Yuko Ando

Preoperative administration of intravenous flurbiprofen axetil reduces postoperative pain for spinal fusion surgery.

PurposeThe aim of the study was to investigate postoperative analgesia and the opioid-sparing effect of the preoperative administration of intravenous flurbiprofen axetil in patients undergoing spinal fusion surgery.MethodsThirty-six patients were randomly allocated into one of three groups. Group A received preoperative flurbiprofen axetil, 1 mg·kg−1. Group B received postoperative flurbiprofen axetil, 1 mg·kg−1. Group C received a placebo. All groups were given a standardized anesthesia and intravenous morphine via a patient-controlled analgesia device for postoperative analgesia. The pain score was evaluated by a visual analog scale (VAS) at 0 (T0), 1 (T1), 2 (T2), 6 (T3), 12 (T4), and 24 (T5) h after surgery, and the morphine requirement was recorded during the study period.ResultsVAS in group A was significantly lower than that in group B at T0 and T1. VAS in group A was significantly lower than that in group C throughout the time course after surgery. Postoperative morphine consumption in group A was significantly lower than that in groups B and C at T0 to T3.ConclusionAs compared with postoperative administration, preoperative administration of intravenous flurbiprofen axetil provides better postoperative analgesia and an opioid-sparing effect in patients undergoing spinal fusion surgery under general anesthesia.

Desensitization of GABAB receptor signaling by formation of protein complexes of GABAB2 subunit with GRK4 or GRK5

We investigated the role of G protein coupled‐receptor kinases (GRKs) in the desensitization of GABAB receptor‐mediated signaling using Xenopus oocytes and baby hamster kidney (BHK) cells. Baclofen elicited inward K+ currents in oocytes coexpressing heterodimeric GABAB receptor, GABAB1a subunit (GB1aR) and GABAB2 subunit (GB2R), together with G protein‐activated inwardly rectifying K+ channels (GIRKs), in a concentration‐dependent manner. Repetitive application of baclofen to oocytes coexpressing GABABR and GIRKs did not change peak K+ currents in the first and second responses, but the latter responses were significantly attenuated by coexpression of either GRK4 or GRK5 with attenuation efficacy of GRK4 > GRK5. Coexpression of other GRKs including GRK2, GRK3, and GRK6 had no effect on GABAB receptor‐mediated desensitization processes. In BHK cells coexpressing GRK4 fused to Venus (brighter variant of yellow fluorescent protein, GRK4‐Venus) with GB1aR and GB2R, GRK4‐Venus was expressed in the cytosol but was translocated to the plasma membranes by GABABR activation. In BHK cells coexpressing GRK4 fused to Cerulean (brighter variant of cyan fluorescent protein, GRK4‐Cerulean) with GB1aR and GB2R‐Venus, fluorescence resonance energy transfer (FRET) analysis demonstrated that GRK4‐Cerulean formed a protein complex with GB2R‐Venus. Immunoprecipitation and Western blot analysis confirmed GB2R‐GRK4 complex formation. GRK5 also formed a complex with GB2R on the plasma membranes as determined by FRET and Western blotting but not GRK2, GRK3, and GRK6. Our results indicate that GRK4 and GRK5 desensitize GABAB receptor‐mediated responses by forming protein complexes with GB2R subunit of GABABR at the plasma membranes. J. Cell. Physiol. 210: 237–245, 2007.

Influence of low-molecular-weight hydroxyethyl starch on microvascular permeability in patients undergoing abdominal surgery : comparison with crystalloid

PurposeAdequate volume therapy is essential for stable hemodynamics and sufficient urinary output perioperatively. Hydroxyethyl starch (HES) has been reported to attenuate the microvascular hyperpermeability which occasionally occurs in surgical patients. This study was carried out to evaluate the effect of low-molecular-weight HES on the urinary microalbumin/creatinine ratio (MACR), a marker of microvascular permeability, in surgical patients.MethodsIn a prospective, controlled, and randomized clinical trial, 21 patients undergoing abdominal surgery were divided into two groups. Group HES (n = 10) received HES at 2 ml·kg−1·h−1 during surgery and at 1 ml·kg−1·h−1 after surgery, and additionally they received acetated Ringer’s solution (AR) at a rate to keep central venous pressure (CVP) 5 mm Hg. Group AR (n = 11) received AR at a rate to keep CVP at 3–5 mmHg. MACR, soluble intercellular adhesion molecule-1 (sICAM-1), and urinary output were measured intermittently in the perioperative period.ResultsMACR was significantly increased during surgery in both groups. There was no significant difference in MACR between the two groups throughout the study period. The serum concentration of sICAM-1 decreased during surgery in both groups, and that in group HES was significantly lower than that in group AR at the end of surgery. Postoperative urinary output in group HES was greater than that in group AR. The intensive care unit (ICU) stay in group HES was shorter than that in group AR.ConclusionAlthough low-molecular-weight HES does not improve microvascular hyperpermeability, the expansion of the intravascular volume by HES results in higher urinary output in the postoperative period than that seen with crystalloid solution. The lower concentration of sICAM-1 after surgery may be due to hemodilution.

