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 [middle dot] kg-1 [middle dot] 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.     

Role of Lipid in Sulfite-dependent Propofol Dimerization

Background: During long-term intravenous infusions, sulfite in sulfite-containing propofol emulsions can cause the peroxidation of lipid and dimerization of propofol. This study evaluated the role of lipid in sulfite-dependent propofol dimerization by determining the effects of individual fatty acids in soybean oil emulsion and peroxidized lipids in a model system.

Methods: Individual fatty acids, stearic (18:0), oleic (18:1), linoleic (18:2), linolenic (18:3), and arachidonic (20:4), were added to sulfite-containing propofol emulsion and incubated for 90 min at 37[degrees]C. Model systems containing soybean oil (100 [mu]l), water (900 [mu]l), propofol (10 mg/ml), and sulfite (0.25 mg/ml) composed of oils with different peroxide values were allowed to react for 60 min at room temperature. After the reactions, propofol dimer and propofol dimer quinone were analyzed by reversed-phase high-pressure liquid chromatography.

Results: Propofol did not dimerize when added to aqueous sulfite unless soybean oil was also included. The addition of the polyunsaturated fatty acids (linoleic, linolenic, arachidonic) to sulfite-containing propofol emulsion resulted in large increases of propofol dimerization compared with stearic or oleic acid. Using biphasic mixtures of soybean oil and aqueous sulfite, propofol dimerization increased with increasing peroxide content of the oil. In propofol emulsion, lipoxidase and ferrous iron in the absence of sulfite also caused the dimerization of propofol.     

Expression of Inducible Nitric Oxide Synthase in Human Lungs

The aim of this study was to investigate the expression of inducible nitric oxide synthase (iNOS) in lungs of patients with or without adult respiratory distress syndrome (ARDS). We compared the expression of iNOS by immunohistochemical analysis and polymerase chain reaction in the human lungs collected during open-lung biopsy or at autopsy. The expression of iNOS mRNA was present in all lung samples; however, only 3 out of 11 lung samples showed weak staining for iNOS. Although the involvement of nitric oxide in animal models of ARDS is reported, production of nitric oxide in human lungs is still controversial. The data presented here suggest that human lungs express iNOS mRNA but that the production of iNOS protein may be tightly regulated and is expressed in pulmonary inflammation.     

The Effect of Propofol on Isolated Human Pregnant Uterine Muscle

Background: Propofol is an alternative to thiopental as an intravenous induction agent for cesarean section. Because it has relaxant effects on vascular and other smooth muscles, the authors set out to determine whether propofol has any effect on pregnant human uterine smooth muscle in an isolated preparation.

Methods: Myometrial specimens were excised from 10 parturients undergoing elective cesarean section. The muscle strips were suspended in tissue baths and isometric tension was recorded. After establishment of rhythmic contractions in the buffer solution as a control, propofol (0.5 to 10 [micro sign]g/ml) in fat emulsion was applied cumulatively to the bath. The effect of the fat emulsion at equivalent concentrations was also examined.

Results: Propofol concentrations of 2.7 x 10-6 M (0.5 [micro sign]g/ml) and 1.1 x 10-5 M (2 [micro sign]g/ml) had no significant effect on the active tension developed by muscle contraction. However, propofol at concentration of 5.5 x 10-5 M (10 [micro sign]g/ml) reduced the active tension by 45% (P < 0.02) compared with the control value. The fat emulsion had no effects on the active tension.     

Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high‐dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic‐treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad‐spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL‐1β and macrophage inflammatory proteins 1α and 1β at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad‐spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.     

