The effect of sevoflurane on retinal angiogenesis in a mouse model of oxygen-induced retinopathy.

BACKGROUND: Sevoflurane is commonly used in general anesthesia for premature neonates. The main mechanism of retinopathy of prematurity (ROP) is increased levels of vascular endothelial growth factor (VEGF). For the investigation of sevoflurane's effect on angiogenesis, the angiogenesis and VEGF expression in the retina were measured after administering sevoflurane in an oxygen-induced retinopathy mice model. MATERIALS AND METHODS: The mice were divided into the normoxic group (Nc and Ns group; n = 6) and the ROP group (C, Rc, and Rs group; n = 6). Rc group were exposed to 75% oxygen for 5 days beginning on postnatal day (P) 7, and then returned to room air. Age-matched mice in the C group were exposed to room air. To observe angiogenesis of the retina, the mice were sacrificed on P16. The Rs group was exposed to 2 vol% sevoflurane for 2 h on P12, P13, and P14 with 40% oxygen. RESULTS: The angiogenic area and the spreading distance of vessels on P4 were statistically decreased in the Ns group, compared to the Nc group. The avascular area on P16 was significantly increased and the expression of VEGF was suppressed in the Rs group compared to the Rc group. CONCLUSIONS: Sevoflurane can inhibit retinal angiogenesis via suppressing VEGF expression in an OIR mice model with exposure to relative hypoxia. Nevertheless, it is still difficult to apply the results of this study immediately to humans because of the heterogeneity of responses to sevoflurane.

Propofol promotes osteoclastic bone resorption by increasing DC-STAMP expression.

BACKGROUND: Propofol is an intravenous anesthetic which has antioxidant effects due to its similarity in molecular structure to α-tocopherol. It has been reported that α-tocopherol increases osteoclast fusion and bone resorption. Here, we investigated the effects of propofol on signaling pathways of osteoclastogenic gene expression, as well as osteoclastogenesis and bone resorption using bone marrow-derived macrophages (BMMs). METHODS: BMMs were cultured with macrophage colony-stimulating factor (M-CSF) alone or M-CSF plus receptor activator of nuclear factor kappa B ligand (RANKL) in the presence of propofol (0-50 µM) for 4 days. Mature osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP) and the numbers of TRAP-positive multinucleated osteoclasts were counted. To examine the resorption activities of osteoclasts, a bone resorption assay was performed. To identify the mechanism of action of propofol on the formation of multinucleated osteoclasts, we focused on dendritic cell-specific transmembrane protein (DC-STAMP), a protein essential for pre-osteoclastic cell fusion. RESULTS: Propofol increased the formation of TRAP-positive multinucleated osteoclasts. In addition, the bone resorption assay revealed that propofol increased the bone resorption area on dentin discs. The mRNA expression of DC-STAMP was upregulated most strongly in the presence of both RANKL and propofol. However, SB203580, a p38 inhibitor, significantly suppressed the propofol/RANKL-induced increase in mRNA expression of DC-STAMP. CONCLUSION: We have demonstrated that propofol enhances osteoclast differentiation and maturation, and subsequently increases bone resorption. Additionally, we identified the regulatory pathway underlying osteoclast cell-cell fusion, which was enhanced by propofol through p38-mediated DC-STAMP expression.

Post-operative intravenous patient-controlled analgesic efficacy of morphine with ketorolac versus nefopam after laparoscopic gynecologic surgery: a randomized non-inferiority trial.

