Olivier Lepage

Mechanisms of Desflurane-induced Preconditioning in Isolated Human Right Atria In Vitro

Background The authors examined the role of adenosine triphosphate-sensitive potassium (KATP) channels, adenosine A1 receptor, and &agr; and &bgr; adrenoceptors in desflurane-induced preconditioning in human myocardium, in vitro. Methods The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrodes solution (34°C; stimulation frequency, 1 Hz). Before a 30-min anoxic period, 3, 6, and 9% desflurane was administered during 15 min. Desflurane, 6%, was also administered in the presence of 10 &mgr;m glibenclamide, a KATP channels antagonist; 10 &mgr;m HMR 1098, a sarcolemmal KATP channel antagonist; 800 &mgr;m 5-hydroxy-decanoate (5-HD), a mitochondrial KATP channel antagonist; 1 &mgr;m phentolamine, an &agr;-adrenoceptor antagonist; 1 &mgr;m propranolol, a &bgr;-adrenoceptor antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine (DPX), the adenosine A1 receptor antagonist. Developed force at the end of a 60-min reoxygenation period was compared (mean ± SD). Results Desflurane at 3% (95 ± 13% of baseline), 6% (86 ± 6% of baseline), and 9% (82 ± 6% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (50 ± 11% of baseline). Glibenclamide (60 ± 12% of baseline), 5-HD (57 ± 21% of baseline), DPX (63 ± 19% of baseline), phentolamine (56 ± 20% of baseline), and propranolol (63 ± 13% of baseline) abolished desflurane-induced preconditioning. In contrast, HMR 1098 (85 ± 12% of baseline) did not modify desflurane-induced preconditioning. Conclusions In vitro, desflurane preconditions human myocardium against simulated ischemia through activation of mitochondrial KATP channels, adenosine A1 receptor, and &agr; and &bgr; adrenoceptors.

Extracorporeal life support in severe drug intoxication: a retrospective cohort study of seventeen cases

IntroductionCardiovascular failure is the leading cause of death in severe acute drug intoxication. In this setting, we report the feasibility, complications, and outcome of emergency extracorporeal life support (ECLS) in refractory shock or cardiac arrest following a drug overdose.MethodsThis is a retrospective cohort study of 17 patients admitted over a 10-year period for prolonged cardiac arrest or refractory shock following a drug overdose and not responding to optimal conventional treatment. Patients were evaluated in the medical ICU and cardiovascular surgery department of a university hospital. ECLS implantation used a centrifugal pump connected to a hollow-fiber membrane oxygenator and was performed in the operating room (n = 13), intensive care unit (n = 3), or emergency department (n = 1). ECLS was employed for refractory shock and prolonged cardiac arrest in 10 and 7 cases, respectively.ResultsThe mean duration of external cardiac massage was 101 ± 55 minutes. Fifteen patients had ingested cardiotoxic drugs, including 11 cases of drugs with membrane stabilizing activity. Time from hospital admission to initiation of ECLS was 6.4 ± 7.0 hours. Time to ECLS implant was 58 ± 11 minutes. The mean ECLS flow rate was 3.45 ± 0.45 L/min. The average ECLS duration was 4.5 ± 2.4 days. Early complications included limb ischemia (n = 6), femoral thrombus (n = 1), cava inferior thrombus (n = 1), and severe bleeding at the site of cannulation (n = 2). Fifteen patients were weaned off ECLS support and 13 (76%) were discharged to hospital without sequelae.ConclusionsBased on our experience, we consider ECLS as a last resort, efficient, and relatively safe therapeutic option in this population. However, the uncontrolled nature of our data requires careful interpretation.

