Coherence of Visual-Evoked Gamma Oscillations Is Disrupted by Propofol but Preserved Under Equipotent Doses of Isoflurane

Previous research demonstrates that the underlying state of the brain influences how sensory stimuli are processed. Canonically, the state of the brain has been defined by quantifying the spectral characteristics of spontaneous fluctuations in local field potentials (LFP). Here, we utilized isoflurane and propofol anesthesia to parametrically alter the spectral state of the murine brain. With either drug, we produce slow wave activity, with low anesthetic doses, or burst suppression, with higher doses. We find that while spontaneous LFP oscillations were similar, the average visual-evoked potential (VEP) was always smaller in amplitude and shorter in duration under propofol than under comparable doses of isoflurane. This diminished average VEP results from increased trial-to-trial variability in VEPs under propofol. One feature of single trial VEPs that was consistent in all animals was visual-evoked gamma band oscillation (20–60 Hz). This gamma band oscillation was coherent between trials in the early phase (<250 ms) of the visual evoked potential under isoflurane. Inter trial phase coherence (ITPC) of gamma oscillations was dramatically attenuated in the same propofol anesthetized mice despite similar spontaneous oscillations in the LFP. This suggests that while both anesthetics lead to loss of consciousness (LOC), elicit slow oscillations and burst suppression, only the isoflurane permits phase resetting of gamma oscillations by visual stimuli. These results demonstrate that accurate characterization of a brain state must include both spontaneous as well as stimulus-induced perturbations of brain activity

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Variability in adequacy of ventilation during transport of cardiac surgery patients: a cohort study

Inadequate ventilation of intubated patients during transport from the operating theatre to the intensive care unit with attendant hypercarbia may adversely affect haemodynamics. In a retrospective observational study, we assessed the incidence of inadequate ventilation during transport from the operating theatre to the intensive care unit in 99 consecutive cardiac surgery patients admitted to our university tertiary hospital. Demographic, clinical, arterial blood gas and haemodynamic measurements were made on arrival in the intensive care unit after cardiac surgery. The relationships between arterial carbon dioxide tension (PCO), mean pulmonary artery pressure (MPAP) and other relevant haemodynamic variables were explored. Overall, hypocarbia (PCO 45 mmHg). Pulmonary hypertension was common, with nearly half of the cohort having MPAP ≥25 mmHg and 17.2% ≥30 mmHg. However, there was no association between PCO and MPAP (R =0.0076, P=0.39). Contrary to expectation, neither hypercarbia nor high MPAP were associated with measured adverse outcomes, although this may have been because we studied an insufficient number of patients with extreme values. Associations of higher MPAP, which would be expected to compromise cardiovascular status, included acidaemia, hypoxia and the requirement for noradrenaline. These factors define a group of high-risk patients who should receive particular attention and who should be the focus of future studies

Development and validation of brain target controlled infusion of propofol in mice.

Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice

Electrocorticographic verification of anesthetic depth.

<p>Each trace represents a 10 second segment of spontaneous ECoG recorded over the mouse somatosensory cortex while the mouse is receiving TCI propofol. This data was collected beginning 20 minutes into a 30 minute recording. The target brain concentration of propofol is 10 μg⋅g^-1 in the top trace (A). This trace shows that the alpha frequency is prominent from 4–7 seconds. In contrast, the target brain concentration in the bottom is 15 μg⋅g^-1 (B), during which a deeper anesthetic state is illustrated by burst suppression.</p

Blood propofol concentration data used for model fitting.

<p>Blood propofol concentrations measured from the same experiments represented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194949#pone.0194949.g003" target="_blank">Fig 3</a>. As in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194949#pone.0194949.g003" target="_blank">Fig 3</a>, the shaded grey area shows the infusion rate in mg⋅kg^-1⋅min^-1 used in each set of experiments. Heavy red lines show the propofol concentration predicted in the blood. Connected points indicate the propofol concentration measured in the blood of a single subject. (A) and (B) show the simple infusions used. (A) 150 mg⋅kg^-1⋅min^-1 for 6 seconds. (B) 2 mg⋅kg^-1⋅min^-1 for 1 hour. (C) and (D) show the infusions resulting from the first and second attempts at achieving brain TCI, both targeting 10 μg/g in the brain.</p

Model validation data.

<p>The infusion (grey shaded area) was computed to target brain concentration of 10 μg⋅g^-1 (A and B) or 15 μg⋅g^-1 (C). Predicted propofol concentration in the brain (A and C) and blood (B) are shown by thick black and red lines, respectively. Measured propofol concentration in the brain (A and C) and blood (B) are shown as points. Points are colour coded by subject. The data from panels A and C were replotted in (D) as the moving average and standard deviation of the normalized propofol concentration in brain tissue, relative to the target concentration.</p

Constants of final model.

<p>Constants of final model.</p

Schematic of model creation methods.

<p>The first image represents the initial infusion used, which was delivered at a fixed rate. The second image shows that data collected from these experiments were fit and used to produce estimates of the pharmacokinetic parameters, as described in the methods. Third, these parameter estimates were used to calculate the infusion rate necessary to maintain a target brain concentration for the brain TCI experiments. After each experimental set, accuracy of TCI model was determined and fit was updated to incorporate all experimental findings. The methodology represented in images 2 and 3 was repeated until time-invariant and unbiased target brain concentration of propofol was maintained for at least 1 hour.</p