Assessing the antinociceptive effect of nitrous oxide to tetanic stimulation in anaesthetised patients with new intra-operative nociception monitors: An observational study.

BACKGROUND: Nitrous oxide (N2O) has been used since the 19th century for its analgesic, antinociceptive and anxiolytic effects during surgical procedures in awake and anaesthetised patients. However, quantification of noxious stimuli that occur under general anaesthesia is a constant challenge for anaesthesiologists, and recently two new indices have been developed to assess intra-operative nociception. OBJECTIVE: The aim of this study was to quantify with new indices as well as with more classical clinical parameters the antinociceptive effect of N2O during general anaesthesia. DESIGN: Prospective, open label, patient-blinded, observational and descriptive trial. SETTING: Single-centre academic hospital. PARTICIPANTS: Forty American Society of Anesthesiologists' physical status 1 to 3 patients undergoing general anaesthesia for elective abdominal surgery via laparotomy were recruited. MAIN OUTCOMES MEASURES: Intra-operative pain was assessed using a standardised electrical stimulation of the forearm (tetanic stimulation at 70 mA, 100 Hz for 30 s), at 0, 25 and 50% inhaled N2O/O2. Heart rate (HR), mean arterial blood pressure, bispectral index, the analgesia nociception index and the nociception level (NOL) index were used to evaluate intra-operative nociception before and after each standardised tetanic stimulation. RESULTS: There was a 16% reduction of the analgesia nociception index reaction, a 31% reduction of the NOL reaction and a 51% reduction of the HR reaction to a standardised electrical tetanic nociceptive stimulation during administration of 50% N2O. Administration of 50 or 25% inhaled N2O produced the same quality of antinociception based on HR and NOL index analyses. HR and the NOL index were the best parameters to identify the antinociceptive effect of intra-operatively administered N2O. CONCLUSION: In anaesthetised patients, our study demonstrated clinically significant antinociceptive properties of N2O. Our results showed that low concentrations of N2O (25%) are as effective as higher concentrations (50%) to achieve a significant antinociceptive effect. These findings may help decrease negative effects of using higher concentrations of N2O, including its side effects and its environmental pollution. TRIAL REGISTRATION: ClinicalTrials.gov registration identifier: NCT02701478.

Impact of intravenous phenylephrine bolus administration on the nociceptive level index (NOL).

Recently, the nociceptive level index (NOL) was shown to more specifically and sensitively detect noxious stimuli during anesthesia, in comparison to previous methods that relied on such parameters as heart rate (HR) and mean blood pressure (MAP). An ongoing study (NCT#03410485) evaluates the intraoperative combination of both NOL and bispectral (BIS) indices to improve quality of recovery after colorectal surgery. Our ethical committee (REB approval #CER15083) initially agreed on an interim analysis of the data from the first 30 patients. More specifically, this present report analyzed all the intravenous phenylephrine (PE) boluses administered during anesthesia as part of our study protocol to see whether they had a significant impact on NOL values as well as other parameters: HR, MAP, BIS index. For this trial, remifentanil and phenylephrine were given in both groups based on a specific algorithm. All study parameters were recorded electronically. Our analysis for the present specific outcome evaluated NOL index for 30 s before the intravenous PE bolus (1 µg kg-1) was given and until 5 min afterwards. The average NOL values after PE bolus, as well as MAP, HR and BIS indices, were recorded and analyzed. A total of 178 events of PE boluses were identified for 28 patients (two were excluded). Median baseline NOL was 3 (1.8-8.3) CI 95% 5.7-8.7; post-PE bolus: 5.3 (2.7-9.9) (95% CI 6.6-8.9; Wilcoxon matched-pairs signed rank test (WMPSRT), P = 0.0003). When analyzing delta NOL (difference between pre- and post-PE bolus in NOL values) for each patient, the median delta NOL was 2.9 (1.2-6.1) (95% CI 3.6-5.5) with 95% of the subjects keeping a delta NOL under 10. MAP and HR values showed expected significant variations after PE bolus: a slight increase and slight decrease, respectively. BIS index values did not change after PE bolus. Our present results demonstrate that intravenous phenylephrine boluses of 1 µg kg-1 had the expected impact on hemodynamic parameters: a significant but very slight increase in MAP and decrease in HR, which might lack clinical relevance. Our report also demonstrates that these same phenylephrine boluses induce a statistically significant increase of the NOL index which does not seem to have much of a clinical relevance for the novel NOL index used to monitor intraoperative nociception as well as for the more classical BIS index for depth of anesthesia. Nevertheless, doses of intravenous PE bolus used in the present study (1 µg kg-1) might be regarded as smaller than more conventional ones (100-200 µg per bolus). Further studies need to be done with the latter doses.

