BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arou... more BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexme-detomidine administered intranasally in healthy volunteers. METHODS: Koch’s design for crossover trials (three-treatment and two-period de-sign) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 g/kg) and C (intranasal dexmedetomidine 1.5 g/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain...
BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arou... more BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexmedetomidine administered intranasally in healthy volunteers. METHODS: Koch's design for crossover trials (three-treatment and two-period design) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 g/kg) and C (intranasal dexmedetomidine 1.5 g/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain pressure threshold measured by an electronic algometer, systolic blood pressure (SBP) and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These were repeated during the course of the study. RESULTS: Intranasal dexmedetomidine was well tolerated. Both 1 and 1.5 g/kg doses equally produced significant sedation and decreases in bispectral index, SBP, diastolic blood pressure, and heart rate when compared with placebo (P Ͻ 0.05). The onset of sedation occurred at 45 min with a peak effect at 90-150 min. The maximum reduction in SBP was 6%, 23%, and 21% for Groups A, B, and C respectively. There was no effect on pain pressure threshold, oxygen saturation or respiratory rate. Anxiolysis could not be evaluated as no subjects were anxious at baseline. CONCLUSION: The intranasal route is effective, well tolerated, and convenient for the administration of dexmedetomidine. Future studies are required to evaluate the possible role of the noninvasive route of administration of dexmedetomidine in various clinical settings, including its role as premedication prior to induction of anesthesia.
15‐F2t‐Isoprostane (IsoP), a specific marker of oxidative stress, is increased after myocardial i... more 15‐F2t‐Isoprostane (IsoP), a specific marker of oxidative stress, is increased after myocardial ischemia. It exerts deleterious effects on postischemic myocardium. We hypothesized that IsoP exacerbates post‐ischemic myocardial injury by stimulating endothelin‐1 (ET‐1) production. Adult rat hearts were perfused by the Langendorff technique. Global myocardial ischemia was induced by stopping perfusion for 40 min followed by 60 min of reperfusion. Hearts were randomized to one of five groups: untreated (C), treated with IsoP (100 nM) or the ET‐1 receptor A/B antagonist bosentan (1 μM) alone or in combination 10 min prior to ischemia and for 15 min during reperfusion or treated with IsoP as above plus delayed bosentan administration 15 min after reperfusion. Coronary effluent ET‐1 levels in the IsoP group were higher than those in the C group during reperfusion accompanied with increased release of cardiac‐specific creatine kinase, reduced cardiac contractility and increased myocardial ...
Open Access Journallink_to_OA_fulltextExperimental Biology Annual Meeting (EB 2012), San Diego, C... more Open Access Journallink_to_OA_fulltextExperimental Biology Annual Meeting (EB 2012), San Diego, CA., 21-25 April 2012. In The FASEB Journal, 2012, v. 26 Meeting abstracts suppl., abstract no. 1117.
Clinical science (London, England : 1979), May 4, 2016
Isoflurane postconditioning(IsoPostC) attenuates myocardial ischemia-reperfusion injury. STAT3 is... more Isoflurane postconditioning(IsoPostC) attenuates myocardial ischemia-reperfusion injury. STAT3 is critical in ischemic postconditioning cardioprotection, which can be regulated by Brg1 and Nrf2. However, Brg1 and Nrf2 are reduced in diabetic hearts. We hypothesized that reduced Brg1/Nrf2 and STAT3 activation may jeopardize IsoPostC-mediated cardioprotection in diabetic hearts. In this study, Langendorff-perfused non-diabetic (control) and 8-week streptozotocin-induced type-1 diabetic rat hearts were subjected to 30 minutes global ischemia and 120 minutes of reperfusion without or with IsoPostC achieved by administrating emulsified isoflurane(2.0%, v/v) in Krebs-Henseleit solution immediately at the onset of reperfusion for 10 minutes and switching to Krebs-Henseleit solution perfusion alone thereafter. Cultured H9C2 cells were exposed to normal glucose(NG, 5.5 mM) or high glucose(HG, 30 mM) and subjected to hypoxia/re-oxygenation(HR) in the presence or absence of IsoPostC. Diabetic ...
Clinical science (London, England : 1979), Jan 7, 2015
Activation of Protein Kinase Cβ (PKCβ) plays a critical role in myocardial ischemia/reperfusion (... more Activation of Protein Kinase Cβ (PKCβ) plays a critical role in myocardial ischemia/reperfusion (I/R) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 is overexpressed that is associated with increased vulnerability to post-ischemic I/R injury with concomitantly impaired cardiomyocyte caveolin (Cav)-3 and Akt signaling as compared with non- diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signaling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxistaurin (RBX, 1 mg/kg/day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding left descending coronary artery followed by reperfusion. Cardiac function was measured using pressure-volume conductance system. In in vitro study, cardiac H9C2 cells were exposed to high glucose (30 mmol/L) and subjected to hypoxia followed by reoxyge...