BACKGROUND: Nefopam is a non-opioid non-steroidal centrally acting analgesic. This study was conducted to assess the analgesic efficacy of intravenous patient-controlled analgesia (IV-PCA) using nefopam alone, compared with a combination of morphine and ketorolac, after laparoscopic gynecologic surgery. METHODS: Sixty patients undergoing laparoscopic gynecologic surgery received IV-PCA. Group A (n = 30) received IV-PCA with a combination of morphine 60 mg and ketorolac 180 mg, while group B (n = 30) received nefopam 200 mg (basal rate 1 ml/h, bolus 1 ml, and lockout time 15 min for both). The primary outcome evaluated was analgesic efficacy using the visual analogue scale (VAS). Other evaluated outcomes included the incidence rate of postoperative nausea and vomiting (PONV), patient satisfaction of pain control, percentage of patients requiring additional opioids, and incidence rate of postoperative adverse effects. RESULTS: Group B was not inferior to group A in relation to the VAS in the post-anesthesia care unit, and at 12, 24, and 48 h after surgery (mean difference [95% confidence interval], 0.50 [-0.43 to 1.43], -0.30 [-1.25 to 0.65], -0.05 [-0.65 to 0.55], and 0.10 [-0.55 to 0.75], respectively). The incidence rate of nausea was lower in group B than in group A at 12 and 24 h after surgery (P = 0.004 and P = 0.017, respectively). There were no significant differences in the other outcomes between groups. CONCLUSIONS: IV-PCA using nefopam alone has a non-inferior analgesic efficacy and produces a lower incidence of PONV in comparison with IV-PCA using a combination of morphine and ketorolac after laparoscopic gynecologic surgery.

Administration of four different doses of gabapentin reduces awakening from breakthrough pain and adverse effects in outpatients with neuropathic pain during the initial titration.

BACKGROUND: Gabapentin is a safe and well-tolerated anticonvulsant with a wide therapeutic index, and it is used for neuropathic pain. The aim of this study was to compare previous dosing methods with the administration of four different doses of gabapentin while maintaining the same maximum daily dose for the safe administration of high doses of the medication. METHODS: THE SUBJECTS WERE OUTPATIENTS WITH VARIOUS NEUROPATHIC PAIN SYNDROMES, WITH AT LEAST TWO OF THE FOLLOWING SYMPTOMS: allodynia, burning pain, shooting pain, or hyperalgesia. The TID group received equal doses of gabapentin 3 times per day, while the QID group received 4 different doses of gabapentin per day. The pain score, frequency of breakthrough pain (BTP), severity and the duration of pain, sleep disturbance due to nocturnal pain, and adverse effects were recorded each day. RESULTS: The average daily pain score and sleep disturbance were significantly reduced in the QID group between days 3 and 10 of the experiment. The adverse effects of the medication were also reduced in the QID group. However, the frequency of BTP and severity and duration of pain were not significantly different between two groups. CONCLUSIONS: Administration of 4 different doses of gabapentin during the initial titration in outpatients with neuropathic pain resulted in a significant reduction in awakening from breakthrough pain and a reduction in the adverse effects of the medication.

Optimal dose of dexmedetomidine for sedation during spinal anesthesia.

BACKGROUND: Sedation in spinal anesthesia can reduce patient's anxiety and discomfort. Dexmedetomidine has a sedative, hypnotic, analgesic, and minimal respiratory depression effect. However, use of the dexmedetomidine is associated with prolonged recovery. This study was designed to investigate the optimal dose of intravenous dexmedetomidine for proper sedation with minimal recovery time in spinal anesthesia. METHODS: One hundred twenty eight patients, aged 20-70 years (58.8 ± 0.7), were recruited. After performing the spinal anesthesia with hyperbaric bupivacaine (13 mg), a loading dose of dexmedetomidine (1 µg/kg) was administered for 10 min, followed by the maintenance infusion of the following: Group A (n = 33; normal saline), Group B (n = 35; dexmedetomidine 0.2 µg/kg/hr), and Group C (n = 39; dexmedetomidine 0.4 µg/kg/hr). Heart rate, blood pressure, and the bispectral index score (BIS) were recorded during the operation. In the recovery room, modified aldrete score (MAS) was measured. RESULTS: There were no significant differences in mean blood pressure and heart rate among the three groups. BIS was not significantly different among the three groups from baseline to 60 min after the infusion of dexmedetomidine. BIS were significantly increased in Group A after 70 and 80 min, and Group A and B after 90, 100, 110 min of dexmedetomidine infusion (P < 0.05). MAS was higher in Group A as compared to Group B and C, within 30 min after admission in the recovery room (P < 0.05). CONCLUSIONS: The loading dose (1 µg/kg/10 min) of dexmedetomidine was sufficient for surgery of less than 60 min. Dexmedetomidine infusion followed by maintenance dose (0.2 µg/kg/hr) was sufficient for surgery within 90 min.

The changes of mitochondrial cytochrome c and GABAergic neuron in neuropathic pain model.

