Simulation scripts: update 1

<p>Scripts used to simulate and analyze the hypothetical pharmacokinetic model data. The aici.R and aicp.R scripts have been updated from http://dx.doi.org/10.6084/m9.figshare.157246.</p

Simulation scripts

<p>Scripts used to simulate and analyze the hypothetical pharmacokinetic model data</p

Datasheet1_Effect of spinal anesthesia-induced deafferentation on pain processing in healthy male volunteers: A task-related fMRI study.pdf

BackgroundSpinal anesthesia causes short-term deafferentation and alters the crosstalk among brain regions involved in pain perception and pain modulation. In the current study, we examined the effect of spinal anesthesia on pain response to noxious thermal stimuli in non-deafferented skin areas using a functional magnetic resonance imaging (fMRI) paradigm.MethodsTwenty-two healthy subjects participated in the study. We performed a task-based fMRI study using a randomized crossover design. Subjects were scanned under two conditions (spinal anesthesia or control) at two-time points: before and after spinal anesthesia. Spinal anesthesia resulted in sensory loss up to dermatome Th6. Calibrated heat-pain stimuli were administered to the right forearm (C8-Th1) using a box-car design (blocks of 10s on/25s off) during MRI scanning. Pain perception was measured using a visual analogue scale (1–100) at the beginning and the end of each session. Generalized estimating equations were used to examine the effect of intervention by time by order on pain scores. Similarly, higher-level effects were tested with appropriate general linear models (accounting for within-subject variations in session and time) to examine: (1) Differences in BOLD response to pain stimulus under spinal anesthesia versus control; and (2) Effects of spinal anesthesia on pain-related modulation of the cerebral activation.ResultsComplete fMRI data was available for eighteen participants. Spinal anesthesia was associated with moderate pain score increase. Significant differences in brain response to noxious thermal stimuli were present in comparison of spinal versus control condition (post—pre). Spinal condition was associated with higher BOLD signal in the bilateral inferior parietal lobule and lower BOLD signal in bilateral postcentral and precentral gyrus. Within the angular regions, we observed a positive correlation between pain scores and BOLD signal. These observations were independent from order effect (whether the spinal anesthesia was administered in the first or the second visit). However, we did observe order effect on brain regions including medial prefrontal regions, possibly related to anticipation of the experience of spinal anesthesia.ConclusionsThe loss of sensory and motor activity caused by spinal anesthesia has a significant impact on brain regions involved in the sensorimotor and cognitive processing of noxious heat pain stimuli. Our results indicate that the anticipation or experience of a strong somatosensory response to the spinal intervention might confound and contribute to increased sensitivity to cognitive pain processing. Future studies must account for individual differences in subjective experience of pain sensation within the experimental context.</p

Mean eVAS responses following treatment with placebo (A), oral morphine immediate release 40 mg (B) and oral tapentadol immediate release 100 mg (C) at 60–90 min after drug intake.

<p>The blue dots are the responses to the test stimulus without conditioning stimulus, the orange dots the responses to the test stimulus with conditioning stimulus. The broken line is the mean temperature of the test stimulus. Values are ± SEM.</p

The setup used to induce Conditioned Pain Modulation (CPM).

<p>The volunteer sits on the bed while a thermal test stimulus is applied to the arm <i>via</i> a 3×3 cm thermode (insert top right). The leg is placed in a bucket filled with cold water (<i>ie</i>. the conditioning stimulus) and the subject scores the heat pain to the arm using an electronic visual analogue scale (insert top middle). The cold water is applied via the Icydip system; the heat pain via Medoc’s pathway system.</p

Consort flow diagram.

<p>The test stimulus temperatures (heat pain) as determined prior to treatment averaged to 47 ± 0.5°C, 46.6 ± 0.5°C and 46.9 ± 0.5°C on placebo, morphine and tapentadol experimental sessions (one-way anova: NS). The target conditioning stimulus temperatures were 7.9 ± 0.5°C, 8.1 ± 0.6°C and 8.3 ± 0.6°C on placebo, morphine and tapentadol experimental sessions (one-way anova: NS).</p

Impact of high- <i>versus</i> low-dose neuromuscular blocking agent administration on unplanned 30-day readmission rates in retroperitoneal laparoscopic surgery

<div><p>Recent data shows that a neuromuscular block (NMB) induced by administration of high doses of rocuronium improves surgical conditions in certain procedures. However, there are limited data on the effect such practices on postoperative outcomes. We performed a retrospective analysis to compare unplanned 30-day readmissions in patients that received high-dose <i>versus</i> low-dose rocuronium administration during general anesthesia for laparoscopic retroperitoneal surgery. This retrospective cohort study was performed in the Netherlands in an academic hospital where routine high-dose rocuronium NMB has been practiced since July 2015. Charts of patients receiving anesthesia between January 2014 and December 2016 were searched for surgical cases receiving high-dose rocuronium and matched with respect to procedure, age, sex and ASA classification to patients receiving low-dose rocuronium. The primary post-operative outcome was unplanned 30-day readmission rate. There were 130 patients in each cohort. Patients in the high- and low-dose rocuronium cohorts received 217 ± 49 <i>versus</i> 37 ± 5 mg rocuronium, respectively. In the high-dose rocuronium group neuromuscular activity was consistently monitored; matched patients were unreliably monitored. All patients receiving high-dose rocuronium were reversed with sugammadex, while just 33% of matched patients were reversed with sugammadex and 20% with neostigmine; the remaining patients were not reversed. Unplanned 30-day readmission rate was significantly lower in the high-dose compared to the low-dose rocuronium cohort (3.8% <i>vs</i>. 12.7%; p = 0.03; odds ratio = 0.33, 95% C.I. 0.12–0.95). This small retrospective study demonstrates a lower incidence of unplanned readmissions within 30-days following laparoscopic retroperitoneal surgery with high-dose relaxant anesthesia and sugammadex reversal in comparison to low-dose relaxant anesthesia. Further prospective studies are needed in larger samples to corroborate our findings and additionally assess the pharmacoeconomics of high-dose relaxant anesthesia taking into account the benefits (reduced readmissions) and harm (cost of relaxants and reversal agents) of such practice.</p></div

30-day unplanned readmission.

<p>30-day unplanned readmission.</p

Patient characteristics and retroperitoneal laparoscopic procedures.

<p>Patient characteristics and retroperitoneal laparoscopic procedures.</p

QRT-PCR primers and probes used in this study.

<p>Primers and probes used for the quantification of mRNA from NMDA receptor subtypes NR1, NR2A and NR2B (Grin); microglia marker Iba-1 (AIF-1), astrocyte (GFAP) and CCL2; f, Reporter dye1 (FAM:6-carboxyfluorescein); t, Reporter dye2 (TET:Tetrachloro-6-carboxyfluorescein); q, Quencher dye (TAMRA: 6-carboxytetramethyl1-rhodamine).</p