Search

Background Recent preclinical and clinical studies have shed light on the possible impact of sex and estrous/menstrual cycle on ketamine’s antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioral responses to a subanesthetic dose of S-ketamine in males vs females and in different estrous phases in free-cycling females in a well-powered translational approach. Methods We evaluated the behavioral sensitivity to 20 mg/kg S-ketamine (i.p.) in male and female Flinders Sensitive Line rats (FSLs) and their counterpart Flinders Resistant Line rats (FRLs) subjected to the open field and forced swim tests. Female rats were disaggregated into different estrous phases, and the behavioral outcomes were compared. Results Acute administration of S-ketamine had robust antidepressant-like effects in FSLs. Within our study power, we could not detect sex– or estrous cycle–specific different antidepressant-like responses to S-ketamine in FSLs. Fluctuations in the levels of ovarian sex hormones across different estrous cycles did not behaviorally affect S-ketamine’s rapid-acting antidepressant mode of action. No sex-related or estrous cycle–related impact on behavioral despair was observed even among FRLs and saline-treated FSLs. Conclusions We conclude that physiological oscillations of estrogen and progesterone levels neither amplify nor diminish the behavioral antidepressant-like effect of S-ketamine. In addition, fluctuations of ovarian sex hormones do not predispose female animals to exhibit enhanced or reduced depressive-like and anxiety-like behaviors.

Objective: To describe our experience performing ED procedural sedation in a country where emergency medicine (EM) is a relatively new specialty. Methods: This is a prospective observational study of adult patients undergoing procedural sedation by emergency physicians (EPs) or EM residents in eight hospitals in the Netherlands. Data were collected on a standardised form, including patient characteristics, sedative and analgesic used, procedural success, adverse events (classified according to World SIVA) and rescue interventions. Results: 1711 adult cases were included from 2006 to 2013. Propofol, midazolam and esketamine (S+ enantiomer of ketamine) were the most used sedatives (63%, 29% and 8%). We had adverse event data on all patients. The overall adverse event rate was 11%, mostly hypoxia or apnoea. There was no difference in adverse event rate between EPs and EM residents. However, there was a significantly higher success rate of the procedure when EPs did the procedural sedation (92% vs 84%). No moderate (unplanned hospital admission or escalation of care) or sentinel SIVA outcomes occurred ( pulmonary aspiration syndrome, death or permanent neurological deficit). Conclusion: Adverse events during procedural sedation occurred in 11% of patients. There were no moderate or sentinel outcomes. All events could be managed by the sedating physician. In a country where EM is a relatively new specialty, procedural sedation appears to be safe when performed by EPs or trained EM residents and has comparable adverse event rates to international studies.

Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and hospital length of stay, and to improve the outcome of critically ill patients. However, patients with severe acute brain injury (ABI; including subjects with coma after traumatic brain injury, ischaemic/haemorrhagic stroke, cardiac arrest, status epilepticus) were excluded from these studies. Therefore, whether the new paradigm of minimal sedation can be translated to the neuro-ICU (NICU) is unclear. In patients with ABI, sedation has 'general' indications (control of anxiety, pain, discomfort, agitation, facilitation of mechanical ventilation) and 'neuro-specific' indications (reduction of cerebral metabolic demand, improved brain tolerance to ischaemia). Sedation also is an essential therapeutic component of intracranial pressure therapy, targeted temperature management and seizure control. Given the lack of large trials which have evaluated clinically relevant endpoints, sedative selection depends on the effect of each agent on cerebral and systemic haemodynamics. Titration and withdrawal of sedation in the NICU setting has to be balanced between the risk that interrupting sedation might exacerbate brain injury (e.g. intracranial pressure elevation) and the potential benefits of enhanced neurological function and reduced complications. In this review, we provide a concise summary of cerebral physiologic effects of sedatives and analgesics, the advantages/disadvantages of each agent, the comparative effects of standard sedatives (propofol and midazolam) and the emerging role of alternative drugs (ketamine). We suggest a pragmatic approach for the use of sedation-analgesia in the NICU, focusing on some practical aspects, including optimal titration and management of sedation withdrawal according to ABI severity.