SummaryIntroductionLimited information is available on the management of the ‘cannot intubate, ca... more SummaryIntroductionLimited information is available on the management of the ‘cannot intubate, cannot ventilate’ (CICV) situation in infants. We compared the time to achieve adequate oxygenation following rescue ventilation using the Enk oxygen flow modulator (OFM) with a jet ventilator in a simulated CICV situation using the rabbit as an infant respiratory model.MethodsFollowing institutional ethics committee approval, needle cricothyrotomy was performed under direct vision in nine anesthetized rabbits following surgical exposure of the larynx. After ensuring adequate level of anesthesia and analgesia, and confirming proper positioning of the 18G cannula, apnea was induced by the administration of myorelaxant and the SpO2 was allowed to drop to 75% before initiating rescue ventilation via either the OFM or jet ventilator.ResultsFive rabbits were ventilated with the OFM and four with the jet ventilator. Ventilation was maintained with either device for 15 min. All rabbits were succe...
The aim of the study was to compare the standard technique of cardiac output determination by pul... more The aim of the study was to compare the standard technique of cardiac output determination by pulmonary artery catheter thermodilution (PAC-TD) with a noninvasive ultrasound Doppler monitor (USCOM Pty., Ltd., Coffs Harbour, Australia) in surgery for liver transplantation. We wished to determine if the degree of accuracy would allow the ultrasound cardiac output monitor (USCOM) to be used as an alternative monitor in a clinical setting in which wide fluctuations in cardiac output could be expected. This was a prospective method comparison study, with 71 paired measurements obtained in 12 patients undergoing liver transplantation in a university teaching hospital. Bland-Altman analysis of the 2 techniques showed a bias of 0.39 L/minute, with the USCOM cardiac output lower compared with that of PAC-TD. The bias was small and did not vary with the magnitude of the cardiac output. The 95% limits of agreement were Ϫ1.47 and 2.25 L/minute. There was good repeatability for USCOM measurements, with a repeatability coefficient of 0.43 for USCOM versus 0.77 for PAC-TD. We conclude that USCOM is acceptable for the clinical determination of noninvasive cardiac output, particularly in situations in which tracking changes over time is more important than knowing the precise value. However, the utility of USCOM is limited by its inability to measure pulmonary artery pressure.
Background. 15-F 2t-isoprostane (IsoP), a marker of reactive oxygen species-induced oxidative str... more Background. 15-F 2t-isoprostane (IsoP), a marker of reactive oxygen species-induced oxidative stress, is increased after myocardial ischemia and reperfusion. It exerts deleterious effects on postischemic myocardium accompanied with increased release of endothelin-1 (ET-1), a potent vasoconstrictor. We hypothesized that IsoP exacerbates myocardial ischemia-reperfusion injury by stimulating ET-1 production, and that ET-1 blockade can attenuate or prevent these deleterious effects of IsoP. Methods. Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit solution (KH) at a constant flow rate of 10 mL/min. Global myocardial ischemia was induced by stopping KH perfusion for 40min followed by 60 min of reperfusion. Hearts were randomized to one of the five groups (n [ 8 each): untreated control, treated with IsoP (100 nM), or the ET-1 receptor A/B antagonist bosentan (1 mM) alone or in combination 10 min prior to, during 40 min global ischemia and 15 min of reperfusion, or treated with IsoP as above plus delayed administration of bosentan after 15 min of reperfusion. Results. Coronary effluent ET-1 concentrations in the IsoP group were higher than those in the control group during ischemia and reperfusion (P < 0.05), which was associated with increased release of cardiac-specific creatine kinase, reduced cardiac contractility during reperfusion, and increased myocardial infarct size (all P < 0.05 versus control). Bosentan administration during early reperfusion exacerbated the IsoP deleterious effects, while delayed administration attenuated it. Conclusion. 15-F 2t-isoprostane-induced ET-1 production during later reperfusion is detrimental to functional recovery of damaged myocardium, while ET-1 increase during early reperfusion seems to improve it.