Deep brain stimulation for Gilles de la Tourette syndrome in children and youth: a meta-analysis with individual participant data.

Objective: Gilles de la Tourette syndrome (GTS) is a disorder characterized by motor and vocal tics. Although by definition the onset of GTS is before age 18 years, clinical trials of deep brain stimulation (DBS) have been conducted only in adults. Using individual participant data (IPD) meta-analysis methodology, the current study investigated the safety and efficacy of DBS as a treatment for GTS in children and youth. Methods: A systematic review with no date or language restrictions was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Three electronic databases were searched: PubMed, EMBASE, and Web of Science. From 843 articles screened, the IPD of 58 children and youth (ages 12­21 years) extracted from 21 articles were collected and analyzed. A mixed-effects univariable analysis followed by multivariable hierarchical regression was performed using change in the Yale Global Tic Severity Scale (YGTSS) score as the primary outcome and reported measures of comorbidities as secondary outcomes. Results: The authors' results showed an average improvement of 57.5% ± 24.6% across studies on the YGTSS. They also found that comorbid depression and stimulation pulse width each correlated negatively with outcome (p < 0.05). In patients with less severe GTS, greater improvements were evident following thalamic stimulation. More than one-quarter (n = 16, 27.6%) of participants experienced side effects, the majority of which were minor. Conclusions: DBS in the pediatric population may be an effective option with a moderate safety profile for treatment of GTS in carefully selected children and youth. Large, prospective studies with long-term follow-up are necessary to understand how DBS influences tic symptoms and may alter the natural course of GTS in children.

Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia.

Fibromyalgia (FM) syndrome is characterized by chronic widespread pain, muscle tenderness and emotional distress. Previous studies found reduced endogenous pain modulation in FM. This deficiency of pain modulation may be related to the attributes of chronic pain and other clinical symptoms experienced in patients with FM. Thus, we tested whether there is a link between the clinical symptoms of FM and functional connectivity (FC) of the periaqueductal gray (PAG), a key node of pain modulation. We acquired resting state 3T functional MRI (rsfMRI) data from 23 female patients with FM and 16 age- and sex- matched healthy controls (HC) and assessed FM symptoms with the Brief Pain Inventory (BPI), Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS) and Pain Catastrophizing Scale (PCS). We found that patients with FM exhibit statistically significant disruptions in PAG FC, particularly with brain regions implicated in negative affect, self-awareness and saliency. Specifically, we found that, compared to HCs, the FM patients had stronger PAG FC with the lingual gyrus and hippocampus but weaker PAG FC with regions associated with motor/executive functions, the salience (SN) and default mode networks (DMN). The attenuated PAG FC was also negatively correlated with FIQ scores, and positively correlated with the magnification subscale of the PCS. These alterations were correlated with emotional and behavioral symptoms of FM. Our study implicates the PAG as a site of dysfunction contributing to the clinical manifestations and pain in FM.

Intrinsic functional connectivity of periaqueductal gray subregions in humans.

The periaqueductal gray matter (PAG) is a key brain region of the descending pain modulation pathway. It is also involved in cardiovascular functions, anxiety, and fear; however, little is known about PAG subdivisions in humans. The aims of this study were to use resting-state fMRI-based functional connectivity (FC) to parcellate the human PAG and to determine FC of its subregions. To do this, we acquired resting-state fMRI scans from 79 healthy subjects and (1) used a data-driven method to parcellate the PAG, (2) used predefined seeds in PAG subregions to evaluate PAG FC to the whole brain, and (3) examined sex differences in PAG FC. We found that clustering of the left and right PAG yielded similar patterns of caudal, middle, and rostral subdivisions in the coronal plane, and dorsal and ventral subdivisions in the sagittal plane. FC analysis of predefined subregions revealed that the ventolateral(VL)-PAG was supfunctionally connected to brain regions associated with descending pain modulation (anterior cingulate cortex (ACC), upper pons/medulla), whereas the lateral (L) and dorsolateral (DL) subregions were connected with brain regions implicated in executive functions (prefrontal cortex, striatum, hippocampus). We also found sex differences in FC including areas implicated in pain, salience, and analgesia including the ACC and the insula in women, and the MCC, parahippocampal gyrus, and the temporal pole in men. The organization of the human PAG thus provides a framework to understand the circuitry underlying the broad range of responses to pain and its modulation in men and women.

The periaqueductal gray and descending pain modulation: why should we study them and what role do they play in chronic pain?

