Low-Dose Remifentanil in Preterm Cesarean Section with General Anesthesia: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVE: The conventional technique of general anesthesia induction during a Cesarean section involves the use of opioids only after cord clamping. We hypothesized that the use of remifentanil before cord clamping might reduce the use of maternal supplemental anesthetic agents and improve the maternal hemodynamics status and neonatal adaptation of the preterm neonate. METHODS: A phase III, double-blind, randomized, placebo-controlled, hospital-based trial enrolled parturients undergoing a Cesarean section under general anesthesia before 37 weeks of gestation. Block randomization allocated pregnant women to remifentanil or placebo. The primary outcome was the rate of newborns with Apgar scores < 7 at 5 min. Secondary outcomes were maternal hemodynamic parameters, complications of anesthetic induction, use of adjuvant anesthetic agents, neonatal respiratory distress, umbilical cord pH, and lactate levels. RESULTS: A total of 52/55 participants were analyzed, comprising 27 women in the remifentanil group and 25 in the placebo group. Nine of 27 (33.3%) neonates had an Apgar score < 7 at 5 min in the remifentanil group versus 11/25 (44.0%) in the placebo group (p = 0.45, odds ratio = 0.66, 95 confidence interval 0.20-2.18). The blood cord gases, cognitive, behavior, sensory, sleeping, and feeding scores at 1 and 2 years of corrected age were not different. For the mothers, hemodynamic parameters, anesthesia duration, and the cumulative treatment dose until cord clamping did not differ between the groups. CONCLUSIONS: The use of a low dose of remifentanil before cord clamping for a Cesarean section appears to be safe both for the mother and the preterm newborn, but it does not improve maternal or neonatal outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02029898.

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice.

Background: Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in ex vivo experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury. Methods: Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 µg). Cerebral reactive oxygen species (ROS) production, cell death, in situ labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18. Results: In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1ß levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice. Conclusions: In vivo exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated.

The antiapoptotic effect of remifentanil on the immature mouse brain: an ex vivo study.

BACKGROUND: The use of remifentanil in a context of potential prematurity led us to explore ex vivo the opioid effects on the immature mouse brain. Remifentanil enhances medullary glutamatergic N-methyl-D-aspartate (NMDA) receptor activity. Furthermore, in neonatal mouse cortex, NMDA was previously shown to exert either excitotoxic or antiapoptotic effects depending on the cortical layers. With the use of a model of acute cultured brain slices, we evaluated the potential necrotic and apoptotic effects of remifentanil, alone or associated with its glycine vehicle (commercial preparation of remifentanil, C.P. remifentanil), on the immature brain. METHODS: Cerebral slices from postnatal day 2 mice were treated up to 5 hours with the different compounds, incubated alone or in the presence of NMDA. The necrotic effect was studied by measuring lactate dehydrogenase activity and 7-Aminoactinomycin D labeling. Apoptotic death was evaluated by measurement of caspase-3 activity and cleaved caspase-3 protein levels, using Western blot and immunohistochemistry. Extrinsic and intrinsic apoptotic pathways were investigated by measuring caspase-8, caspase-9 activities, Bax protein levels, and mitochondrial integrity. RESULTS: C.P. remifentanil was ineffective on necrotic death, whereas it significantly reduced caspase-3 activity and cortical cleaved caspase-3 levels. C.P. remifentanil inhibited cortical Bax protein expression, caspase-9 activity, and preserved mitochondrial integrity, whereas it had no effect on caspase-8 activity. Its action targeted the neocortex superficial layers, and it was reversed by the opioid receptors antagonist naloxone and the NMDA antagonist MK801. Remifentanil and glycine acted synergistically to inhibit apoptotic death. In addition, C.P. remifentanil enhanced the antiapoptotic effect of NMDA, whereas it did not improve NMDA excitotoxicity in brain slices. CONCLUSION: The present data indicate that at a supraclinical concentration C.P. remifentanil had no pronecrotic effect but exerted ex vivo antiapoptotic action on the immature mouse brain, involving the opioid and NMDA receptors, and the mitochondrial-dependent apoptotic pathway. Assessment of the impact of the antiapoptotic effect of remifentanil in in vivo neonatal mouse models of brain injury will also be essential to measure its consequences on the developing brain.

Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier.

Podocytes possess the complete machinery for glutamatergic signaling, raising the possibility that neuron-like signaling contributes to glomerular function. To test this, we studied mice and cells lacking Rab3A, a small GTPase that regulates glutamate exocytosis. In addition, we blocked the glutamate ionotropic N-methyl-d-aspartate receptor (NMDAR) with specific antagonists. In mice, the absence of Rab3A and blockade of NMDAR both associated with an increased urinary albumin/creatinine ratio. In humans, NMDAR blockade, obtained by addition of ketamine to general anesthesia, also had an albuminuric effect. In vitro, Rab3A-null podocytes displayed a dysregulated release of glutamate with higher rates of spontaneous exocytosis, explained by a reduction in Rab3A effectors resulting in freedom of vesicles from the actin cytoskeleton. In addition, NMDAR antagonism led to profound cytoskeletal remodeling and redistribution of nephrin in cultured podocytes; the addition of the agonist NMDA reversed these changes. In summary, these results suggest that glutamatergic signaling driven by podocytes contributes to the integrity of the glomerular filtration barrier and that derangements in this signaling may lead to proteinuric renal diseases.