Purpose: Tranexamic acid has been used to reduce blood loss and the subsequent need for transfusi... more Purpose: Tranexamic acid has been used to reduce blood loss and the subsequent need for transfusion in orthopedic, spinal, and cardiac surgery. Orthognathic surgery can be associated with significant bleeding yet its efficacy in this setting is not clear. The purpose of this study was to investigate the effect of tranexamic acid on blood loss during bimaxillary osteotomy. Patients and Methods: Seventy-three consecutive patients, scheduled for elective bimaxillary osteotomy, were included in this double blind, randomized, controlled trial. They received either a bolus of tranexamic acid (20 mg/kg) or placebo (normal saline) intravenously just before surgery. All patients received induced mild hypotension and had surgery according to a standard protocol. Intraoperative blood loss, operation time, transfusion of blood products, perioperative hemoglobin, and hematocrit were recorded. Results: The total blood loss and blood loss during maxillary surgery was reduced significantly in the tranexamic acid group compared with the control group (878.6 Ϯ 577.7 mL vs 1,257.2 Ϯ 817.8 mL and 428.0 Ϯ 233.3 mL vs 643.8 Ϯ 430.0 mL, respectively; P Ͻ .05). Considering the duration of operation and the treatment groups only, the mean total blood loss in the control group was 422 mL more than that in the tranexamic acid group (P Ͻ .001). There was no significant difference in blood transfusion or the length of hospital stay between the 2 groups. Conclusion: Preoperative intravenous bolus administration of tranexamic acid at 20 mg/kg reduces blood loss compared with placebo during bimaxillary osteotomy.
Supplementation of L-arginine, a nitric oxide precursor, during the late phase of myocardial isch... more Supplementation of L-arginine, a nitric oxide precursor, during the late phase of myocardial ischemia/reperfusion increases myocyte apoptosis and exacerbates myocardial injury, but the underlying mechanism is unclear. During myocardial ischemia/ reperfusion, apoptosis of endothelial cells precedes that of cardiomyocyte. Tumor necrosis factor-a (TNF) production is increased during myocardial ischemia/reperfusion, which may exacerbate myocardial injury by inducing endothelial cell apoptosis. We postulated that L-arginine may exacerbate TNF-induced endothelial cell apoptosis by enhancing peroxynitrite-mediated nitrative stress. Cultured human umbilical vein endothelial cells were either not treated (control) or treated with TNF alone or with TNF in the presence of Larginine, the nonselective nitric oxide synthase inhibitor N (omega)nitro-L-arginine (L-NNA), propofol (an anesthetic that scavenges peroxynitrite), or L-arginine plus propofol, respectively, for 24 hours. TNF increased intracellular superoxide and hydrogen peroxide production accompanied by increases of inducible nitric oxide synthase (iNOS) protein expression and nitric oxide production. This was accompanied by increased protein expression of nitrotyrosine, a fingerprint of peroxynitrite and an index of nitrative stress, and increased endothelial cell apoptosis. L-arginine did not enhance TNF-induced increases of superoxide and peroxynitrite production but further increased TNF-induced increase of nitrotyrosine production and exacerbated TNF-mediated cell apoptosis. L-NNA and propofol, respectively, reduced TNF-induced nitrative stress and attenuated TNF cellular toxicity. The L-arginine-mediated enhancement of nitrative stress and TNF toxicity was attenuated by propofol. Thus, under pathological conditions associated with increased TNF production, L-arginine supplementation may further exacerbate TNF cellular toxicity by enhancing nitrative stress.
Our previous clinical study reported that isoflurane preconditioning and high-dose propofol postt... more Our previous clinical study reported that isoflurane preconditioning and high-dose propofol posttreatment attenuated myocardial ischemia/reperfusion injury of patients in surgery with cardiopulmonary bypass (CPB). This study was designed to confirm this cardiac protection by use of a dog CPB model and to elucidate the related mechanism. Adult mongrel male dogs undergoing standard CPB were assigned into 4 groups: Sham group, Propofol group, Isoflurane (Iso) group and isoflurane in combination of propofol (pre-Iso + P) group. After induction, anesthesia was maintained with propofol (Propofol group), isoflurane (Iso group) or isoflurane preconditioning in combination with propofol posttreatment (pre-Iso + P group). After 2 h cardiac arrest and CPB, aortic cross-clamping was released to allow 2 h reperfusion. The results demonstrated that joint use of isoflurane and propofol facilitated cardiac functional recovery, improved myocardial oxygen utilization and decreased cardiac enzyme release. Also, the oxidative damage caused by ischemia/reperfusion injury was remarkably attenuated. Linear regression analysis showed that cardiac function performance and oxidative stress status were inversely correlated, indicating the improved cardiac function was in closed association with the attenuation of oxidative stress. In addition, the cardiac oxygen consumption (VO 2) was found to be significantly associated with the above cardiac function and oxidative stress parameters, suggesting VO 2 was predictive for the levels of cardiac damage and oxidative stress. Therefore, we conclude that alternative use of isoflurane and propofol confers superior cardioprotection against postischemic myocardial injury and dysfunction, and this protection was probably mediated by attenuation of cardiac oxidative damage.
