G. T. C. Wong

Remifentanil reduces the release of biochemical markers of myocardial damage after coronary artery bypass surgery: a randomized trial.

OBJECTIVE Opioids, including remifentanil, have been demonstrated to confer cardiac protection against ischemia reperfusion injury in animals. This study evaluated whether remifentanil preconditioning is protective in first-time elective on-pump coronary artery bypass surgery patients receiving a standardized fentanyl (25 μg/kg in total) and propofol anesthetic. DESIGN A prospective, double blind, randomized, controlled study. SETTING University hospital; single institution. PARTICIPANTS Forty patients scheduled for first-time elective, on-pump coronary artery bypass surgery for at least 3 diseased vessels. INTERVENTIONS Patients randomized to the remifentanil group (n = 20) received a 1 μg/kg bolus followed by a 0.5 μg/kg/min infusion for 30 minutes after induction but before sternotomy, while the control group (n = 20) received normal saline. Serial samples for measurement of creatine kinase (CK-MB), cardiac troponin I (cTnI), ischemia-modified albumin (IMA) and heart-type fatty-acid-binding protein (hFABP) were taken at baseline, prebypass, T = 10 minutes, 2, 6, 12, and 24 hours after cross-clamp release, to assess the degree of myocardial damage. MEASUREMENTS AND MAIN RESULTS Patients in the remifentanil group had lower levels of CK-MB from T = 2 hours to 24 hours, cTnI from T = 10 minutes to T = 12 hours, IMA from T = 10 minutes to T = 2 hours and h-FABP from T = 10 minutes to T = 12 hours (p < 0.05). The time to tracheal extubation was shorter in patients in the remifentanil group. The overall lengths of ICU and hospital stays were not different. CONCLUSIONS The addition of remifentanil to the anesthesia regimen reduced the degree of myocardial damage. This incremental benefit may be attributable either to remifentanil itself or to an overall increased opioid dose, the latter may be necessary to trigger cardiac protection.

Remifentanil post-conditioning attenuates cardiac ischemia–reperfusion injury via κ or δ opioid receptor activation

Background: Ischemic pre‐ or post‐conditioning of the heart has been shown to involve opioid receptors. Remifentanil, an ultra‐short‐acting selective μ opioid receptor agonist in clinical use, pre‐conditions the rat heart against ischemia–reperfusion injury. This study investigates whether remifentanil post‐conditioning is also cardioprotective.

N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes

N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.

A comparison of dexmedetomidine and midazolam for sedation in third molar surgery.

This randomised, double‐blind study compared dexmedetomidine and midazolam for intravenous sedation during third molar surgery under local anaesthesia. Sixty patients received either dexmedetomidine (up to 1 μg.kg−1) or midazolam (up to 5 mg), which was infused until the Ramsay Sedation Score was four or the maximum dose limit was reached. Intra‐operative vital signs, postoperative pain scores and analgesic consumption, amnesia, and satisfaction scores for patients and surgeons, were recorded. Sedation was achieved by median (IQR (range)) doses of 47 μg (39–52 (25–76)) or 0.88 μg.kg−1 (0.75–1.0 (0.6–1.0)) dexmedetomidine, and 3.6 mg (3.3–4.4 (1.9–5.0)) or 0.07 mg.kg−1 (0.055–0.085 (0.017–0.12)) midazolam. Heart rate and blood pressure during surgery were lower in dexmedetomidine group. There was no significant difference in satisfaction or pain scores. Midazolam was associated with greater amnesia. Dexmedetomidine produces comparable sedation to midazolam.

Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients

Either isoflurane preconditioning or high-dose propofol treatment has been shown to attenuate myocardial IRI (ischaemia/reperfusion injury) in patients undergoing CABG (coronary artery bypass graft) surgery. It is unknown whether isoflurane and propofol may synergistically attenuate myocardial injury in patients. The present study investigated the efficacy of IsoPC (isoflurane preconditioning), propofol treatment (postconditioning) and their synergy in attenuating postischaemic myocardial injury in patients undergoing CABG surgery using CPB (cardiopulmonary bypass). Patients (n = 120) selected for CABG surgery were randomly assigned to one of four groups (n = 30 each). After induction, anaesthesia was maintained either with fentanyl and midazolam (control; group C); with propofol at 100 μg x kg(-1) of body weight x min(-1) before and during CPB followed by propofol at 60 μg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group P); with isoflurane 1-1.5% end tidal throughout the surgery (group I) or with isoflurane 1-1.5% end tidal before CPB and switching to propofol at 100 μg x kg(-1) of body weight x min(-1) during CPB followed by propofol at 60 μg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group IP, i.e. IsoPC plus propofol postconditioning). A joint isoflurane and propofol anaesthesia regimen synergistically reduced plasma levels of cTnI (cardiac troponin I) and CK-MB (creatine kinase MB) and f-FABP (heart-type fatty acid-binding protein) (all P < 0.05 compared with control, group P or group I) and facilitated postoperative myocardial functional recovery. During reperfusion, myocardial tissue eNOS (endothelial NO synthase) protein expression in group IP was significantly higher, whereas nitrotyrosine protein expression was lower than those in the control group. In conclusion, a joint isoflurane preconditioning and propofol anaesthesia regimen synergistically attenuated myocardial reperfusion injury in patients.

Remifentanil Preconditioning Reduces Hepatic Ischemia― Reperfusion Injury in Rats via Inducible Nitric Oxide Synthase Expression

BACKGROUND Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms. METHODS A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated. RESULTS Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups. CONCLUSION Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

Intrathecal Morphine Preconditioning Induces Cardioprotection via Activation of Delta, Kappa, and Mu Opioid Receptors in Rats

BACKGROUND: Small doses of intrathecal morphine provide cardioprotection similar to that conferred by IV morphine. However, the extent of intrathecal morphine preconditioning (IT-MPC) relative to that resulting from ischemic preconditioning (IPC) is unknown. Further, it is uncertain whether IT-MPC is mediated by opioid receptor dependent pathways. In this study, we compared the extent of cardioprotection conferred by IT-MPC with IPC and investigated the role of opioid receptors in this effect. METHODS: Eighty anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 13 groups (n = 6–7) after successful intrathecal catheter placement. Rats in the IPC group were subjected to three 5-min cycles of myocardial ischemia (induced by occlusion of the left main coronary artery) interspersed with 5 min of reperfusion. After IPC, myocardial ischemia and reperfusion injury was induced by 30 min of left main coronary artery occlusion followed by 2 h of reperfusion. In the IT-MPC groups, the rats were given 3 consecutive 5 min intrathecal morphine infusions (0.03, 0.3, 3.0, or 30.0 &mgr;g/kg, respectively) interspersed with 5 min infusion-free periods, before myocardial ischemia reperfusion injury. In 2 other groups either 300&mgr;g/kg of IV morphine or 10 &mgr;L of intrathecal normal saline were given. The selective delta, kappa, and mu opioid receptor antagonists naltrindole, nor-binaltorphimine, and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), respectively, were given to groups of animals receiving IT-MPC to evaluate the relative role of the specific opioid receptor subtypes in IT-MPC preconditioning. Myocardial infarct size (IS), as a percentage of the area at risk (AAR), was determined by 2,3,5-triphenyltetrazolium staining. RESULTS: Intrathecal morphine 0.3 to 30 &mgr;g/kg reduced myocardial IS compared with intrathecal normal saline control animals. The IS/AAR were 33% ± 10% (0.3 &mgr;g/kg), 29% ± 10% (3 &mgr;g/kg) and 29% ± 16% (30 &mgr;g/kg), versus 53% ± 8% for the control group (P < 0.01). The reduction in IS/AAR with IT-MPC was similar to that produced by IV morphine (33% ± 6%, P = 0.84) and IPC (22% ± 4%, P = 0.41). Myocardial preconditioning due to IT-MPC was attenuated by co-administration of any one of the opioid receptor antagonists (IT-MPC + naltrindole 50% ± 9%, IT-MPC + nor binaltorphimine 43% ± 6%, IT-MPC + CTOP 53% ± 9%, P = 0.14). CONCLUSIONS: IT-MPC produced comparable cardioprotection to myocardial IPC and IV morphine. Myocardial preconditioning from intrathecal morphine seems to involve delta, kappa, and mu opioid receptors.

