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PubMed | Brigham and Women's Hospital and Perioperative and Pain Medicine.
Type: | Journal: Journal of cardiothoracic and vascular anesthesia | Year: 2017

To test whether a model using a historical average of a surgeons surgical times for primary aortic valve replacements is a more accurate predictor of actual surgical times than solely relying on a surgeons estimate.Retrospective review.Single university hospital that serves as a tertiary referral center.All patients undergoing primary aortic valve replacement between October 2008 and September 2014.None.Estimation biases, calculated as the difference between actual and predicted surgical time, were compared between the surgeon and the model, which included between 2 and 20 cases in the historical average. Kruskal-Wallis analysis of variance was used to compare all values. Pairwise comparisons were made using the Steel-Dwass test to determine whether using more cases in the model resulted in smaller estimation biases. Using the historical model reduced mean overestimation bias from 55.30 minutes to 0.90-to-4.67 minutes. No significant difference was seen based on the number of cases used.An uncomplicated model can assist in providing comparatively unbiased estimations of surgical time for aortic valve replacements. The model can rely on a fewer number of cases (eg, 5) and does not benefit from including more cases (eg, 20).

PubMed | Perioperative and Pain Medicine., Bristol Myers Squibb and Gunma University
Type: | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2017

The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers including pain, itch and temperature. Because local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is importantly involved in signal processing there, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor expressing (NK1R+) neurons in lamina I were GABA dominant while protein kinase C gamma expressing (PKC+) neurons at the lamina IIi/III border were glycine dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following Complete Freunds Adjuvant (CFA) injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor 1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition.Pain associated with inflammation is a sensation we would all like to minimize. Persistent inflammation leads to cellular and molecular changes in the spinal cord dorsal horn, including diminished inhibition, which may be responsible for enhance excitability. Investigating inhibition in the dorsal horn following peripheral inflammation is essential for development of improvements to control the associated pain. In this study, we have elucidated regional differences in inhibition of excitatory interneurons in mouse dorsal horn. We have also discovered switching of the dominating inhibitory neurotransmission within specific regions of dorsal horn following peripheral inflammation and the accompanying hypersensitivity to thermal and mechanical stimuli. Our novel findings contribute to a more complete understanding of inflammatory pain.

News Article | November 15, 2016

Placebos are essential in any controlled clinical trial, providing a yardstick against which the test drug is measured. Placebos are even starting to be used as a treatment in their own right, as studies show that they make people feel better via a "mind-body" healing effect. But do parents find placebos acceptable for their children? A study led by Boston Children's Hospital found the answer is mostly yes, provided ethical guidelines are followed. Findings will appear online November 15 in The Journal of Pediatrics. "The question of placebos is more complex when it comes to children, since parents must make medical decisions on their behalf," says Vanda Faria, PhD, a research fellow at Boston Children's Hospital's Center for Pain and the Brain. "Large placebo responses have been seen in a variety of pediatric conditions, and parent's perceptions can influence how well placebos work. At the same time, little is still known about the potential harms of prolonged drug therapy on children's development. Sometimes, the best intervention might not involve pharmacotherapy." The researchers used an online survey to ask 1,000 U.S. parents about their attitudes toward placebos. Their findings: When parents were given a list of 17 conditions, a majority considered placebo acceptable for only seven: the common cold, ear infection, occasional pain, anxiety disorders, mood disorders, sleep disturbance and ADHD. As the researchers note, the study had a number of limitations. The survey respondents were mostly white, half were college graduates and nearly all of their children were in good health. Also, the survey did not distinguish between honesty toward parents or honesty toward the children in disclosing that the treatment is placebo; parents might have different views on that. "We need to refresh traditional pediatric therapeutic models to best support parental decisions around the potential use of placebos," says Faria. "Open-label placebo seems to be a promising adjuvant therapy with the potential to improve pediatric care, as acknowledged by the great majority of the parents we surveyed. Future studies should continue to investigate its therapeutic role." David Borsook, MD, PhD, co-director of the Center for Pain and the Brain, was senior author on the paper. Co-authors were Joe Kossowsky, PhD, Ted J. Kaptchuk, Irving Kirsch, PhD, and Alyssa Lebel, MD, PhD, of Boston Children's Department of Anesthesiology, Perioperative and Pain Medicine, and Mike Petkov of the Center for Pain and the Brain. Faria, Kaptchuk, Kirsch and Kossowsky are also affiliated with the Program in Placebo Studies at Beth Israel Deaconess Medical Center. The study was supported by the Swedish Research Council, the Swiss National Science Foundation and the National Institutes of Health (NIH)/National Center for Complimentary and Integrative Health (NCCIH). Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 404-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the primary pediatric teaching affiliate of Harvard Medical School. For more, visit our Vector and Thriving blogs and follow us on our social media channels: @BostonChildrens, @BCH_Innovation, Facebook and YouTube.