BACKGROUND: Role of cytochrome c (Cyt c) is an apoptogenic agent under certain conditions. The mitochondrial permeability transition pore (MPTP) plays an important role in cell death since it opens, leading to mitochondrial swelling and release of Cyt c, which initiates apoptosis. By inhibiting the opening of MPTP, cyclosporine A (CSA) may contribute to maintaining mitochondrial homeostasis. We investigate the effects of the partial sciatic nerve injury (PSNI)-induced neuropathic pain model on mitochondrial Cyt c release and the effects of CSA on neuroprotection by mitochondrial stabilizing activity in PSNI rats. METHODS: Rats were assigned to two groups that received different operations (Group P; PSNI operation, Group S; sham operation). The changes of cyt c and GABAergic neuron were evaluated in the spinal cord tissue. After which, PSNI rats randomly received CSA (Group C) or saline (Group S), and the changes of mechanical thresholds with Cyt c and GABAergic neuron were checked. RESULTS: PSNI in rats increased the release of cytosolic Cyt c. However, GABAergic cells were not decreased in the spinal cord level on the ipsilateral side to the PSNI. The second experiment reveal a reduction in Cyt c release, using CSA in PSNI model. Rats receiving CSA were afforded the antiallodynia without decrease of GABAergic cell. CONCLUSIONS: The Cyt c probably contributes to nerve dysfunction after PSNI. PSNI induced neuropathic pain was profoundly linked to mitochondrial stabilization. Thus, the potent neuroprotector, CSA, might produce antiallodynia through its capability to inhibit the opening of MPTP.

Effects of etomidate on bispectral index scale and spectral entropy during induction of anesthesia by means of the raw electroencephalographic and electromyographic characteristics.

BACKGROUND: Etomidate frequently induces myoclonus, so it may affect electromyographics (EMG). And EMG commonly has an effect on the bispectral index scale (BIS) and spectral entropy. This study was performed to compare the effect of etomidate on BIS, response entropy (RE) and state entropy (SE) during induction of anesthesia. METHODS: Fifty patients (ASA I or II) scheduled for elective surgery were included in this study. Anesthesia was induced with etomidate (0.3 mg/kg) and rocuronium (0.6 mg/kg). Patients also inhaled 4 vol% sevoflurane and 100% oxygen and, then intubated. BIS, RE, SE and Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) were measured 4 times (before injection of etomidate [T0], at loss of eyelash reflex [T1], 90 seconds after rocuronium injection [T2], and after intubation [T3]). We also checked whether myoclonus occurred. RESULTS: Baseline values (T0) were 93.1 ± 4.7 for BIS, 95.8 ± 3.7 for RE and, 87.3 ± 3.5 for SE. In comparison with T0, there were significantly differences in BIS (50.2 ± 16.3), RE (76.8 ± 18.5) and SE (66.3 ± 17.4) at T1 (all P < 0.05). There were no significant differences at T2 and T3. Thirty one patients had myoclonus. At the occurrence of myoclonus, RE and SE values significantly increased but not BIS (P < 0.05). CONCLUSIONS: In patients with myoclonus, at the loss of consciousness, spectral entropy did not decrease where as BIS did, suggesting that BIS may evaluate hypnotic levels better than spectral entropy during induction of anesthesia with etomidate.

Accidental epidural injection of rocuronium.

Epidural administration of local anesthetics or opioid during general anesthesia is a widespread method for postoperative analgesia. Despite the availability of this technique, inadvertent administration of nonepidural medications into the epidural space can be associated with serious neurological complications. We report a case of accidental epidural rocuronium injection.

Heparin responsiveness during off-pump coronary artery bypass graft surgery: predictors and clinical implications.

AIM: To evaluate the clinical impact of reduced heparin responsiveness (HR(reduced)) on the incidence of myocardial infarction (MI) following off-pump coronary artery bypass graft surgery (OPCAB), and to identify the predictors of HR(reduced). METHODS: A total of 199 patients scheduled for elective OPCAB were prospectively enrolled. During anastomosis, 150 U/kg of heparin was injected to achieve an activated clotting time (ACT) of ≥ 300 s, and the heparin sensitivity index (HSI) was calculated. HSIs below 1.0 were considered reduced (HR(reduced)). The relationships between the HSI and postoperative MI, cardiac enzyme levels and preoperative risk factors of HR(reduced) were investigated. RESULTS: There was no significant relationship between the HSI and cardiac enzyme levels after OPCAB. The incidence of MI after OPCAB was not higher in HR(reduced) patients. HR(reduced) occurred more frequently in patients with low plasma albumin concentrations and high platelet counts. CONCLUSION: HR(reduced) was not associated with adverse ischemic outcomes during the perioperative period in OPCAB patients, which seemed to be attributable to a tight prospective protocol for obtaining a target ACT regardless of the presence of HR(reduced).