Postoperative analgesic effect of preoperative intravenous flurbiprofen in arthroscopic rotator cuff repair

PurposeThis study was carried out to evaluate the postoperative analgesic effects of preoperative intravenous flurbiprofen in patients undergoing arthroscopic rotator cuff repair under general anesthesia.MethodsWe studied 44 patients who underwent an elective arthroscopic rotator cuff repair in a prospective, randomized, and double-blind fashion. The patients were divided into two groups. Group A (n = 22) received lipid emulsion 0.1 ml·kg−1 as a placebo, and group B (n = 22) received flurbiprofen 1 mg·kg−1 before the surgery. Intralipid or flurbiprofen was given intravenously 5 min before the surgery. General anesthesia was maintained with sevoflurane and nitrous oxide, and 10 ml of 0.75% ropivacaine was administered intraarticularly at the end of the surgery. Postoperative analgesia was supplied with intravenous 0.1 mg buprenorphine according to the patient’s demand. The effectiveness of flurbiprofen’s analgesic effect was measured by a visual analog scale (VAS) and by the amount of buprenorphine consumption at 0.5, 1, 2, 4, 6, 12, and 24 h after the surgery. Time to the first analgesic was also recorded.ResultsVAS in group B was significantly (P < 0.01) lower than that in group A during the first 6 h postoperatively. The amount of buprenorphine consumption in group B was also significantly (P < 0.01) less than that in group A within the first 2 h postoperatively. The time to first analgesic request in group B was significantly (P < 0.01) longer than that in group A.ConclusionThese results show that preoperative intravenous flurbiprofen facilitates the analgesic effect in the early postoperative period after arthroscopic rotator cuff repair.

S(+)-ketamine suppresses desensitization of γ-aminobutyric acid type B receptor-mediated signaling by inhibition of the interaction of γ-aminobutyric acid type B receptors with G protein-coupled receptor kinase 4 or 5.

Background:Intrathecal baclofen therapy is an established treatment for severe spasticity. However, long-term management occasionally results in the development of tolerance. One of the mechanisms of tolerance is desensitization of &ggr;-aminobutyric acid type B receptor (GABABR) because of the complex formation of the GABAB2 subunit (GB2R) and G protein–coupled receptor kinase (GRK) 4 or 5. The current study focused on S(+)-ketamine, which reduces the development of morphine tolerance. This study was designed to investigate whether S(+)-ketamine affects the GABABR desensitization processes by baclofen. Methods:The G protein–activated inwardly rectifying K+ channel currents induced by baclofen were recorded using Xenopus oocytes coexpressing G protein–activated inwardly rectifying K+ channel 1/2, GABAB1a receptor subunit, GB2R, and GRK. Translocation of GRKs 4 and 5 and protein complex formation of GB2R with GRKs were analyzed by confocal microscopy and fluorescence resonance energy transfer analysis in baby hamster kidney cells coexpressing GABAB1a receptor subunit, fluorescent protein–tagged GB2R, and GRKs. The formation of protein complexes of GB2R with GRKs was also determined by coimmunoprecipitation and Western blot analysis. Results:Desensitization of GABABR-mediated signaling was suppressed by S(+)-ketamine in a concentration-dependent manner in the electrophysiologic assay. Confocal microscopy revealed that S(+)-ketamine inhibited translocation of GRKs 4 and 5 to the plasma membranes and protein complex formation of GB2R with the GRKs. Western blot analysis also showed that S(+)-ketamine inhibited the protein complex formation of GB2R with the GRKs. Conclusion:S(+)-Ketamine suppressed the desensitization of GABABR-mediated signaling at least in part through inhibition of formation of protein complexes of GB2R with GRK 4 or 5.

Postoperative analgesia with minidose intrathecal morphine for bipolar hip prosthesis in extremely elderly patients.

