Luciana Paula Cadore Stefani

Clinical efficacy of dexmedetomidine alone is less than propofol for conscious sedation during ERCP

BACKGROUND Propofol is an accepted method of sedation for an ERCP and generally achieves deep sedation rather than conscious sedation, and dexmedetomidine has sedative properties of equivalent efficacy. OBJECTIVE To examine the hypothesis that dexmedetomidine is as effective as propofol combined with fentanyl for providing conscious sedation during an ERCP. DESIGN AND SETTING Randomized, blind, double-dummy clinical trial. PATIENTS Twenty-six adults, American Society of Anesthesiologists status I to III, underwent an ERCP. INTERVENTIONS Patients were randomized to receive either propofol (n = 14) (target plasma concentration range 2-4 microg/mL) combined with fentanyl 1 microg/kg, or dexmedetomidine (n = 12) 1 microg/kg for 10 minutes, followed by 0.2 to 0.5 microg/kg/min. Additional sedatives were used if adequate sedation was not achieved at the maximum dose allowed. MAIN OUTCOMES MEASUREMENTS The sedation level was assessed by the Richmond alertness-sedation scale and the demand for additional sedatives. Furthermore, heart rate, blood pressure, oxygen saturation, and respiratory rate were continuously assessed. RESULTS The relative risk (RR) was 2.71 (95% CI, 1.31-5.61) and the number of patients that needed to be treated (NNT) was 1.85 (95% CI, 1.19-4.21) to observe one additional patient with drowsiness 15 minutes after sedation in the dexmedetomidine group. Also, the RR was 9.42 (95% CI, 1.41-62.80), and the NNT was 1.42 (95% CI, 1.0-2.29) to require additional analgesic. However, there was also a greater reduction in blood pressure, a lower heart rate, and greater sedation after the procedure. CONCLUSIONS Dexmedetomidine alone was not as effective as propofol combined with fentanyl for providing conscious sedation during an ERCP. Furthermore, dexmedetomidine was associated with greater hemodynamic instability and a prolonged recovery.

Validation of a Brazilian quantitative sensory testing (QST) device for the diagnosis of small fiber neuropathies.

Quantitative sensory testing (QST) is defined as the determination of thresholds for sensory perception under controlled stimulus. Our aim was to validate a new QST device for Brazilian sample. In 20 healthy adults, thermoalgesic thresholds were assessed using a QST prototype (Heat Pain Stimulator-1.1.10; Brazil). A 30 × 30 mm(2) thermode with a 1°C/s stimulus change rate were applied. Thresholds of three consecutive stimuli were averaged in two different sessions separated by at least two weeks. Additionally long thermal heat pain stimulus was performed. To evaluate the consistency of our method we also analyzed 11 patients with small fiber neuropathy. Results showed good reproducibility of thermal perception thresholds in normal individuals and plausible abnormal thresholds in patients. We conclude that our QST device is reliable when analyzing the nociceptive pathway in controls and patients.

BDNF as an effect modifier for gender effects on pain thresholds in healthy subjects

BDNF is an important marker of neuronal plasticity. It has also been associated with pain processing. Increased BDNF levels are observed in chronic pain syndromes. In order to understand the role of BDNF associated with other factors such as gender on experimental pain we aimed to determine whether experimental heat or pressure pain threshold is correlated with brain derived neurotrophic factor (BDNF) level, gender and age. Heat pain threshold and pressure pain threshold were measured in 49 healthy volunteers (27 females). The multivariate linear regression models (on heat and pressure pain thresholds) revealed a significant effect of gender (p=0.001 for both models), serum BDNF (p<0.004 for both models) and interaction between BDNF and gender (<0.001 for both models). In fact, when adjusting for BDNF levels and age, heat and pressure pain thresholds were significantly reduced in women as compared to men (p<0.001 for both models). These effects were not observed when gender was analyzed alone. These finding suggests that experimental heat and pressure pain threshold is gender-related and BDNF dependent. In fact BDNF has a facilitatory effect on pain threshold in females but has an opposite effect in males; supporting the notion that BDNF is an effect modifier of the gender effects on pain threshold in healthy subjects.