International audience; Genetically modified mouse models of many human diseases reflecting cardiovascular alterations are currently available. To date, little information on absolute myocardial perfusion in mice is found in the literature. High-resolution quantitative myocardial blood flow maps (in-plane resolution 156 x 312 mum(2), slice thickness 1.5 mm) have been obtained noninvasively within 25 min at 4.7 T in 30 freely breathing C57/Bl6J mice using electrocardiogram- and respiration-gated spin labeling magnetic resonance imaging (MRI). Regional myocardial blood flow measurements were carried out, and the effects of isoflurane at two different concentrations and ketamine/xylazine anesthesia were assessed. The mean blood flow value in the left ventricular myocardium was 6.0 +/- 1.9 mL g(-1) min(-1) under ketamine/xylazine and 6.9 +/- 1.7 mL g(-1) min(-1) (group average +/- SD) under isoflurane (1.25%). Under the influence of higher isoflurane concentration (2.00%), myocardial blood flow increased dramatically to 16.9 +/- 1.8 mL g(-1)min(-1) with no significant change in heart rate. This work illustrates the feasibility of noninvasive quantitative myocardial perfusion mapping in mice using MRI. The study of the influence of anesthesia shows that myocardial blood flow is highly sensitive to isoflurane concentration. The method employed offers a noninvasive approach to longitudinal studies of murine models of cardiac disease.

Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1−/− mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1−/− mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1−/− prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1−/− mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1−/− mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.

Nicotinic acetylcholine receptors are members of the ligand-gated ion channel superfamily, that includes also gamma-amino-butiric-acid(A), glycine, and 5-hydroxytryptamine(3) receptors. Functional nicotinic acetylcholine receptors result from the association of five subunits each contributing to the pore lining. The major neuronal nicotinic acetylcholine receptors are heterologous pentamers of alpha4beta2 subunits (brain), or alpha3beta4 subunits (autonomic ganglia). Another class of neuronal receptors that are found both in the central and peripheral nervous system is the homomeric alpha7 receptor. The muscle receptor subtypes comprise of alphabetadeltagamma (embryonal) or alphabetadeltaepsilon (adult) subunits. Although nicotinic acetylcholine receptors are not directly involved in the hypnotic component of anesthesia, it is possible that modulation of central nicotinic transmission by volatile agents contributes to analgesia. The main effect of anesthetic agents on nicotinic acetylcholine receptors is inhibitory. Volatile anesthetics and ketamine are the most potent inhibitors both at alpha4beta2 and alpha3beta4 receptors with clinically relevant IC(50) values. Neuronal nicotinic acetylcholine receptors are more sensitive to anesthetics than their muscle counterparts, with the exception of the alpha7 receptor. Several intravenous anesthetics such as barbiturates, etomidate, and propofol exert also an inhibitory effect on the nicotinic acetylcholine receptors, but only at concentrations higher than those necessary for anesthesia. Usual clinical concentrations of curare cause competitive inhibition of muscle nicotinic acetylcholine receptors while higher concentrations may induce open channel blockade. Neuronal nAChRs like alpha4beta2 and alpha3beta4 are inhibited by atracurium, a curare derivative, but at low concentrations the alpha4beta2 receptor is activated. Inhibition of sympathetic transmission by clinically relevant concentrations of some anesthetic agents is probably one of the factors involved in arterial hypotension during anesthesia.

Induction of c-fos in the spinal cord due to pain is well established. This study aims to look at the effects of acute swim stress on Fos-like immunoreactivity (FLI) induced by formalin and how it is modulated by ketamine and morphine. Acutely-stressed and non-stressed adult male Sprague Dawley rats were pretreated with intraperitoneal injection of ketamine 5 mg/kg (Ketava, Atlantic Lab), morphine 10 mg/kg (Rhotard, Custom Pharmaceutical), or saline, 5 minutes prior to experimentation. Rats were acutely stressed by swimming for 3 min in 20°C water. Dilute formalin (Formaldehyde, Merck) was injected to the hindpaw and the formalin score recorded. Rats were then sacrificed and spinal cords (L4-L5) removed for immunohistochemical analysis of FLI. Two-way ANOVA showed significant effects of stress, drug and stress-drug interactions in formalin test and FLI. Both morphine and ketamine produced analgesia in the formalin test. In the saline stressed group, FLI was suppressed on the ipsilateral side (p