Dickinson J.R.,Perioperative and Pain Medicine | Dickinson J.R.,Stanford University | Scherrer G.,Perioperative and Pain Medicine
Neuron | Year: 2015

In this issue of Neuron, Santello and Nevian (2015) report HCN channel plasticity and increased temporal summation in layer 5 ACC neurons following nerve injury. They are able to restore HCN channel function and reduce behavioral hypersensitivity with selective serotonin receptor targeting. © 2015 Elsevier Inc.

Chu Sin Chung P.,University of Strasbourg | Boehrer A.,University of Strasbourg | Stephan A.,University of Strasbourg | Matifas A.,University of Strasbourg | And 6 more authors.
Behavioural Brain Research | Year: 2015

The delta opioid receptor (DOR) has raised much interest for the development of new therapeutic drugs, particularly to treat patients suffering from mood disorders and chronic pain. Unfortunately, the prototypal DOR agonist SNC80 induces mild epileptic seizures in rodents. Although recently developed agonists do not seem to show convulsant properties, mechanisms and neuronal circuits that support DOR-mediated epileptic seizures remain to be clarified. DORs are expressed throughout the nervous system. In this study we tested the hypothesis that SNC80-evoked seizures stem from DOR activity at the level of forebrain GABAergic transmission, whose inhibition is known to facilitate the development of epileptic seizures. We generated a conditional DOR knockout mouse line, targeting the receptor gene specifically in GABAergic neurons of the forebrain (Dlx-DOR). We measured effects of SNC80 (4.5, 9, 13.5 and 32. mg/kg), ARM390 (10, 30 and 60. mg/kg) or ADL5859 (30, 100 and 300. mg/kg) administration on electroencephalograms (EEGs) recorded in Dlx-DOR mice and their control littermates (Ctrl mice). SNC80 produced dose-dependent seizure events in Ctrl mice, but these effects were not detected in Dlx-DOR mice. As expected, ARM390 and ADL5859 did not trigger any detectable change in mice from both genotypes. These results demonstrate for the first time that SNC80-induced DOR activation induces epileptic seizures via direct inhibition of GABAergic forebrain neurons, and supports the notion of differential activities between first and second-generation DOR agonists. © 2014 .

Bertolizio G.,Perioperative and Pain Medicine | Dinardo J.A.,Perioperative and Pain Medicine | Laussen P.C.,Perioperative and Pain Medicine | Polito A.,Perioperative and Pain Medicine | And 3 more authors.
Journal of Cardiothoracic and Vascular Anesthesia | Year: 2015

Objective Superior vena cava pressure after the bidirectional Glenn operation usually is higher than that associated with the preceding shunt-dependent circulation. The aim of the present study was to determine whether the acute elevation in central venous pressure was associated with changes in cerebral oxygenation and perfusion. Design Single-center prospective, observational cohort study. Setting Academic children's hospital. Participants Infants with single-ventricle lesions and surgically placed systemic-to-pulmonary artery shunts undergoing the bidirectional Glenn operation. Interventions Near-infrared spectroscopy and transcranial Doppler sonography were used to measure regional cerebral oxygen saturation and cerebral blood flow velocity. Measurements and Main Results Mean differences in regional cerebral oxygen saturation and cerebral blood flow velocity before anesthetic induction and shortly before hospital discharge were compared using the F-test in repeated measures analysis of variance. In the 24 infants studied, mean cerebral oxygen saturation increased from 49%±2% to 57%±2% (p = 0.007), mean cerebral blood flow velocity decreased from 57±4 cm/s to 47±4 cm/s (p = 0.026), and peak systolic cerebral blood flow velocity decreased from 111±6 cm/s to 99±6 cm/s (p = 0.046) after the bidirectional Glenn operation. Mean central venous pressure was 8±2 mmHg postinduction of anesthesia and 14±4 mmHg on the first postoperative day and was not associated with a change in cerebral perfusion pressure (p = 0.35). Conclusions The bidirectional Glenn operation in infants with a shunt-dependent circulation is associated with an improvement in cerebral oxygenation, and the lower cerebral blood flow velocity is likely a response of intact cerebral autoregulation. © 2014 Elsevier Inc.