Pain–autonomic interaction after work-induced sleep restriction

Poor sleep is commonly associated with alterations in pain perception. However, there is a lack of studies that address work‐associated sleep restriction (SR) and changes in non‐nociceptive perception and autonomic responses after work‐induced SR.

A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

Background Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. Results Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 0.584 for PPTo). Conclusions The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre.

Combined neuromodulatory interventions in acute experimental pain: assessment of melatonin and non-invasive brain stimulation.

Transcranial direct current stimulation (tDCS) and melatonin can effectively treat pain. Given their potentially complementary mechanisms of action, their combination could have a synergistic effect. Thus, we tested the hypothesis that compared to the control condition and melatonin alone, tDCS combined with melatonin would have a greater effect on pain modulatory effect, as assessed by quantitative sensory testing (QST) and by the pain level during the Conditioned Pain Modulation (CPM)-task. Furthermore, the combined treatment would have a greater cortical excitability effect as indicated by the transcranial magnetic stimulation (TMS) and on the serum BDNF level. Healthy males (n = 20), (aged 18–40 years), in a blinded, placebo-controlled, crossover, clinical trial, were randomized into three groups: sublingual melatonin (0.25 mg/kg) + a-tDCS, melatonin (0.25 mg/kg) + sham-(s)-tDCS, or sublingual placebo+sham-(s)-tDCS. Anodal stimulation (2 mA, 20 min) was applied over the primary motor cortex. There was a significant difference in the heat pain threshold (°C) for melatonin+a-tDCS vs. placebo+s-tDCS (mean difference: 4.86, 95% confidence interval [CI]: 0.9 to 8.63) and melatonin+s-tDCS vs. placebo+s-tDCS (mean: 5.16, 95% CI: 0.84 to 8.36). There was no difference between melatonin+s-tDCS and melatonin+a-tDCS (mean difference: 0.29, 95% CI: −3.72 to 4.23). The mean change from the baseline on amplitude of motor evocate potential (MEP) was significantly higher in the melatonin+a-tDCS (−19.96% ± 5.2) compared with melatonin+s-tDCS group (−1.36% ± 5.35) and with placebo+s-tDCS group (3.61% ± 10.48), respectively (p < 0.05 for both comparisons). While melatonin alone or combined with a-tDCS did not significantly affect CPM task result, and serum BDNF level. The melatonin effectively reduced pain; however, its association with a-tDCS did not present an additional modulatory effect on acute induced pain.

Derivation and validation of a preoperative risk model for postoperative mortality (SAMPE model) : an approach to care stratification

Ascertaining which patients are at highest risk of poor postoperative outcomes could improve care and enhance safety. This study aimed to construct and validate a propensity index for 30-day postoperative mortality. A retrospective cohort study was conducted at Hospital de Clínicas de Porto Alegre, Brazil, over a period of 3 years. A dataset of 13524 patients was used to develop the model and another dataset of 7254 was used to validate it. The primary outcome was 30-day in-hospital mortality. Overall mortality in the development dataset was 2.31% [n = 311; 95% confidence interval: 2.06–2.56%]. Four variables were significantly associated with outcome: age, ASA class, nature of surgery (urgent/emergency vs elective), and surgical severity (major/intermediate/minor). The index with this set of variables to predict mortality in the validation sample (n = 7253) gave an AUROC = 0.9137, 85.2% sensitivity, and 81.7% specificity. This sensitivity cut-off yielded four classes of death probability: class I, <2%; class II, 2–5%; class III, 5–10%; class IV, >10%. Model application showed that, amongst patients in risk class IV, the odds of death were approximately fivefold higher (odds ratio 5.43, 95% confidence interval: 2.82–10.46) in those admitted to intensive care after a period on the regular ward than in those sent to the intensive care unit directly after surgery. The SAMPE (Anaesthesia and Perioperative Medicine Service) model accurately predicted 30-day postoperative mortality. This model allows identification of high-risk patients and could be used as a practical tool for care stratification and rational postoperative allocation of critical care resources.