Chronic administration of high dose opioids such as morphine is known to create intracellular oxi... more Chronic administration of high dose opioids such as morphine is known to create intracellular oxidative stress via an opioid receptor dependent mechanism and this can interfere with cellular function. This study aimed at examining whether such changes can occur following short term exposure to high concentration of remifentanil, a potent short acting opioid. We conducted a experimental study using rat myocardium and systematically quantified tissue levels of superoxide anions, malondialdehyde (MDA) and nitrotyrosine following exposure to increasing duration (15 min, 1 or 2 h) or escalating doses of remifentanil (1 μg, 5 μg, 10 μg or 20 μg/kg/min). Concurrently the susceptibility of the heart to ischaemia reperfusion injury was assessed under the similar conditions. For any given duration of remifentanil infusion, there was increasing superoxide anions generated as the dose of remifentanil was increased. MDA concentrations were significantly increased when the animal was exposed to 10 μg/kg/min for 2 h or 20 μg/kg/min for any duration. There was a trend towards an increased nitrotyrosine concentration with increasing dose of remifentanil, becoming significant when the dose was 20 μg/kg/min. The infarct limiting ability of remifentanil was compromised when the dihydroethidium fluorescence positive cell percentage exceeded 50%, MDA concentration greater than 2 nmol/mg of protein and nitrotyrosine content exceeding 1.5 μg/mg of protein. Short term high dose opioid exposure can induce oxidative changes seen previously only with chronic opioid use and this high oxidative stress environment corrupts the heart's sensitivity to be preconditioned by opioids.
The development and refinement of an acute pain service based on the increased availability of cl... more The development and refinement of an acute pain service based on the increased availability of clinical evidence would be expected to improve the quality of postoperative pain control. This report reviews the application of postoperative patient-controlled analgesia (PCA) using intravenous morphine in a single institution between 2002 and 2005. More than 5000 patients were evaluated and the results were compared with a similar study performed 10 years ago. Prescription of PCA had increased by more than threefold. Morphine consumption from post-operative day 1 to day 3 (19.1 vs. 26.1, 8.6 vs. 18.1 and 4.5 vs. 19.0 lg/kg/h, respectively), demand-to-delivery ratio (1.35-1.76 vs. 2.4-2.8) and the incidence of respiratory depression (0.06% vs. 2%) were significantly reduced (p < 0.001), but there was no improvement in pain relief. A substantial proportion of patients still experienced postoperative nausea (47%) and vomiting (18.5%) despite a reduction in morphine consumption. Most patients ranked PCA as good and only 0.3% were dissatisfied. We conclude that, in our institution over the last decade, PCA has become more popular for postoperative pain management but with no attendant improvement in pain relief or reduction in side effects. Using PCA alone may result in poorer quality postoperative analgesia. Our findings add to the growing body of evidence that postoperative pain management has not substantially improved despite increased adoption of acute pain services.
Protein kinase C (PKC)β2 is preferably overexpressed in the diabetic myocardium, which induces ca... more Protein kinase C (PKC)β2 is preferably overexpressed in the diabetic myocardium, which induces cardiomyocyte hypertrophy and contributes to diabetic cardiomyopathy, but the underlying mechanisms are incompletely understood. Caveolae are critical in signal transduction of PKC isoforms in cardiomyocytes. Caveolin (Cav)-3, the cardiomyocyte-specific caveolar structural protein isoform, is decreased in the diabetic heart. The current study determined whether PKCβ2 activation affects caveolae and Cav-3 expression. Immunoprecipitation and immunofluorescence analysis revealed that high glucose (HG) increased the association and colocalization of PKCβ2 and Cav-3 in isolated cardiomyocytes. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 small interfering (si)RNA transfection prevented HG-induced PKCβ2 phosphorylation. Inhibition of PKCβ2 activation by compound CGP53353 or knockdown of PKCβ2 expression via siRNA attenuated the reductions of Cav-3 expression and Akt/endothelial nitri...
Oxidative stress plays critical roles in the development of diabetic cardiovascular complications... more Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immuno...
BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arou... more BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexme-detomidine administered intranasally in healthy volunteers. METHODS: Koch’s design for crossover trials (three-treatment and two-period de-sign) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 g/kg) and C (intranasal dexmedetomidine 1.5 g/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain...
BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arou... more BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexmedetomidine administered intranasally in healthy volunteers. METHODS: Koch's design for crossover trials (three-treatment and two-period design) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 g/kg) and C (intranasal dexmedetomidine 1.5 g/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain pressure threshold measured by an electronic algometer, systolic blood pressure (SBP) and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These were repeated during the course of the study. RESULTS: Intranasal dexmedetomidine was well tolerated. Both 1 and 1.5 g/kg doses equally produced significant sedation and decreases in bispectral index, SBP, diastolic blood pressure, and heart rate when compared with placebo (P Ͻ 0.05). The onset of sedation occurred at 45 min with a peak effect at 90-150 min. The maximum reduction in SBP was 6%, 23%, and 21% for Groups A, B, and C respectively. There was no effect on pain pressure threshold, oxygen saturation or respiratory rate. Anxiolysis could not be evaluated as no subjects were anxious at baseline. CONCLUSION: The intranasal route is effective, well tolerated, and convenient for the administration of dexmedetomidine. Future studies are required to evaluate the possible role of the noninvasive route of administration of dexmedetomidine in various clinical settings, including its role as premedication prior to induction of anesthesia.
15‐F2t‐Isoprostane (IsoP), a specific marker of oxidative stress, is increased after myocardial i... more 15‐F2t‐Isoprostane (IsoP), a specific marker of oxidative stress, is increased after myocardial ischemia. It exerts deleterious effects on postischemic myocardium. We hypothesized that IsoP exacerbates post‐ischemic myocardial injury by stimulating endothelin‐1 (ET‐1) production. Adult rat hearts were perfused by the Langendorff technique. Global myocardial ischemia was induced by stopping perfusion for 40 min followed by 60 min of reperfusion. Hearts were randomized to one of five groups: untreated (C), treated with IsoP (100 nM) or the ET‐1 receptor A/B antagonist bosentan (1 μM) alone or in combination 10 min prior to ischemia and for 15 min during reperfusion or treated with IsoP as above plus delayed bosentan administration 15 min after reperfusion. Coronary effluent ET‐1 levels in the IsoP group were higher than those in the C group during reperfusion accompanied with increased release of cardiac‐specific creatine kinase, reduced cardiac contractility and increased myocardial ...
Open Access Journallink_to_OA_fulltextExperimental Biology Annual Meeting (EB 2012), San Diego, C... more Open Access Journallink_to_OA_fulltextExperimental Biology Annual Meeting (EB 2012), San Diego, CA., 21-25 April 2012. In The FASEB Journal, 2012, v. 26 Meeting abstracts suppl., abstract no. 1117.
Clinical science (London, England : 1979), May 4, 2016
Isoflurane postconditioning(IsoPostC) attenuates myocardial ischemia-reperfusion injury. STAT3 is... more Isoflurane postconditioning(IsoPostC) attenuates myocardial ischemia-reperfusion injury. STAT3 is critical in ischemic postconditioning cardioprotection, which can be regulated by Brg1 and Nrf2. However, Brg1 and Nrf2 are reduced in diabetic hearts. We hypothesized that reduced Brg1/Nrf2 and STAT3 activation may jeopardize IsoPostC-mediated cardioprotection in diabetic hearts. In this study, Langendorff-perfused non-diabetic (control) and 8-week streptozotocin-induced type-1 diabetic rat hearts were subjected to 30 minutes global ischemia and 120 minutes of reperfusion without or with IsoPostC achieved by administrating emulsified isoflurane(2.0%, v/v) in Krebs-Henseleit solution immediately at the onset of reperfusion for 10 minutes and switching to Krebs-Henseleit solution perfusion alone thereafter. Cultured H9C2 cells were exposed to normal glucose(NG, 5.5 mM) or high glucose(HG, 30 mM) and subjected to hypoxia/re-oxygenation(HR) in the presence or absence of IsoPostC. Diabetic ...
Clinical science (London, England : 1979), Jan 7, 2015
Activation of Protein Kinase Cβ (PKCβ) plays a critical role in myocardial ischemia/reperfusion (... more Activation of Protein Kinase Cβ (PKCβ) plays a critical role in myocardial ischemia/reperfusion (I/R) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 is overexpressed that is associated with increased vulnerability to post-ischemic I/R injury with concomitantly impaired cardiomyocyte caveolin (Cav)-3 and Akt signaling as compared with non- diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signaling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxistaurin (RBX, 1 mg/kg/day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding left descending coronary artery followed by reperfusion. Cardiac function was measured using pressure-volume conductance system. In in vitro study, cardiac H9C2 cells were exposed to high glucose (30 mmol/L) and subjected to hypoxia followed by reoxyge...