Refractory shock and asystole related to tramadol overdose

Introduction. Tramadol use is largely considered safe. However, several lethal cases of tramadol intoxication were reported, suggesting an underestimated toxicity. We report for a tramadol overdose case in combination with other central nervous system depressants, leading to refractory shock requiring extracorporeal life support. Case report. A 33-year-old man was admitted in our intensive care unit for drug intoxication with coma, seizures, and hypotension without signs of heart failure. A few hours later, he developed a ventricular tachycardia, followed by a brief cardiac arrest in asystole with refractory shock requiring an extracorporeal life support, vasopressors, and hemofiltration. With this aggressive support, his overall status gradually improved. Repeated echocardiography showed an improvement in the cardiac function. The patient was weaned off extracorporeal life support on day eight and discharged on day 12. On admission, a urine analysis, using gas chromatography-mass spectrometry, showed high peaks of tramadol and desmethyltramadol with the presence of hydroxyzine, gabapentine, and clonazepam. The tramadol blood concentration measured by the high-performance liquid chromatography method-diode array detector was 23.9 mg/L, much higher than many previously reported fatal overdoses. No other drugs with potential cardiac toxicity, such as beta-blockers, calcium antagonists, antiarrythmic, antidepressants, meprobamate, or other xenobiotics were detected. Conclusion. This case illustrates that tramadol overdose may cause refractory shock and asystole when taken in combination with CNS depressants, and reminds all physicians to be vigilant with regard to the potential toxic effects of tramadol.

Reactive oxygen species mediate sevoflurane- and desflurane-induced preconditioning in isolated human right atria in vitro.

BACKGROUND:We examined the role of reactive oxygen species (ROS) in sevoflurane- and desflurane-induced preconditioning on isolated human right atrial myocardium. METHODS:We recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode’s solution (34°C, stimulation frequency 1 Hz). In all groups, a 30-min hypoxic period was followed by 60 min of reoxygenation. Ten minutes before hypoxia reoxygenation, muscles were exposed to 5 min of sevoflurane 2% or desflurane 6%. In separate groups, the sevoflurane 2% (Sevo + N-(2-mercaptopropionyl)-glycine [MPG]) or desflurane 6% (Des + MPG) was administered in the presence of 0.1 mM MPG, a ROS scavenger. The effect of 0.1 mM MPG alone was tested. Recovery of force after a 60-min reoxygenation period was compared between groups (mean ± sd). RESULTS:Preconditioning with sevoflurane 2% (85% ± 4% of baseline) or desflurane 6% (86% ± 7% of baseline) enhanced the recovery of the force of myocardial contraction after 60 min reoxygenation compared with the control group (53% ± 11% of baseline, P < 0.001). This effect was abolished in the presence of MPG (56% ± 12% of baseline for Sevo + MPG, 48% ± 13% of baseline for Des + MPG). The effect of MPG alone on the recovery of force was not different from the control group (57% ± 7% of baseline versus 53% ± 11%; P = NS). CONCLUSIONS:In vitro, sevoflurane and desflurane preconditioned human myocardium against hypoxia through a ROS-dependent mechanism.

Signaling pathways involved in desflurane-induced postconditioning in human atrial myocardium in vitro.

Background:Isoflurane and sevoflurane have been shown to elicit myocardial postconditioning, but the effect of desflurane remain unknown. The authors studied the mechanisms involved in desflurane-induced myocardial postconditioning. Methods:Contracting isolated human right atrial trabeculae (34°C, stimulation frequency 1 Hz) were exposed to 30-min hypoxia followed by 60-min reoxygenation. Desflurane at 3%, 6%, and 9% was administered during the first 5-min of reoxygenation. Postconditioning with 6% desflurane was studied in the presence of 1 &mgr;m calphostin C, a protein kinase C inhibitor; 800 mm 5-hydroxydecanoate, a mitochondrial adenosine triphosphate–sensitive potassium channels antagonist; 1 &mgr;m Akt inhibitor; 20 &mgr;m PD89058, an extracellular-regulated kinase 1/2 inhibitor; and 1 &mgr;m SB 202190, a p38 mitogen-activated protein kinase inhibitor. The force of contraction at the end of the 60-min reoxygenation period was compared (mean ± SD). The p38 mitogen-activated protein kinase phosphorylation was studied using Western blotting. Results:Desflurane at 3% (77 ± 10% of baseline), 6% (90 ± 14% of baseline), and 9% (86 ± 11% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (51 ± 9% of baseline; P < 0.001). Calphostin C (55 ± 3% of baseline), 5-hydroxydecanoate (53 ± 3% of baseline), Akt inhibitor (57 ± 8% of baseline), PD89058 (64 ± 6% of baseline), and SB 202190 (61 ± 3% of baseline) abolished desflurane-induced postconditioning. Western blot analysis showed that 6% desflurane increased p38 mitogen-activated protein kinase phosphorylation. Conclusions:In vitro, desflurane postconditioned human atrial myocardium through protein kinase C activation, opening of mitochondrial adenosine triphosphate–sensitive potassium channels, Akt and extracellular-regulated kinase 1/2 activation, and p38 mitogen-activated protein kinase phosphorylation.