Cardioprotection from remote preconditioning involves spinal opioid receptor activation

AIMS Remote preconditioning is a powerful and potentially clinically viable mode of cardioprotection. The mechanisms underlying its transmission process have not been extensively studied. The aim of this study was to test the hypothesis that spinal opioid receptors are involved with signal transmission of remote cardiac preconditioning. MAIN METHODS Two established models of remote preconditioning were used, one using intermittent ischaemia of the lower limb (remote ischaemic preconditioning, RIPC) and the other by stimulation of cutaneous pain fibres via an abdominal incision (remote preconditioning of trauma, RPOT). Classic ischaemic preconditioning (IPC) was used as positive control. Selective blockade of spinal opioid receptors was achieved through intrathecal injection of naloxone methiodide, a compound not known to cross the blood-brain barrier. KEY FINDINGS The prior introduction of naloxone methiodide abolished the cardioprotective effects of RIPC, RPOT but not IPC, as assessed by infarct size as a percentage of area at risk following 30min of ischaemia and 120min reperfusion. Of the specific receptor antagonists, only that specific for the mu receptor subtype, and not delta or kappa receptor, block the protective response. SIGNIFICANCE These results suggest that the central nervous system at the spinal cord level is involved with the relaying of signals between the afferent and efferent arms of remote preconditioning.

Persistent pain in patients following scoliosis surgery

Chronic or persistent pain is increasingly recognised as a consequence of surgery in a number of different disciplines. The pain often exhibit qualities that differ from the acute post-operative pain and may represent changes in the central nervous system. There is lack of information regarding the incidence of persistent pain in patients following spinal surgery for scoliosis. This study aims to estimate the incidence of persistent pain following spinal surgery for scoliosis in a group of mainly adolescent patients. Questionnaires were distributed to consecutive patients attending the outpatient clinic of a hospital with specialist services in paediatric orthopaedics and spinal surgery. One hundred and five patients out of 122 eligible patients completed the survey. Fifty-two percent had ongoing pain upon hospital discharge either in the primary surgical site and/or in the iliac bone graft site. Approximately 10 and 7% of all patients had back and pelvic pain persisting beyond 12 months, respectively. A small proportion described elements of neuropathic pain. There was a trend suggesting that those who experienced more severe post-operative pain were more likely to develop persistent pain. These data are consistent with those reports that implicate surgery as the trigger for chronic pain.

Activation of Central Opioid Receptors Induces Cardioprotection Against Ischemia-Reperfusion Injury

BACKGROUND: Small doses of intrathecal morphine provide cardioprotection similar to that conferred by IV morphine and ischemic preconditioning (IPC). We investigated the relative role of central versus peripheral opioid receptors in intrathecal morphine preconditioning (ITMPC). METHODS: Forty-eight anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 7 treatment groups (n = 6–7) after successful intrathecal catheter placement. ITMPC was achieved by 3 consecutive 5-min intrathecal infusions of morphine (1.0 &mgr;g/kg each). This was repeated in the presence of either IV (IV naloxone methiodide + ITMPC) or intrathecally (intrathecal naloxone methiodide [ITNM] + ITMPC) administered naloxone methiodide. This compound was also given via these same routes in the absence of ITMPC (IV naloxone methiodide + ITNM). Intrathecal normal saline and IPC were used as negative and positive controls, respectively. Myocardial ischemia and reperfusion injury were induced by 30 min of left main coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size, as a percentage of the area-at-risk, was determined by 2,3,5-triphenyltetrazolium staining. RESULTS: The infarct size/area-at-risk were significantly reduced in the IPC (22% ± 3%) and ITMPC (26% ± 5%) groups compared with the control group (48% ± 9%) (P < 0.01). The addition of ITNM reversed the cardioprotective effects of ITMPC (45% ± 4%), whereas IV administration of the drug did not have any effect on ITMPC (28% ± 9%, P < 0.01). CONCLUSIONS: Intrathecally administered morphine can produce cardioprotective effects via the activation of central opioid receptors, without the apparent involvement of peripheral opioid receptors.