异丙酚对血小板聚集及凝血功能的影响

目的;观察异丙酚对血小板聚集及凝血功能的影响。方法：ＡＳＡⅠ－Ⅱ级择期上腹部手术病人,全凭异丙酚静脉麻醉,分别于麻醉前（Ｔ０）,麻醉后３０分钟手术开始前（Ｔ１）,停药后１小时（Ｔ２）采血测定血小板１分钟分钟及最大聚集率（ＰＡＧ１,ＰＡＧ５和ＰＡＧＭ）血小板计数（ＢＰＣ）,凝血酶原时间（ＰＴ）,凝血酶时间（ＴＴ）,部分凝血酶时间（ＫＰＴＴ）。结果：与Ｔ０相比,Ｔ１时ＰＡＧ１,ＰＡＧ５,ＰＡＧＭ均显著     

Hypoxic Pulmonary Vasoconstriction in Human Lungs: A Stimulus-Response Study

Background: A stimulus-response relation between alveolar oxygen tension and pulmonary vascular resistance has been observed in animals. This study investigated this relation in healthy human lungs. The distribution of pulmonary blood flow was measured during unilateral (1) graded hypoxia (fractional concentration of oxygen in inspired gas [FI O2 = 0.12, 0.08, and 0.05) and contralateral hyperoxia (FI O (2) = 1.0; n = 6); (2) single-step hypoxia (FI O2 = 0.05) and contralateral hyperoxia (n = 5); and (3) normobaric hyperoxia and contralateral normoxia (FI O2 = 0.25; n = 6).

Methods: Seventeen patients with healthy lungs were studied during intravenous anesthesia. The lungs were separately and synchronously ventilated. The relative perfusion of each lung was assessed by the inert gas (sulfurhexafluoride) elimination technique.

Results: (1) Unilateral graded hypoxia reduced the perfusion of the hypoxic lung from a mean (+/- SD) of 52 (2)% of cardiac output (Q with dot) during bilateral hyperoxia, to 47 (5)% (P > 0.05), 40 (3)% (P <0.01), and 30 (8)% (P < 0.001) of Q with dot, respectively. These progressive reductions in the perfusion of the hypoxic lung were all significantly different from each other. (2) Unilateral single-step hypoxia caused a blood flow diversion of the same magnitude as when the lung was previously ventilated with FI O2 of 0.12 and 0.08. The perfusion of the hypoxic lung was reduced from 46 (9)% of Q with dot (bilateral hyperoxia), to 26 (4)% of Q with dot (P < 0.01). (3) Unilateral hyperoxia did not significantly change the relative blood flow distribution between the two lungs or the pulmonary artery pressure.     

Propofol Increases Presynaptic Inhibition of Ia Afferents in the Intact Human Spinal Cord

Background: In vitro studies indicate that the primary molecular targets of propofol in the spinal cord are [gamma]-aminobutyric acid (GABA) type A receptors. Because of the complexity of the central nervous system, specific GABA-mediated effects have not yet been isolated in humans. Here, the authors used heteronymous Ia facilitation of the soleus H-reflex from the femoral nerve as a specific pathway involving GABA to demonstrate a presynaptic GABA-mediated effect of propofol in humans.

Methods: The study was performed in 10 volunteers aged 23-32 yr. The soleus H-reflex was evoked by stimulation of the tibial nerve in the popliteal fossa. The stimulation current was adjusted to yield an unconditioned H-reflex of 15% of the maximal muscle response to electric stimulation of the tibial nerve. The soleus H-reflex was conditioned by stimulating Ia afferents from the quadriceps femoris in the femoral triangle. The stimulus was applied 0.3-0.4 ms after the onset of facilitation, to assure a purely monosynaptic excitatory postsynaptic potential from quadriceps Ia afferents to the soleus motoneuron. At least 45 conditioned (femoral and tibial) and unconditioned (only tibial) stimuli were applied in random order. The authors compared the amount of heteronymous H-reflex facilitation under a concentration of 2 [mu]g/ml propofol with control values obtained before and after the propofol infusion.

Results: H-reflex facilitation due to the conditioning stimulus during propofol administration was significantly (P < 0.05, t test) decreased by an average of 43% in all patients in comparison with the control values.     

Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation

The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells “rehabilitated” marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose‐dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co‐administration of microvesicles with anti‐CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.