Wei-Zen Sun

Effect of combining dexmedetomidine and morphine for intravenous patient-controlled analgesia

BACKGROUND Perioperative use of dexmedetomidine is associated with reduction in postoperative analgesic requirements. This study examined whether dexmedetomidine added to i.v. patient-controlled analgesia (PCA) morphine could improve analgesia while reducing opioid-related side-effects. METHODS In this double-blinded, randomized, controlled study, 100 women undergoing abdominal total hysterectomy were allocated to receive either morphine 1 mg ml(-1) alone (Group M) or morphine 1 mg ml(-1) plus dexmedetomidine 5 microg ml(-1) (Group D) for postoperative i.v. PCA, which was programmed to deliver 1 ml per demand with a 5 min lockout interval and no background infusion. Cumulative PCA requirements, pain intensities, cardiovascular and respiratory variables, and PCA-related adverse events were recorded for 24 h after operation. RESULTS Compared with Group M, patients in Group D required 29% less morphine during the 0-24 h postoperative period and reported significantly lower pain levels from the second postoperative hour onwards and throughout the study. Whereas levels of sedation were similar between the groups at each observational time point, decreases in heart rate and mean blood pressure from presurgery baseline at 1, 2, and 4 h after operation were significantly greater in Group D (by a range of 5-7 beats min(-1) and 10-13%, respectively). The 4-24 h incidence of nausea was significantly lower in Group D (34% vs 56.3%, P<0.05). There was no bradycardia, hypotension, oversedation, or respiratory depression. CONCLUSIONS The addition of dexmedetomidine to i.v. PCA morphine resulted in superior analgesia, significant morphine sparing, less morphine-induced nausea, and was devoid of additional sedation and untoward haemodynamic changes.

Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery.

Pruritus is a common side effect of intrathecal morphine injection for postoperative pain control. Its incidence is especially high in patients undergoing cesarean delivery. We investigated the effectiveness of ondansetron in preventing intrathecal morphine-induced pruritus in such patients. We included 60 consecutive nonbreastfeeding women who were scheduled for elective cesarean delivery. After the administration of spinal anesthesia with bupivacaine and intrathecal morphine 0.15 mg injection, the patients were randomly divided into three groups. Group 1 received placebo (normal saline) IV injection, Group 2 diphenhydramine 30 mg IV injection, and Group 3 ondansetron 0.1 mg/kg IV injection. The incidence of pruritus was significantly lower in the ondansetron group (25%) when compared with that in the placebo group (85%) and in the diphenhydramine group (80%) (both P < 0.05). The postoperative pain score and time to flatus passage were not significantly different among the three groups. There were no headache or extrapyramidal signs associated with ondansetron use. In conclusion, ondansetron prophylaxis significantly reduced the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Implications Ondansetron prophylaxis significantly decreases the incidence of pruritus, a common side effect of intrathecal morphine used to treat postcesarean delivery pain.

Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia.

Background:Recent studies have implicated the activation of stress-activated mitogen-activated protein kinase (MAPK) p38 in spinal microglial cells for development of neuropathic and inflammatory pain. The aim of the present study was to investigate whether phosphorylation of p38 (p-p38) also mediates mechanical allodynia and thermal hyperalgesia induced by plantar incision. Methods:After rats received a plantar incision surgery, mechanical allodynia and thermal hyperalgesia were determined by von Frey filaments and radiant heat, respectively, and the number of p-p38 immunoreactive cells in the dorsal horn was quantified to determine p38 activation at different time points after incision. The p38 inhibitor FR167653 was administered intrathecally 30 min before hind paw plantar incision to determine the role of p38 in postoperative pain. Results:A significant increase in number of p-p38 immunoreactive cells was observed in the ipsilateral L4-5 spinal dorsal horn from 1 h to 3 days after the incision. p-p38 was found predominantly in microglia. However, microglial activation (assessed by OX-42 upregulation) was not evident until 3 days after plantar incision. Intrathecal pretreatment of FR167653 attenuated incision-induced mechanical allodynia from 1 h to day 2 and significantly reduced activation of p38 in the dorsal horn 1 day after plantar incision. However, FR167653 only inhibited heat hyperalgesia at an early time point. Conclusions:Plantar incision-induced mechanical allodynia can be prevented by the p38 inhibitor. Our results suggest that p38 activation in spinal microglia play a role in incision-induced mechanical allodynia in rats. Therefore, p38 inhibition may be useful in treating postsurgical pain.

Preoperative plasma N‐terminal pro‐brain natriuretic peptide as a marker of cardiac risk in patients undergoing elective non‐cardiac surgery

Plasma N‐terminal pro‐brain natriuretic peptide (NTproBNP) is a sensitive marker for heart failure. This study tested whether the preoperative plasma level of NTproBNP could predict cardiac complications in patients undergoing non‐cardiac surgery.