Effect of thromboembolic deterrent stockings at spinal anesthesia-induced hypotension.

BACKGROUND: Hypotension during spinal anesthesia is mainly result of sympathetic blockade, which causes pooling of blood into the lower extremities. Mechanical compression of lower limbs prevents venous pooling of blood. Thromboembolic deterrent (TED) stockings are in general surgical use for prophylaxis against lower limb deep vein thrombosis and TED stockings also supply pressure to lower limb. So we investigated the effect of TED stockings to prevent hypotension during spinal anesthesia. METHODS: Sixty patients were randomized to receive fluid loading (crystalloid, 10 ml/kg) or TED stockings. After spinal anesthesia (heavy bupivacaine 14 mg), patients were placed in supine position for 12 minutes and in lithotomy position for 18 minutes. Blood pressure, pulse rates, shivering, and nausea were checked every 3 minutes for 30 minutes. If the systolic blood pressure was less than 90 mmHg or mean blood pressure was less than 80% of baseline mean blood pressure then i.v. ephedrine 5 mg was administered. RESULTS: There was no statistically significant difference in baseline characteristics and blocked sensory level between the two groups. There was no statistically significant difference in the incidence of hypotension and mean arterial blood pressure at each time. CONCLUSIONS: We conclude that, under the conditions of this study, TED stockings decrease the pooling of blood into the lower limbs and prevent hypotension after spinal anesthesia. Although TED stockings prevent hypotension after spinal anesthesia, it does not reduce the incidence of hypotension.

Effects of sevoflurane on wound healing process.

BACKGROUND: Wound healing process is a tissue response to trauma which leads to tissue repair through complex biological stages. Sevoflurane is a widely used inhalation anesthetic for surgery, but there has been no study about its effect on wound healing process. This study was undertaken to evaluate the effect of sevoflurane on wound healing process. METHODS: Male Sprague-Dawley rats (200-300 g) were used. Two circular full-thickness skin defects of 8 mm in diameter were made on dorsum of rats. After wound formation, the animals were divided into 4 groups: 1, 2, 4, 8 hr exposure to sevoflurane, respectively. Wound sizes and regional blood flow around the wounds were measured. The expression of basic fibroblast growth factor (bFGF), transforming growth factor beta1 (TGFbeta1), collagen 1, and collagen 3 mRNA were detected 7 days after wound formation by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Wound size was significantly increased in 8 hr group at 3 and 7 days after wound formation. Regional blood flow was significantly decreased in 4 hr and 8 hr groups at 3 days after wound formation. The bFGF, collagen 1 and 3 mRNA expressions were significantly decreased in 8 hr exposure group. CONCLUSIONS: These results suggest that sevoflurane exposure influences the regional blood flow, wound size, expression of bFGF, and production of collagen 1 and 3 during the wound healing process.

Apoptosis of the GABAergic interneuron in the dorsal horn of the chronic post-ischemic pain model.

BACKGROUND: It is well known that the GABAergic inhibitory interneuronal system plays an important role in modulation of the noxious stimulation transmitted from the primary afferent input. Some studies have revealed the role that the GABA inhibitory interneuronal system plays in the modulation of pain transmission and the changes in the GABAergic interneurons that occur during the neuropathic pain. This study was conducted to evaluate the apoptosis of the GABAergic interneuron, which is assumed to contribute to neuropathic pain. METHODS: Male Sprague-Dawley rats weighing 290-310 g were used to create a CPIP (chronic post-ischemic pain) model, which was made by placing a tourniquet on the left hindpaw of the rats. The tourniquet was maintained for 3 hours, after which it was released to allow reperfusion. Thirty minutes prior to reperfusion, N-acetyl-L-cysteine (NAC group) or normal saline (control group) was injected. After reperfusion, mechanical allodynia and cold allodynia were measured. In addition, the release of cytochrome c into the cytosol was evaluated through western blot or immunohistochemistry of the spinal cord. RESULTS: Mechanical and cold allodynia developed and the number of GABA interneurons was reduced in the control group. Additionally, The cytochrome c from the GABA interneuron was released into the cytosol in the control group, but the amount released was reduced in response to treatment with NAC. CONCLUSIONS: The results of this study showed that the GABA interneuron in the Rexed laminae I, II released cytochrome c into the cytosol in CPIP neuropathic pain model, which is known to lead to apoptosis. However, treatment with N-acetyl-L-cysteine prevented this process.