SummaryIntroductionLimited information is available on the management of the ‘cannot intubate, ca... more SummaryIntroductionLimited information is available on the management of the ‘cannot intubate, cannot ventilate’ (CICV) situation in infants. We compared the time to achieve adequate oxygenation following rescue ventilation using the Enk oxygen flow modulator (OFM) with a jet ventilator in a simulated CICV situation using the rabbit as an infant respiratory model.MethodsFollowing institutional ethics committee approval, needle cricothyrotomy was performed under direct vision in nine anesthetized rabbits following surgical exposure of the larynx. After ensuring adequate level of anesthesia and analgesia, and confirming proper positioning of the 18G cannula, apnea was induced by the administration of myorelaxant and the SpO2 was allowed to drop to 75% before initiating rescue ventilation via either the OFM or jet ventilator.ResultsFive rabbits were ventilated with the OFM and four with the jet ventilator. Ventilation was maintained with either device for 15 min. All rabbits were succe...
The aim of the study was to compare the standard technique of cardiac output determination by pul... more The aim of the study was to compare the standard technique of cardiac output determination by pulmonary artery catheter thermodilution (PAC-TD) with a noninvasive ultrasound Doppler monitor (USCOM Pty., Ltd., Coffs Harbour, Australia) in surgery for liver transplantation. We wished to determine if the degree of accuracy would allow the ultrasound cardiac output monitor (USCOM) to be used as an alternative monitor in a clinical setting in which wide fluctuations in cardiac output could be expected. This was a prospective method comparison study, with 71 paired measurements obtained in 12 patients undergoing liver transplantation in a university teaching hospital. Bland-Altman analysis of the 2 techniques showed a bias of 0.39 L/minute, with the USCOM cardiac output lower compared with that of PAC-TD. The bias was small and did not vary with the magnitude of the cardiac output. The 95% limits of agreement were Ϫ1.47 and 2.25 L/minute. There was good repeatability for USCOM measurements, with a repeatability coefficient of 0.43 for USCOM versus 0.77 for PAC-TD. We conclude that USCOM is acceptable for the clinical determination of noninvasive cardiac output, particularly in situations in which tracking changes over time is more important than knowing the precise value. However, the utility of USCOM is limited by its inability to measure pulmonary artery pressure.
Background. 15-F 2t-isoprostane (IsoP), a marker of reactive oxygen species-induced oxidative str... more Background. 15-F 2t-isoprostane (IsoP), a marker of reactive oxygen species-induced oxidative stress, is increased after myocardial ischemia and reperfusion. It exerts deleterious effects on postischemic myocardium accompanied with increased release of endothelin-1 (ET-1), a potent vasoconstrictor. We hypothesized that IsoP exacerbates myocardial ischemia-reperfusion injury by stimulating ET-1 production, and that ET-1 blockade can attenuate or prevent these deleterious effects of IsoP. Methods. Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit solution (KH) at a constant flow rate of 10 mL/min. Global myocardial ischemia was induced by stopping KH perfusion for 40min followed by 60 min of reperfusion. Hearts were randomized to one of the five groups (n [ 8 each): untreated control, treated with IsoP (100 nM), or the ET-1 receptor A/B antagonist bosentan (1 mM) alone or in combination 10 min prior to, during 40 min global ischemia and 15 min of reperfusion, or treated with IsoP as above plus delayed administration of bosentan after 15 min of reperfusion. Results. Coronary effluent ET-1 concentrations in the IsoP group were higher than those in the control group during ischemia and reperfusion (P < 0.05), which was associated with increased release of cardiac-specific creatine kinase, reduced cardiac contractility during reperfusion, and increased myocardial infarct size (all P < 0.05 versus control). Bosentan administration during early reperfusion exacerbated the IsoP deleterious effects, while delayed administration attenuated it. Conclusion. 15-F 2t-isoprostane-induced ET-1 production during later reperfusion is detrimental to functional recovery of damaged myocardium, while ET-1 increase during early reperfusion seems to improve it.