The inotropic and lusitropic effects of ketamine in isolated human atrial myocardium: the effect of adrenoceptor blockade.

We studied the direct myocardial effects of racemic ketamine, in the presence of α- and &bgr;-adrenoceptor blockade, on isolated human right atrial myocardium. Isometric force of contraction (FoC), its first derivative with time (+dF/dt), the contraction relaxation coupling parameter R2 = (+dF/dt) / (−dF/dt), and time to half relaxation (T1/2) were recorded before and after addition of 10−6, 10−5 and 10−4 M racemic ketamine alone and in the presence of α-adrenoceptor blockade (phentolamine 10−6 M) and &bgr;-adrenoceptor blockade (propranolol at 10−6 M). Ketamine had a moderate positive inotropic effect at 10−5 M (FoC, 104% ± 5% of baseline value; P = 0.03) and 10−4 M (FoC, 107% ± 11% of baseline value; P = 0.09). Racemic ketamine had a negative inotropic effect in the presence of propranolol (FoC, ketamine 10−6 M, 77% ± 11%; ketamine 10−5 M, 63% ± 16%; ketamine 10−4 M, 62% ± 17% of baseline; P < 0.001) but not phentolamine (FoC, ketamine at 10−6 M, 94% ± 6%; ketamine 10−5 M, 96% ± 5%; and ketamine 10−4 M, 98% ± 15% of baseline). Ketamine decreased T1/2 (ketamine 10−5 M, 94% ± 3% of baseline value; P < 0.001 and ketamine 10−4 M, 90% ± 9% of baseline value; P = 0.007) but did not modify R2. In human right atrial myocardium, racemic ketamine induced a moderate positive inotropic effect and hastened isometric relaxation. In the presence of &bgr;-adrenoceptor blockade it induced a direct negative inotropic effect.

Desflurane-induced postconditioning of diabetic human right atrial myocardium in vitro

AIM We tested the hypothesis that brief exposure to desflurane at the time of reoxygenation might be able to protect against hypoxia-reoxygenation injury in human myocardium from diabetic (insulin-dependent, ID; and non-insulin-dependent, NID) patients and non-diabetic (ND) subjects. METHODS The force of contraction (34 degrees C, stimulation frequency 1Hz) in the right atrial trabeculae was recorded during 30min of hypoxia followed by 60min of reoxygenation. Desflurane (at 3, 6 and 9%) was administered during the first 5min of reoxygenation. The force of contraction at the end of the 60-min reoxygenation period (FoC(60)) was compared in the study groups (means+/-SD). RESULTS In the ND group, desflurane at 3, 6 and 9% (FoC(60): respectively 78+/-10%, 84+/-4% and 85+/-12% of baseline) enhanced the recovery of FoC(60) compared with the ND-controls (53+/-7% of baseline; P<0.05). In the ID group, desflurane at 3% (61+/-4%) did not modify the recovery of FoC(60) compared with the ID-controls (54+/-6%), whereas desflurane at 6 and 9% (75+/-11% and 81+/-8%, respectively) enhanced the recovery of FoC(60)vs the controls (P<0.05). In the NID group, desflurane at 3% (57+/-5%) also failed to modify the recovery of FoC(60) compared with the NID-controls (52+/-10%), while desflurane at 6 and 9% (80+/-10% and 79+/-7%, respectively) enhanced the recovery of FoC(60)vs the controls (P<0.05). CONCLUSION Desflurane in vitro was able to postcondition diabetic (both ID and NID) human myocardium at 6 and 9%, but not at 3%.

Sevoflurane- and desflurane-induced human myocardial post-conditioning through Phosphatidylinositol-3-kinase/Akt signalling.

Background: The role of phosphatidylinositol‐3‐kinase (PI3K) in sevoflurane‐ and desflurane‐induced myocardial post‐conditioning remains unknown.