Percutaneous vertebroplasty and facet joint block.

It is surprising that about 24% of patients with benign osteoporotic vertebral fracture die within a year from respiratory infection and urinary tract infection because of coughing and voiding difficulties, depending on the sites of compression fractures. We reviewed 500 patients on whom percutaneous vertebroplasty (PVP) was performed, at 612 levels in terms of patient selection, operation technique, medication, and clinical outcomes during the follow-up course for 2 yr study period. To confirm the most painful level among the multiple fracture sites, physical examination after facet joint block under the fluoroscope was the most reliable method. The mean total lumbar spine fracture threshold of bone mineral density was 0.81+/-0.05 g/cm2. The mean changes of numeric rating scale scores, Oswestry Disability Index except sex life, and Karnofsky performance status were -72.00, -83.50 and +60.62% in the osteoporosis group and -51.89, -45.02, and 69.03% in the tumor group. Complications related to the procedure were lateral spinal cord damage, transient paresthesia and transient hypotension. PVP with facet joint block is a profitable method for the vertebral compression fracture because of low risk and short duration of procedure with a high chance to result in pain relief and early mobilization.

Epigallocatechin-3-gallate, constituent of green tea, suppresses the LPS-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and NF-kappaB.

The effects of epigallocatechin-3-gallate (EGCG) on dendritic cells (DC) maturation were investigated. EGCG, in a dose-dependent manner, profoundly inhibited CD80, CD86, and MHC class I and II expression on bone marrow-derived murine myeloid DC. EGCG restored the decreased dextran-FITC uptake and inhibited enhanced IL-12 production by LPS-treated DC. EGCG-treated DC were poor stimulators of nai;ve allogeneic T-cell proliferation and reduced levels of IL-2 production in responding T cells. EGCG-pretreated DC inhibited LPS-induced MAPKs, such as ERK1/2, p38, JNK, and NF-kappaB p65 translocation. Therefore, the molecular mechanisms by which EGCG antagonized LPS-induced DC maturation appeared to involve the inhibition of MAPK and NF-kappaB activation. These novel findings provide new insight into the immunopharmacological role of EGCG and suggest a novel approach to the manipulation of DC for therapeutic application of autoimmune and allergic diseases.

Initial dose cascade of TTS fentanyl with proper adjuvant medications in cancer pain.

According to the three step-ladder analgesics in patients with cancer pain, adjuvant drugs are required for pain relief according to the pain character and also to reduce side effects of opioids. Pain clinicians sometimes want to decide to jump directly from naive and mild opioid to transdermal therapeutic system (TTS) fentanyl with less side effects. We investigated the safety, efficacy, and satisfaction of the patients of TTS fentanyl converting from opioid-naive and mild-opioid with adjuvant drug medications in related to dose cascade of TTS fentanyl. Both opioid-naive (n=3) and opioid-using (n=34) patients started with TTS fentanyl in the lowest available delivery rate (25 microg/hr) with rescue medication. A numeric rating scale (NRS, from 0=no pain to 10=worst pain imaginable), satisfaction of the patients with the transdermal therapy and side effects were recorded everyday during 29 days. Average reductions of NRS scores were 1.79 and 2.77, and the mean doses were 35.14 and 44.12 microg/hr on the 15th and 29th day, respectively. Reported level of satisfaction with the transdermal patch and generalized pain management were 'completely satisfied' and 'satisfied'. Frequent side effects were nausea, vomiting, and constipation. In conclusion, initial application of TTS fentanyl with proper adjuvant medications is effective, safe, and well tolerated.