PurposeIt is known that an optimal dose of intrathecal morphine for analgesia after total hip arthroplasty in older patients is 0.1 mg. On the other hand, minidose intrathecal morphine (0.05 mg) is useful for analgesia after the transurethral resection of the prostate in elderly patients. We evaluated the postoperative analgesic effect of minidose intrathecal morphine after bipolar hip prosthesis in seniors (age 85 years or more) undergoing spinal anesthesia.MethodsTwenty seniors undergoing bipolar hip prosthesis under spinal anesthesia were randomly allocated to one of two groups. Group A (n = 10) received intrathecal injection of 0.5% isobaric bupivacaine, 2.8 ml, and group B (n = 10) received intrathecal injection of 0.5% isobaric bupivacaine, 2.8 ml, plus morphine, 0.05 mg. Pain, nausea, and itching were evaluated using a numerical rating scale, ranging from 0 to 10, at 0, 4, 8, 12, and 24 h after the operation.ResultsThe values on the numerical rating scale for pain in group B were significantly lower than those in group A at 4, 8, and 12 h after the operation. There were no significant differences between the groups in the values on the numerical rating scale for nausea or itching throughout the time course of the study. No patient in either group showed hypoxemia or respiratory depression throughout the time course.ConclusionThe results show that minidose intrathecal morphine provides a good analgesic effect without side effects, and it would be an effective and safe procedure for bipolar hip prosthesis in seniors.

GABAB receptors do not internalize after baclofen treatment, possibly due to a lack of β-arrestin association: Study with a real-time visualizing assay

The mechanism of agonist‐induced GABAB receptor (GABABR) internalization is not well understood. To investigate this process, we focused on the interaction of GABABR with β‐arrestins, which are key proteins in the internalization of most of the G protein‐coupled receptors, and the agonist‐induced GABABR internalization and the interaction of GABABR with β‐arrestin1 and β‐arrestin2 were investigated in real time using GABABR and β‐arrestins both of which were fluorescent protein‐tagged. We then compared these profiles with those of μ‐opioid receptors (μOR), well‐studied receptors that associate and cointernalize with β‐arrestins. When stimulated by the specific GABABR agonist baclofen, GABABR composed of GABAB1aR (GB1aR) and fluorescent protein‐tagged GABAB2R‐Venus (GB2R‐V) formed functional GABABR; they elicited G protein‐activated inwardly rectifying potassium channels as well as nontagged GABABR. In cells coexpressing GB1aR, GB2R‐V, and β‐arrestin1‐Cerulean (βarr1‐C) or β‐arrestin2‐Cerulean (βarr2‐C), real‐time imaging studies showed that baclofen treatment neither internalized GB2R‐V nor mobilized βarr1‐C or βarr2‐C to the cell surface. This happened regardless of the presence of G protein‐coupled receptor kinase 4 (GRK4), which forms a complex with GABABR and causes GABABR desensitization. On the other hand, in cells coexpressing μOR‐Venus, GRK2, and βarr1‐C or βarr2‐C, the μOR molecule formed μOR/βarr1 or μOR/βarr2 complexes on the cell surface, which were then internalized into the cytoplasm in a time‐dependent manner. Fluorescence resonance energy transfer assay also indicated scarce association of GB2R‐V and β‐arrestins‐C with or without the stimulation of baclofen, while robust association of μOR‐V with β‐arrestins‐C was detected after μOR activation. These findings suggest that GABABRs failure to undergo agonist‐induced internalization results in part from its failure to interact with β‐arrestins. Synapse 66:759–769, 2012.© 2012 Wiley Periodicals, Inc.

Landiolol, a new ultra-short-acting β1-blocker, reduces anaesthetic requirement during sevoflurane/N2O/fentanyl anaesthesia in surgical patients

Background and objective It is known that esmolol, a short-acting β1-blocker, reduces anaesthetic requirement. In this study, we evaluated whether a low dose of landiolol, a new ultra-short-acting β1-blocker, can reduce the sevoflurane requirement. Methods Twenty-five patients undergoing hip surgery were randomly divided into two groups. Group A (n = 13) received landiolol (bolus injection of 0.031 mg· kg−1 and continuous infusion at a rate of 0.01 mg·kg−1·min−1). Group B (n = 12) received physiological saline. Landiolol and physiological saline were started before the induction of anaesthesia and continued until the end of anaesthesia. Anaesthesia was maintained with sevoflurane, 60% N2O and fentanyl. Sevoflurane concentration was controlled to keep the bispectral index at approximately 50. The end-tidal sevoflurane concentration and haemodynamics were measured during anaesthesia. Results The average end-tidal sevoflurane concentration in group A was significantly lower than that in group B (1.2 ± 0.30 vs. 1.8 ± 0.3%, P < 0.01). Maximum values of systolic arterial pressure showed no difference between the groups, whereas the maximum value of heart rate in group A was significantly less than that in group B (61 ± 10 vs. 76 ± 14 beats min−1, P < 0.05). Conclusion The results suggest that a low dose of landiolol significantly reduces the intraoperative sevoflurane requirement during sevoflurane/N2O/fentanyl anaesthesia in patients undergoing hip surgery.