In this Neuro Forum we discuss the significance of a recent study by Yu et al. (Neuroimage Clin 6: 100-108, 2014). The authors examined functional connectivity of a key node of the descending pain modulation pathway, the periaqueductal gray (PAG), in chronic back pain patients. Altered PAG connectivity to pain-related regions was found; we place results within the context of recent literature and emphasize the importance of understanding the descending component of pain in pain research.

Decreased drebrin mRNA expression in Alzheimer disease: correlation with tau pathology.

To investigate the mRNA expression of the dendritic spine protein drebrin in Alzheimer's disease (AD), we performed post-mortem in situ hybridization studies in brain sections from 20 AD patients and 21 controls. AD diagnosis was confirmed by decreased drebrin protein and increased Abeta(40) (+464%; P < 0.05), Abeta(42) (+369%; P < 0.0001), Abeta(42/40) ratio (+226%; P < 0.01), total tau (+2,725%; P < 0.0001), and paired helical filament tau (PHFtau; +867%; P < 0.001) compared with controls. We found significant decreases in drebrin mRNA in the parietal cortex (-27%; P < 0.01), the temporal cortex (-22%; P < 0.05), and the hippocampus (-25%; P < 0.05) of AD patients compared with controls. Cortical levels of drebrin mRNA correlated positively with soluble total tau (r(2) = +0.244) but negatively with duration of symptoms (r(2) = -0.357) and PHFtau (r(2) = -0.248). Drebrin mRNA levels were correlated to a lesser degree with the drebrin protein content (r(2) = +0.136) and with sim2 (r(2) = +0.176), a potential modulator of drebrin transcription. Our results suggest that the down-regulation of drebrin mRNA expression plays an important role in AD and is closely related to the progression of the disease.

Fluoroquinolones and risk for methicillin-resistant Staphylococcus aureus, Canada.

Receipt of fluoroquinolones was the predominant risk factor for Clostridium difficile-associated disease (CDAD) during an epidemic in Quebec, Canada. To determine the role of antimicrobial drugs in facilitating healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection and to compare this role with their effects on methicillin-susceptible S. aureus infection and CDAD, we conducted a retrospective cohort study of patients in a Quebec hospital. For 7371 episodes of care, data were collected on risk factors, including receipt of antimicrobial drugs. Crude and adjusted hazard ratios (AHR) were calculated by Cox regression. Of 150 episodes of MRSA colonization and 23 of MRSA infection, fluoroquinolones were the only antimicrobials that increased risk for colonization (AHR 2.57, 95% confidence interval [CI] 1.84-3.60) and infection (AHR 2.49, 95% CI 1.02-6.07). Effect of antimicrobial drugs on MRSA colonization and infection was similar to effect on CDAD and should be considered when selecting antimicrobial drugs to treat common infections.

Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec.

BACKGROUND: Since 2002, an epidemic of Clostridium difficile-associated-diarrhea (CDAD) associated with a high case-fatality rate has involved >30 hospitals in the province of Quebec, Canada. In 2003, a total of 55% of patients with CDAD at our hospital had received fluoroquinolones in the preceding 2 months. It has been suggested that massive use of proton pump inhibitors might have facilitated this epidemic. METHODS: To delineate the risk of CDAD associated with specific classes of antibiotics and whether this is modulated by concomitant use of proton pump inhibitors and other drugs altering gastric acidity or gastrointestinal motility, we conducted a retrospective cohort study of patients hospitalized in a teaching hospital in Sherbrooke, Canada, during the period of January 2003 through June 2004. We obtained data on 7421 episodes of care corresponding to 5619 individuals. Patients were observed until they either developed CDAD or died or for 60 days after discharge from the hospital. Adjusted hazard ratios (AHRs) were calculated using Cox regression. RESULTS: CDAD occurred in 293 patients. Fluoroquinolones were the antibiotics most strongly associated with CDAD (AHR, 3.44; 95% confidence interval [CI], 2.65-4.47). Almost one-fourth of all inpatients received quinolones, for which the population-attributable fraction of CDAD was 35.9%. All 3 generations of cephalosporins, macrolides, clindamycin, and intravenous beta-lactam/beta-lactamase inhibitors were intermediate-risk antibiotics, with similar AHRs (1.56-1.89). Proton pump inhibitors (AHR, 1.00, 95% CI, 0.79-1.28) were not associated with CDAD. CONCLUSIONS: Administration of fluoroquinolones emerged as the most important risk factor for CDAD in Quebec during an epidemic caused by a hypervirulent strain of C. difficile.