Gaillard S.,Aix - Marseille University | Lo L.R.,Aix - Marseille University | Mantilleri A.,Aix - Marseille University | Hepp R.,Paris-Sorbonne University | And 20 more authors.
Neuron | Year: 2014

One feature of neuropathic pain is a reduced GABAergic inhibitory function. Nociceptors have been suggested to play a key role in this process. However, the mechanisms behind nociceptor-mediated modulation of GABA signaling remain to be elucidated. Here we describe the identification of GINIP, aGαi-interacting protein expressed in two distinct subsets of nonpeptidergic nociceptors. GINIP null mice develop a selective and prolonged mechanical hypersensitivity in models of inflammation and neuropathy. GINIP null mice show impaired responsiveness to GABAB, but not to delta or mu opioid receptor agonist-mediated analgesia specifically in the sparednerve injury (SNI) model. Consistently, GINIP-deficientdorsal root ganglia neurons had lower baclofen-evoked inhibition of high-voltage-activated calcium channels and a defective presynaptic inhibition of lamina IIi interneurons. These results further support the role of unmyelinated C fibers in injury-induced modulation of spinal GABAergic inhibition and identify GINIP as a key modulator of peripherally evoked GABAB-receptors signaling. © 2014 Elsevier Inc.

Mehta N.M.,Critical Care Medicine | Mehta N.M.,Boston Childrens Hospital | Mehta N.M.,Harvard University | Bechard L.J.,Boston Childrens Hospital | And 7 more authors.
American Journal of Clinical Nutrition | Year: 2015

Background: The impact of protein intake on outcomes in pediatric critical illness is unclear. Objective: We examined the association between protein intake and 60-d mortality in mechanically ventilated children. Design: In a prospective, multicenter, cohort study that included 59 pediatric intensive care units (PICUs) from 15 countries, we enrolled consecutive children (age: 1 mo to 18 y) who were mechanically ventilated for ≥48 h. We recorded the daily and cumulative mean adequacies of energy and protein delivery as a percentage of the prescribed daily goal during the PICU stay ≤10 d. We examined the association of the adequacy of protein delivery with 60-d mortality and determined variables that predicted protein intake adequacy. Results: We enrolled 1245 subjects (44% female) with a median age of 1.7 y (IQR: 0.4, 7.0 y). A total of 985 subjects received enteral nutrition, 354 (36%) of whom received enteral nutrition via the postpyloric route. Mean ± SD prescribed energy and protein goals were 69 ± 28 kcal/kg per day and 1.9 ± 0.7 g/kg per day, respectively. The mean delivery of enteral energy and protein was 36 ± 35% and 37 ± 38%, respectively, of the prescribed goal. The adequacy of enteral protein intake was significantly associated with 60-d mortality (P < 0.001) after adjustment for disease severity, site, PICU days, and energy intake. In relation to mean enteral protein intake <20%, intake ≥60% of the prescribed goal was associated with an OR of 0.14 (95% CI: 0.04, 0.52; P = 0.003) for 60-d mortality. Early initiation, postpyloric route, shorter interruptions, larger PICU size, and a dedicated dietitian in the PICU were associated with higher enteral protein delivery. Conclusions: Delivery of >60% of the prescribed protein intake is associated with lower odds of mortality in mechanically ventilated children. Optimal prescription and modifiable practices at the bedside might enhance enteral protein delivery in the PICU with a potential for improved outcomes. © 2015 American Society for Nutrition.

Murthy S.,University of Pennsylvania | Hepner D.L.,Perioperative and Pain Medicine | Cooper Z.,Brigham and Women's Hospital | Bader A.M.,Perioperative and Pain Medicine | Neuman M.D.,University of Pennsylvania
British Journal of Anaesthesia | Year: 2015

As the population of the world is rapidly ageing, the amount of surgery being performed in older patients is also increasing. Special attention is required for the anaesthetic and perioperative management of these patients. The clinical and non-clinical issues specific to older surgical patients are reviewed, with a special emphasis on areas of debate related to anaesthesia care in this group. These issues include the role of frailty and disability in preoperative assessment, choice of anaesthesia technique for hip fracture, postoperative delirium, and approaches to shared decision-making before surgical procedures. © 2015 The Author.

PubMed | Perioperative and Pain Medicine and Stanford University
Type: Journal Article | Journal: Journal of clinical pharmacology | Year: 2016

Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, 2-center clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight, 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot liquid chromatography-tandem mass spectrometry assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. The clearance of morphine and glucuronide metabolites was best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5-kg neonate, morphine clearance was 0.77 L/h (CV, 48%), and the steady-state volume of distribution was 8.0 L (CV, 49%). Compared with previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10 and 40 ng/mL. An optimized morphine loading dose of 50 g/kg followed by a continuous infusion of 5 g/kg/h was predicted across birthweights.

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