Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

Assessment of endothelial glycocalyx disruption in term parturients receiving a fluid bolus before spinal anesthesia: a prospective observational study.

BACKGROUND: Fluid bolus administration is a standard treatment for hypotension. However, the effectiveness of the traditional prophylactic bolus in parturients undergoing spinal anesthesia for cesarean delivery has been questioned. One potential mechanism for the failure of a prophylactic fluid bolus to prevent hypotension is hypervolemia-induced destruction of the endothelial glycocalyx, a structure that plays a vital role in regulating intravascular fluid shifts. METHODS: Thirty healthy parturients undergoing elective cesarean delivery under spinal anesthesia were recruited. Known endothelial glycocalyx biomarkers, heparan sulfate and syndecan-1 along with atrial natriuretic peptide, were measured before and after a 750-mL crystalloid fluid bolus. Cardiac performance parameters, cardiac index and systemic vascular resistance, were monitored during the fluid bolus using thoracic-impedance cardiography. RESULTS: A significant increase in both heparan sulfate 96 ng/mg (P=0.0098) and syndecan-1 2.4 ng/mg (P=0.045) were observed after the fluid bolus. There was a non-significant increase in atrial natriuretic peptide 0.6 pg/mg (P=0.293). Cardiac parameters showed a small but significant change; over an average of 15 min, cardiac index increased by 0.1L/min/m2 (P=0.0005) and systemic vascular resistance decreased by 30.7 dyn.s/cm5 (P=0.0025). CONCLUSIONS: A prophylactic fluid bolus in parturients undergoing spinal anesthesia for cesarean delivery disrupts the endothelial glycocalyx, as noted by a statistically significant increase in post-bolus heparan sulfate and syndecan-1 levels. Although studied in the past, atrial natriuretic peptide could not explain this disruption. Our fluid bolus did not have a clinically relevant effect on cardiac performance.

Effects of mild to moderate sedation on saccadic eye movements.

Sedatives alter the metrics of saccadic eye movements. If these effects are nonspecific consequences of sedation, like drowsiness and loss of attention to the task, or differ between sedatives is still unresolved. A placebo-controlled multi-step infusion of one of three sedatives, propofol or midazolam, both GABA-A agonists, or dexmedetedomidine, an α2-adrenergic agonist, was adopted to compare the effects of these three drugs in exactly the same experimental conditions. 60 healthy human volunteers, randomly divided in 4 groups, participated in the study. Each infusion step, delivered by a computer-controlled infusion pump, lasted 20min. During the last 10min of each step, the subject executed a saccadic task. Target concentration was doubled at each step. This block was repeated until the subject was too sedated to continue or for a maximum of 6 blocks. Subjects were unaware which infusion they were receiving. A video eye tracker was used to record the movements of the right eye. Saccadic parameters were modeled as a function of block number, estimated sedative plasma concentration, and subjective evaluation of sedation. Propofol and midazolam had strong effects on the dynamics and latency of the saccades. Midazolam, and to a less extent, propofol, caused saccades to become increasingly hypometric. Dexmedetedomidine had less impact on saccadic metrics and presented no changes in saccadic gain. Suppression of the sympathetic system associated with dexmedetomidine has different effects on eye movements from the increased activity of the inhibitory GABA-A receptors by propofol and midazolam even when the subjects reported similar sedation level.

High-dose oxytocin is not associated with maternal temperature elevation: a retrospective cohort study of mid-trimester pregnancy with intrauterine fetal demise.

BACKGROUND: Maternal intrapartum fever has been associated with an increased incidence of neonatal morbidity. In this retrospective cohort study, we evaluated whether intravenous oxytocin has a fever-inducing effect. Oxytocin augments secretion of prostaglandins E(2) and F(2α) which are inflammatory mediators known to elevate body temperature. METHODS: Between January 2005 and June 2008, 279 patients were admitted with mid-trimester fetal demise. Patients meeting inclusion criteria included 34 women who received a high-dose intravenous oxytocin regimen and 29 patients who delivered after spontaneous labor without the need for augmentation. Oral temperatures were measured on admission and at delivery. RESULTS: The median length of oxytocin infusion was 5.3h. The calculated temperature change was -0.14°C in the oxytocin group and +0.12°C in the control group. These findings were confirmed in a model adjusted for patients' white blood cell count and duration of labor. We did not observe an effect of analgesia type, epidural versus intravenous analgesia, on duration of labor. CONCLUSION: Based on this comparative analysis of pregnant women who received high-doses of oxytocin, we found insufficient evidence to support that high-dose intravenous oxytocin elevates intrapartum maternal temperature.