Signaling pathways involved in postconditioning-induced cardioprotection of human myocardium, in vitro.

We examined the respective role and relationship between protein kinase C (PKC), mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel and p38 mitogen-activated protein kinase (MAPK) in postconditioning of human myocardium, in vitro. Isometrically contracting, isolated human right atrial trabeculae were exposed to 30 min hypoxia and 60 min reoxygenation. Phorbol 12-myristate 13-acetate (a PKC activator), diazoxide (a mitoKATP opener) and anisomycin (a p38 MAPK activator) were superfused in early reoxygenation alone and with calphostin C (a PKC inhibitor), 5-hydroxy-decanoate (5-HD, a mitoKATP channel inhibitor) and SB 202190 (a p38 MAPK inhibitor). Developed force at the end of the 60 min reoxygenation (FoC60) period was compared between groups (mean ± SD). Phorbol 12-myristate 13-acetate (91 ± 4% of baseline), diazoxide (85 ± 5% of baseline) and anisomycin (90 ± 4% of baseline) enhanced the FoC60 as compared with the control group (53 ± 7% of baseline, P < 0.0001). The enhanced FoC60 induced by phorbol 12-myristate 13-acetate was abolished by calphostin C (52 ± 5% of baseline) and 5-HD (56 ± 3% of baseline), but not by SB 202190 (90 ± 8%). The diazoxide-induced recovery of FoC60 was attenuated by 5-HD (55 ± 6% of baseline), but was not modified by calphostin C (87 ± 5% of baseline) and SB 202190 (90 ± 8% of baseline). The anisomycin-induced recovery of FoC60 was abolished by calphostin C (61 ± 9% of baseline) and SB 202190 (52 ± 8% of baseline), but not by 5-HD (88 ± 6% of baseline). In conclusion, PKC activation, opening of mitoKATP channels and p38 MAPK activation in early reoxygenation induced the postconditioning of human myocardium, in vitro. Furthermore, PKC activation was upstream of the opening of mitoKATP channels; p38 MAPK acted on PKC. Therefore, mitoKATP and p38 MAPK seemed to be involved in two independent pathways.

Role of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, glycogen synthase kinase-3 beta, and mitochondrial permeability transition pore in desflurane-induced postconditioning in isolated human right atria

Background:Desflurane during early reperfusion has been shown to postcondition human myocardium. Whether it involves “reperfusion injury salvage kinase” pathway remains incompletely studied. The authors tested the involvement of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, glycogen synthase kinase (GSK)-3&bgr;, and mitochondrial permeability transition pore in desflurane-induced postconditioning. Methods:The authors recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrodes solution (34°C, stimulation frequency 1 Hz). After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of rapamycin, a 70-kDa ribosomal protein S6 kinase inhibitor, NG-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, and atractyloside, the mitochondrial permeability transition pore opener. GSK-3&bgr; inhibitor VII was administered during the first few minutes of reoxygenation alone or in the presence of desflurane 6%, rapamycin, NG-nitro-l-arginine methyl ester, and atractyloside. Developed force at the end of a 60-min reoxygenation period was compared (mean ± SD). Phosphorylation of GSK-3&bgr; was measured using blotting. Results:Desflurane 6% (84 ± 4% of baseline) enhanced the recovery of force after 60 min of reoxygenation when compared with the control group (54 ± 4%, P < 0.0001). Rapamycin (68 ± 8% of baseline), NG-nitro-l-arginine methyl ester (57 ± 8%), atractyloside (52 ± 7%) abolished desflurane-induced postconditioning (P < 0.001). GSK-3&bgr; inhibitor-induced postconditioning (84 ± 5%, P < 0.0001 vs. control) was not modified by desflurane (78 ± 6%), rapamycin (81 ± 6%), and NG-nitro-l-arginine methyl ester (82 ± 10%), but it was abolished by atractyloside (49 ± 6%). Desflurane increased the phosphorylation of GSK-3&bgr; (3.30 ± 0.57-fold increase in desflurane vs. control; P < 0.0001). Conclusions:In vitro, desflurane-induced postconditioning protects human myocardium through the activation of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, inhibition, and phosphorylation of GSK-3&bgr;, and preventing mitochondrial permeability transition pore opening.