Purpose: Tranexamic acid has been used to reduce blood loss and the subsequent need for transfusi... more Purpose: Tranexamic acid has been used to reduce blood loss and the subsequent need for transfusion in orthopedic, spinal, and cardiac surgery. Orthognathic surgery can be associated with significant bleeding yet its efficacy in this setting is not clear. The purpose of this study was to investigate the effect of tranexamic acid on blood loss during bimaxillary osteotomy. Patients and Methods: Seventy-three consecutive patients, scheduled for elective bimaxillary osteotomy, were included in this double blind, randomized, controlled trial. They received either a bolus of tranexamic acid (20 mg/kg) or placebo (normal saline) intravenously just before surgery. All patients received induced mild hypotension and had surgery according to a standard protocol. Intraoperative blood loss, operation time, transfusion of blood products, perioperative hemoglobin, and hematocrit were recorded. Results: The total blood loss and blood loss during maxillary surgery was reduced significantly in the tranexamic acid group compared with the control group (878.6 Ϯ 577.7 mL vs 1,257.2 Ϯ 817.8 mL and 428.0 Ϯ 233.3 mL vs 643.8 Ϯ 430.0 mL, respectively; P Ͻ .05). Considering the duration of operation and the treatment groups only, the mean total blood loss in the control group was 422 mL more than that in the tranexamic acid group (P Ͻ .001). There was no significant difference in blood transfusion or the length of hospital stay between the 2 groups. Conclusion: Preoperative intravenous bolus administration of tranexamic acid at 20 mg/kg reduces blood loss compared with placebo during bimaxillary osteotomy.
Supplementation of L-arginine, a nitric oxide precursor, during the late phase of myocardial isch... more Supplementation of L-arginine, a nitric oxide precursor, during the late phase of myocardial ischemia/reperfusion increases myocyte apoptosis and exacerbates myocardial injury, but the underlying mechanism is unclear. During myocardial ischemia/ reperfusion, apoptosis of endothelial cells precedes that of cardiomyocyte. Tumor necrosis factor-a (TNF) production is increased during myocardial ischemia/reperfusion, which may exacerbate myocardial injury by inducing endothelial cell apoptosis. We postulated that L-arginine may exacerbate TNF-induced endothelial cell apoptosis by enhancing peroxynitrite-mediated nitrative stress. Cultured human umbilical vein endothelial cells were either not treated (control) or treated with TNF alone or with TNF in the presence of Larginine, the nonselective nitric oxide synthase inhibitor N (omega)nitro-L-arginine (L-NNA), propofol (an anesthetic that scavenges peroxynitrite), or L-arginine plus propofol, respectively, for 24 hours. TNF increased intracellular superoxide and hydrogen peroxide production accompanied by increases of inducible nitric oxide synthase (iNOS) protein expression and nitric oxide production. This was accompanied by increased protein expression of nitrotyrosine, a fingerprint of peroxynitrite and an index of nitrative stress, and increased endothelial cell apoptosis. L-arginine did not enhance TNF-induced increases of superoxide and peroxynitrite production but further increased TNF-induced increase of nitrotyrosine production and exacerbated TNF-mediated cell apoptosis. L-NNA and propofol, respectively, reduced TNF-induced nitrative stress and attenuated TNF cellular toxicity. The L-arginine-mediated enhancement of nitrative stress and TNF toxicity was attenuated by propofol. Thus, under pathological conditions associated with increased TNF production, L-arginine supplementation may further exacerbate TNF cellular toxicity by enhancing nitrative stress.
Our previous clinical study reported that isoflurane preconditioning and high-dose propofol postt... more Our previous clinical study reported that isoflurane preconditioning and high-dose propofol posttreatment attenuated myocardial ischemia/reperfusion injury of patients in surgery with cardiopulmonary bypass (CPB). This study was designed to confirm this cardiac protection by use of a dog CPB model and to elucidate the related mechanism. Adult mongrel male dogs undergoing standard CPB were assigned into 4 groups: Sham group, Propofol group, Isoflurane (Iso) group and isoflurane in combination of propofol (pre-Iso + P) group. After induction, anesthesia was maintained with propofol (Propofol group), isoflurane (Iso group) or isoflurane preconditioning in combination with propofol posttreatment (pre-Iso + P group). After 2 h cardiac arrest and CPB, aortic cross-clamping was released to allow 2 h reperfusion. The results demonstrated that joint use of isoflurane and propofol facilitated cardiac functional recovery, improved myocardial oxygen utilization and decreased cardiac enzyme release. Also, the oxidative damage caused by ischemia/reperfusion injury was remarkably attenuated. Linear regression analysis showed that cardiac function performance and oxidative stress status were inversely correlated, indicating the improved cardiac function was in closed association with the attenuation of oxidative stress. In addition, the cardiac oxygen consumption (VO 2) was found to be significantly associated with the above cardiac function and oxidative stress parameters, suggesting VO 2 was predictive for the levels of cardiac damage and oxidative stress. Therefore, we conclude that alternative use of isoflurane and propofol confers superior cardioprotection against postischemic myocardial injury and dysfunction, and this protection was probably mediated by attenuation of cardiac oxidative damage.