Intravenous lidocaine and ephedrine, but not propofol, suppress fentanyl-induced cough

PurposeThe aim of this study was to evaluate the effectiveness of lidocaine, propofol and ephedrine in suppressing fentanyl-induced cough.MethodsOne hundred and eighteen patients were randomly assigned into four groups and the following medications were given intravenously: patients in Group I (n = 31) received normal saline 2 mL, Group II (n = 29) received lidocaine 2 mg · kg−1, Group III (n = 30) received propofol 0.6 mg · kg−1 and Group IV (n = 28) received ephedrine 5 mg. At one minute after the study medication, fentanyl 2.5 μg · kg−1 was given intravenously within two seconds. The occurrence of cough and vital sign profiles were recorded within two minutes after fentanyl bolus by an anesthesiologist blinded to study design.ResultsSixty-five percent of patients in the placebo group had cough, whereas the frequency was significantly decreased in Groups II(14%) and IV (21%). Although a numerically lower frequency of cough was noted in Group III (37%), it was not statistically different from that of the placebo group. SpO2 decreased significantly in patients of Group III compared to placebo; one patient experienced hypoxemia necessitating mask ventilation. Patients in Group III showed a decrease in heart rate and systolic blood pressure (2 beats · min−1 and 8 mmHg vs baseline). Patients in Group IV showed an increase in both measurements (5 beats · min−1 and 8 mmHg vs baseline). No truncal rigidity was observed throughout the study.ConclusionsIntravenous lidocaine 2 mg · kg−1 or ephedrine 5 mg, but not propofol 0.6 mg · kg−1, was effective in preventing fentanyl-induced cough. The results provide a convenient method to decrease fentanyl-induced cough.RésuméObjectifÉvaluer l’efficacité de la lidocaïne, du propofol et de l’éphédrine dans la suppression de la toux induite par le fentanyl.MéthodeCent dix-huit patients ont été répartis au hasard en quatre groupes et ont reçu: Groupe l (n = 31), 2 mL de solution saline; Groupe II (n = 29), 2mg · kg−1de lidocaïne; Groupe III (n = 30), 0,6 mg · kg−1 de propofol et Groupe IV (n = 28), 5 mg d’éphédrine. À une minute après la médication expérimentale, 2,5 μg · kg−1 de fentanyl iv ont été administrés en moins de deux secondes. L’occurrence de toux et les profils des signes vitaux ont été enregistrés par un anesthésiologiste impartial pendant les deux minutes qui ont suivi l’administration de bolus de fentanyl.RésultatsSoixante-cinq pour cent des patients du groupe placebo ont eu de la toux, tandis que la fréquence a significativement diminué dans les Groupes II (14 %) et IV (21 %). Même si une fréquence de toux numériquement plus basse a été notée dans le Groupe III, elle n’était pas statistiquement différente de celle du groupe placebo. La SpO2 a diminué significativement chez les patients du Groupe III comparé au groupe placebo; un patient a présenté de l’hypoxémie nécessitant une ventilation au masque. Les patients du Groupe III ont subi une baisse de la fréquence cardiaque et de la tension artérielle systolique (2 battements · min−1 et 8 mmHg vs les mesures de base). Ceux du Groupe IV ont présenté une augmentation de ces deux paramètres (5 battements · min−1 et 8 mmHg vs les mesures de base). Aucune rigidité tronculaire n’a été observée pendant l’étude.ConclusionL’administration iv de 2 mg · kg−1 de lidocaïne ou de 5 mg d’éphédrine, mais non de 0,6 mg · kg−1 de propofol, a été efficace pour prévenir la toux induite par le fentanyl. Les résultats offrent une méthode pratique de diminuer la toux induite par le fentanyl.

Risk of dementia after anaesthesia and surgery

BACKGROUND The potential relationship between anaesthesia, surgery and onset of dementia remains elusive. AIMS To determine whether the risk of dementia increases after surgery with anaesthesia, and to evaluate possible associations among age, mode of anaesthesia, type of surgery and risk of dementia. METHOD The study cohort comprised patients aged 50 years and older who were anaesthetised for the first time since 1995 between 1 January 2004 and 31 December 2007, and a control group of randomly selected patients matched for age and gender. Patients were followed until 31 December 2010 to identify the emergence of dementia. RESULTS Relative to the control group, patients who underwent anaesthesia and surgery exhibited an increased risk of dementia (hazard ratio = 1.99) and a reduced mean interval to dementia diagnosis. The risk of dementia increased in patients who received intravenous or intramuscular anaesthesia, regional anaesthesia and general anaesthesia. CONCLUSIONS The results of our nationwide, population-based study suggest that patients who undergo anaesthesia and surgery may be at increased risk of dementia.

Activation of transcription factors of nuclear factor kappa B, activator protein-1 and octamer factors in hyperalgesia.

