patient’s legs whilst they are in the lithotomy position (see Fig. 1). To ensure full inflation of the air cells within the blanket around both sides of the patient, it is advisable to force air down each of the two available portals. This can be performed either with a single fan introduced via each in turn or by using two fans. When making modifications to existing devices one should be aware that any such action is likely to invalidate the original product liability and one should be wary of and vigilant for any unexpected complications. Indeed the modified system may be so effective that it is imperative to monitor the patient’s temperature whilst it in use to prevent hyperthermia and caution should be exercised to avoid undue localised heating and consequent tissue damage.

The effect of positive end‐expiratory pressure ventilation on propofol concentrations during general anesthesia in humans

The present study investigated the effects of positive end‐expiratory pressure (PEEP) on propofol concentrations in humans. Eleven patients undergoing elective surgery were enrolled in this study. Anesthesia was induced with propofol, then maintained using 60% nitrous oxide in oxygen, fentanyl 10–20 μg/kg and continuous infusion of propofol. Vecuronium was used to facilitate the artificial ventilation of the lungs. Propofol was administered to all subjects via target‐controlled infusion to achieve a propofol concentration of 6.0 μg/mL at intubation and 2.0 μg/mL after intubation. Before, during and after PEEP level of 10 cmH2O, cardiac output (CO) and effective liver blood flow (LBF) was measured using indocyanine green as an indicator and blood propofol concentration was determined using high‐performance liquid chromatography. Data are expressed as median and range. After PEEP of 10 cmH2O was applied, CO and effective LBF was significantly decreased from 5.5 (3.8–6.8) L/min to 4.5 (3.2–5.8) L/min (P < 0.05), 0.78 (0.65–1.21) L/min to 0.65 (0.50–0.89) L/min (P < 0.05), respectively. Propofol concentration was significantly increased from 2.21 (1.46–2.63) μg/mL to 2.45(1.79–2.89) μg/mL (P < 0.05). These data indicate that propofol concentrations can be increased by PEEP, suggesting the possibility of overdosing following PEEP.