Melatonin receptors mediate improvements of survival in a model of polymicrobial sepsis.

OBJECTIVES: Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice. DESIGN: Prospective, randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats (200-250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22 g). INTERVENTIONS: Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme-linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision. MEASUREMENTS AND MAIN RESULTS: Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response. CONCLUSIONS: Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release.

Parker Flex-It intubation stylet versus a 90-degree curved stylet during intubation with the McGrath videolaryngoscope performed by novices: a manikin study with 5 airway scenarios.

STUDY OBJECTIVE: To compare the Parker Flex-It intubation stylet with a 90-degree curved stylet using the McGrath videolaryngoscope in 5 airway scenarios (from easy to difficult) in a manikin. DESIGN: Prospective, randomized study. SETTING: Academic hospital. SUBJECTS: 20 staff anesthesiologists with no previous experience in videolaryngoscopy. MEASUREMENTS: Subjects performed a total of 200 intubations with the McGrath Series 5 videolaryngoscope and completed a questionnaire afterwards. RESULTS: Overall success rate was significantly higher with the Parker Flex-It intubation stylet (96 successful intubations with the Parker Flex-It vs 79 intubations in the 90° curved stylet group; P < 0.05). Intubation time was not significantly different. Subjects rated the Parker Flex-It intubation stylet as the better device for intubation with the McGrath videolaryngoscope in routine or emergency situations. CONCLUSION: Intubation of the manikin with the McGrath videolaryngoscope had more success with the Parker Flex-It intubation stylet than a 90° curved stylet.

Endothelin-1 contributes to hemoglobin glutamer-200-mediated hepatocellular dysfunction after hemorrhagic shock.

Hemoglobin glutamer-200 (HbG) might be an alternative to human blood. However, artificial oxygen carriers are initially successful to restore oxygen supply but may induce organ dysfunction and increase mortality several days after application in terms of delayed side effects. Impairment of microcirculation and an inflammatory cytokine response through induction of endothelin (ET) 1 may contribute. We investigated the role of HbG for the therapy of hemorrhagic shock and for delayed side effects in a model of hemorrhagic shock and reperfusion (H/R). To analyze early effects, Sprague-Dawley rats (n = 8/group) were resuscitated after hemorrhagic shock (1 h) with shed blood or HbG followed by reperfusion (2 h). Hemorrhagic shock and reperfusion decreased liver microcirculation and hepatic function in both shock groups to the same extent. Thus, HbG was not superior to shed blood regarding resuscitation end points after hemorrhagic shock. To determine delayed effects, rats (n = 8/group) were pretreated with Ringer's solution (vehicle) or HbG (1 g/kg) 24 h before H/R. Endothelin receptors were blocked with bosentan. Subsequently, ET-1 expression, inflammatory response, sinusoidal perfusion, hepatocellular function (plasma disappearance rate of indocyanine green [PDRICG]), and redox state [NAD(P)H] were analyzed. After vehicle pretreatment, H/R increased ET-1, hepatocellular injury, NAD(P)H, and cytokine levels. Sinusoidal perfusion and PDRICG decreased. After HbG pretreatment, a further increase of ET-1 and hepatocellular injury was observed, whereas PDRICG further decreased. Application of bosentan after HbG but not after vehicle pretreatment significantly improved PDRICG and liver perfusion, whereas NAD(P)H and hepatocellular injury decreased. Furthermore, cytokine release changed to an anti-inflammatory response. These data suggest an HbG-dependent increase of ET-1, which may contribute to delayed side effects under shock conditions.