Chronic administration of high dose opioids such as morphine is known to create intracellular oxi... more Chronic administration of high dose opioids such as morphine is known to create intracellular oxidative stress via an opioid receptor dependent mechanism and this can interfere with cellular function. This study aimed at examining whether such changes can occur following short term exposure to high concentration of remifentanil, a potent short acting opioid. We conducted a experimental study using rat myocardium and systematically quantified tissue levels of superoxide anions, malondialdehyde (MDA) and nitrotyrosine following exposure to increasing duration (15 min, 1 or 2 h) or escalating doses of remifentanil (1 μg, 5 μg, 10 μg or 20 μg/kg/min). Concurrently the susceptibility of the heart to ischaemia reperfusion injury was assessed under the similar conditions. For any given duration of remifentanil infusion, there was increasing superoxide anions generated as the dose of remifentanil was increased. MDA concentrations were significantly increased when the animal was exposed to 10 μg/kg/min for 2 h or 20 μg/kg/min for any duration. There was a trend towards an increased nitrotyrosine concentration with increasing dose of remifentanil, becoming significant when the dose was 20 μg/kg/min. The infarct limiting ability of remifentanil was compromised when the dihydroethidium fluorescence positive cell percentage exceeded 50%, MDA concentration greater than 2 nmol/mg of protein and nitrotyrosine content exceeding 1.5 μg/mg of protein. Short term high dose opioid exposure can induce oxidative changes seen previously only with chronic opioid use and this high oxidative stress environment corrupts the heart's sensitivity to be preconditioned by opioids.
The development and refinement of an acute pain service based on the increased availability of cl... more The development and refinement of an acute pain service based on the increased availability of clinical evidence would be expected to improve the quality of postoperative pain control. This report reviews the application of postoperative patient-controlled analgesia (PCA) using intravenous morphine in a single institution between 2002 and 2005. More than 5000 patients were evaluated and the results were compared with a similar study performed 10 years ago. Prescription of PCA had increased by more than threefold. Morphine consumption from post-operative day 1 to day 3 (19.1 vs. 26.1, 8.6 vs. 18.1 and 4.5 vs. 19.0 lg/kg/h, respectively), demand-to-delivery ratio (1.35-1.76 vs. 2.4-2.8) and the incidence of respiratory depression (0.06% vs. 2%) were significantly reduced (p < 0.001), but there was no improvement in pain relief. A substantial proportion of patients still experienced postoperative nausea (47%) and vomiting (18.5%) despite a reduction in morphine consumption. Most patients ranked PCA as good and only 0.3% were dissatisfied. We conclude that, in our institution over the last decade, PCA has become more popular for postoperative pain management but with no attendant improvement in pain relief or reduction in side effects. Using PCA alone may result in poorer quality postoperative analgesia. Our findings add to the growing body of evidence that postoperative pain management has not substantially improved despite increased adoption of acute pain services.
Protein kinase C (PKC)β2 is preferably overexpressed in the diabetic myocardium, which induces ca... more Protein kinase C (PKC)β2 is preferably overexpressed in the diabetic myocardium, which induces cardiomyocyte hypertrophy and contributes to diabetic cardiomyopathy, but the underlying mechanisms are incompletely understood. Caveolae are critical in signal transduction of PKC isoforms in cardiomyocytes. Caveolin (Cav)-3, the cardiomyocyte-specific caveolar structural protein isoform, is decreased in the diabetic heart. The current study determined whether PKCβ2 activation affects caveolae and Cav-3 expression. Immunoprecipitation and immunofluorescence analysis revealed that high glucose (HG) increased the association and colocalization of PKCβ2 and Cav-3 in isolated cardiomyocytes. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 small interfering (si)RNA transfection prevented HG-induced PKCβ2 phosphorylation. Inhibition of PKCβ2 activation by compound CGP53353 or knockdown of PKCβ2 expression via siRNA attenuated the reductions of Cav-3 expression and Akt/endothelial nitri...
Oxidative stress plays critical roles in the development of diabetic cardiovascular complications... more Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immuno...
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Papers by Michael Irwin