Precision and bias of target controlled propofol infusion for sedation.

BACKGROUND: The purpose of this study is to test precision and systematic bias of a target controlled infusion (TCI) of propofol in human volunteers at two sedative concentrations. METHODS: We studied the 'Diprifusor' model (Marsh Pharmacokinetics and a Graseby 3400 infusion pump) in 18 human volunteers at two sedative target plasma concentrations (0.5 and 1.0 microg ml(-1)). Twenty minutes after infusion start or change and 20 min after discontinuation of the infusion plasma propofol concentrations were measured using liquid chromatography-mass spectroscopy (LC-MS). Plasma propofol concentrations were compared with concentrations predicted by the TCI system. Agreement of those two measures (precision and bias) was determined using regression analysis. RESULTS: We found little systematic bias but poor precision. When setting the TCI system to deliver a plasma concentration of 1.0 microg ml(-1) one can predict the actual plasma concentration with 95% confidence only within a range of 0.44-1.38 microg ml(-1). CONCLUSIONS: This finding helps to explain differences in responses to propofol sedation; pharmacokinetic variability appears to be an important factor.

Role of the atrial natriuretic factor in obstetric spinal hypotension.

BACKGROUND: In recent years, the concept of prophylactic volume expansion to prevent hypotension caused by spinal anesthesia has been challenged. Investigators have reevaluated the concept of prehydration in the obstetric patient and the physiologic mechanisms involved. This article addresses whether the hypotensive effects attributed to the atrial natriuretic factor are the reason for the apparent failure of prehydration. METHODS: Atrial natriuretic factor was measured before (baseline) and 10 min after spinal anesthetic drug injection (control) in 48 healthy pregnant patients scheduled for elective cesarean section. Sixteen patients received hydration with 15 ml/kg crystalloid immediately before spinal anesthesia, 16 patients received the same volume starting with the spinal anesthetic injection, and the remaining 16 patients received no prehydration (control). Blood pressure, heart rate, ephedrine requirements, infused fluids, and urine output were measured. RESULTS: Atrial natriuretic factor concentrations increased significantly in prehydrated patients but not in the control group. There was a significant correlation in the change in atrial natriuretic factor concentrations and urine output but no correlation in the control atrial natriuretic factor concentrations and blood pressure or ephedrine requirements. Ephedrine requirements and blood pressure did not differ significantly among study groups. CONCLUSIONS: Atrial natriuretic factor is a potent endogenous diuretic in the pregnant patient but does not appear to be involved in short-term cardiovascular homeostasis after spinal anesthesia. Prehydration appears to be an ineffective measure to prevent post spinal hypotension in the obstetric patient [corrected].

Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket.

IMPLICATIONS: This case describes the narcotic overdose associated with the use of a fentanyl transdermal patch in a patient being rewarmed with an external warming blanket during surgery. The clinical manifestation and the presumed pharmacokinetic mechanism responsible for the fentanyl overdose are discussed.

Pioneers in epidural needle design.

IMPLICATIONS: In this article we discuss the development of epidural needles and the historical factors leading to their invention. The most popular needles are described and their inventors acknowledged.

Thrombopoietin in normal pregnancy and preeclampsia.

OBJECTIVE: In normal pregnancy and pregnancies complicated by preeclampsia it has been demonstrated that there is increased activation of platelets and the clotting and fibrinolytic system. We measured plasma levels of thrombopoietin, a major regulator of platelet production in these conditions. STUDY DESIGN: We compared the thrombopoietin plasma levels of healthy term pregnant patients (n = 21) with those of healthy nonpregnant controls (n = 17), as well as patients with severe preeclampsia (n = 8) and the hemolysis, elevated liver enzymes, low platelets syndrome (n = 6). RESULTS: Thrombopoietin levels in normal pregnant patients and pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome were statistically significantly higher than thrombopoietin levels in nonpregnant controls. Data were analyzed with the Kruskal-Wallis one-way analysis of variance by ranks. CONCLUSIONS: This study is the first to report thrombopoietin levels in pregnancy. Thrombopoietin levels are significantly greater in pregnant patients and in pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome compared with nonpregnant controls.