Involvement of c-fos and neuronal nitric oxide synthase (nNOS) in the hyperalgesia induced by complete Freund adjuvant (CFA) has been reported. In this paper, we attempted to investigate whether the transcription factors regulating the gene expression of c-fos and nNOS, including activator protein-1 (AP-1), nuclear factor kappa B (NF-kappa B), and octamer factors (Oct), are activated by CFA during the development of hyperalgesia. The electrophoretic mobility shift assay (EMSA) was used to determine whether there were changes in the transcription factors in the lumbar spinal cord of adult rats following subcutaneous injection of CFA in one hindpaw of the rats. Maximum binding of AP-1, NF-kappa B and Oct was found at 0.5, 1 and 2 h after CFA injection, respectively. These findings suggest that the activation of these transcription factors is pivotal for the expression of c-Fos and nNOS proteins, which reached a peak at 3 and 48 h after CFA injection, respectively. The behavioral testing of hyperalgesia demonstrated that CFA reduced the thresholds for mechanical and thermal algesia, reaching a minimum at 6 h. The thresholds had only partially recovered after 96 h. Based on these findings, we conclude that AP-1, NF-kappa B and Oct are crucial for the expression of c-Fos proteins at an early stage (at 3 h) and for the expression of nNOS at a late stage of hyperalgesia (48 h post-injection) induced by CFA.

Risk of Dementia in Patients with Insomnia and Long-term Use of Hypnotics: A Population-based Retrospective Cohort Study

Background Hypnotics have been reported to be associated with dementia. However, the relationship between insomnia, hypnotics and dementia is still controversial. We sought to examine the risk of dementia in patients with long-term insomnia and the contribution of hypnotics. Methods Data was collected from Taiwan’s Longitudinal Health Insurance Database. The study cohort comprised all patients aged 50 years or older with a first diagnosis of insomnia from 2002 to 2007. The comparison cohort consisted of randomly selected patients matched by age and gender. Each patient was individually tracked for 3 years from their insomnia index date to identify whether the patient had a first diagnosis of dementia. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results We identified 5693 subjects with long-term insomnia and 28,465 individuals without. After adjusting for hypertension, diabetes mellitus, hyperlipidemia, and stroke, those with long-term insomnia had significantly higher risks of dementia (HR, 2.34; 95% CI, 1.92–2.85). Patients with long-term insomnia and aged 50 to 65 years had a higher increased risk of dementia (HR, 5.22; 95% CI, 2.62–10.41) than those older than 65 years (HR, 2.33; 95% CI, 1.90–2.88). The use of hypnotics with a longer half-life and at a higher prescribed dose predicted a greater increased risk of dementia. Conclusions Patients with long-term use of hypnotics have more than a 2-fold increased risk of dementia, especially those aged 50 to 65 years. In addition, the dosage and half-lives of the hypnotics used should be considered, because greater exposure to these medications leads to a higher risk of developing dementia.

Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways

Morphine has been widely used for pain management. Other than analgesia, it has effects on vascular endothelial cells, including angiogenesis and apoptosis. An in vitro model of human umbilical vein endothelial cells (HUVECs) was made to investigate the effects and comprehensive mechanisms of morphine on vascular endothelial cells. Morphine enhanced apoptosis of HUVECs, increased intracellular reactive oxygen species (ROS), and reduced mitochondrial membrane potentials (MMPs). It also induced the release of NO and activated NF-kappaB in HUVECs. Naloxone, the opioid receptor antagonist, could reverse cell apoptosis and ROS generation, NO production, and MMP loss. Expression levels of Bak and Bax, and the activation of caspases 3 and 7 in HUVECs significantly increased when treated with morphine. Inhibition of NO production by NO synthase inhibitor reduced morphine-induced apoptosis. Morphine could induce apoptosis of HUVECs through both the NO and ROS pathways. Thus, inhibiting NO or ROS may be a potential target in blocking morphine-induced apoptosis of endothelial cells.

Electroporation-mediated pain-killer gene therapy for mononeuropathic rats

The relatively low expression levels achieved from transferred genes have limited the application of nonviral vectors for gene transfer into the spinal cord in vivo. Thus, the aim of this study was to evaluate the efficacy of electroporation-mediated pro-opiomelanocortin (POMC) gene therapy for neuropathic pain using an animal model of chronic constrictive injury (CCI). Firstly, the optimal pulse characteristics (voltage, pulse duration, number of shocks) were investigated for in vivo electroporation-mediated gene transfer into the spinal cord. The electroporation process makes use of plasmid DNA, which expresses the POMC gene. Expression levels were evaluated in this study by Western blot. We conclude that the optimal conditions for electroporation are a pulse voltage of 200 V, 75-ms duration, 925-ms interval, for five iterations. Secondly, electroporation treatment for neuropathic pain was attempted on CCI rats using plasmid DNA that expresses the POMC gene. Intrathecal administrations of the POMC vector elevated spinal beta-endorphin levels, as manifested in a significantly elevated pain threshold for the CCI limbs. This result suggests that gene therapy for neuropathic pain using this novel technique is very efficacious, and thus shows promise for further clinical trials.