Electrical Intramuscular Stimulation in Osteoarthritis Enhances the Inhibitory Systems in Pain Processing at Cortical and Cortical Spinal System.

OBJECTIVE To determine if in knee osteoarthritis (KOA), one session of active electrical intramuscular stimulation (a-EIMS) compared with sham causes an effect on the motor cortex excitability parameters [motor evoked potential (MEP; the primary outcome), short intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP)] and pain measurements [pain pressure threshold (PPT); visual analog scale (VAS) and change in numerical pain scale (NPS0-10 ) during the conditioned pain modulation (CPM)-task]. This study also set out to determine if serum brain-derived neurotrophic factor (BDNF) mediates the effect of treatment on the cortical spinal system as assessed by MEP and PPT. DESIGN Randomized clinical trial. SUBJECTS AND METHODS Women with KOA, 50-75-years old received a 30-min session of either sham (n = 13) or a-EIMS (n = 13) with 2 Hz. The pain measures and excitability parameters were measured before and immediately after a-EIMS or sham. RESULTS The a-EIMS group compared with sham decreased the MEP by 31,67% [confidence interval (CI) 95%, 2.34-60.98]. For the secondary outcomes, the a-EIMS reduced the ICF and increased the CSP but not changed the SICI. The a-EIMS improved the pain reported on VAS, the PPT, and the score of the NPS (0-10) during the CPM-task The BDNF was negatively correlated with the PPT (r = -0.56). CONCLUSIONS The serum BDNF revealed an inverse relationship with PPT independent of the treatment group. These results suggest that a-EIMS enhanced the corticospinal inhibitory systems in cortical and infracortical pain processing sites most likely by bottom-up regulation mechanisms.

Effects of Transcranial Direct Current Stimulation Block Remifentanil-Induced Hyperalgesia: A Randomized, Double-Blind Clinical Trial

Background: Remifentanil-induced hyperalgesia (r-IH) involves an imbalance in the inhibitory and excitatory systems. As the transcranial Direct Current Stimulation (tDCS) modulates the thalamocortical synapses in a top-down manner, we hypothesized that the active (a)-t-DCS would be more effective than sham(s)-tDCS to prevent r-IH. We used an experimental paradigm to induce temporal summation of pain utilizing a repetitive cold test (rCOLDT) assessed by the Numerical Pain Score (NPS 0-10) and we evaluated the function of the descending pain modulatory system (DPMS) by the change on the NPS (0–10) during the conditioned pain modulation (CPM)-task (primary outcomes). We tested whether a-tDCS would be more effective than s-tDCS to improve pain perception assessed by the heat pain threshold (HPT) and the reaction time during the ice-water pain test (IPT) (secondary outcomes). Methods: This double-blinded, factorial randomized trial included 48 healthy males, ages ranging 19–40 years. They were randomized into four equal groups: a-tDCS/saline, s-tDCS/saline, a-tDCS/remifentanil and s-tDCS/remifentanil. tDCS was applied over the primary motor cortex, during 20 min at 2 mA, which was introduced 10 min after starting remifentanil infusion at 0.06 μg⋅kg-1⋅min-1 or saline. Results: An ANCOVA mixed model revealed that during the rCOLDT, there was a significant main effect on the NPS scores (F = 3.81; P = 0.01). The s-tDCS/remifentanil group presented larger pain scores during rCOLDT, [mean (SD) 5.49 (1.04)] and a-tDCS/remifentanil group had relative lower pain scores [4.15 (1.62)]; showing its blocking effect on r-IH. a-tDCS/saline and s-tDCS/saline groups showed lowest pain scores during rCOLDT, [3.11 (1.2)] and [3.15 (1.62)], respectively. The effect of sedation induced by remifentanil during the rCOLDT was not significant (F = 0.76; P = 0.38). Remifentanil groups showed positive scores in the NPS (0–10) during the CPM-task, that is, it produced a disengagement of the DPMS. Also, s-tDCS/Remifentanil compared to a-tDCS showed lower HPT and larger reaction-time during the IPT. Conclusion: These findings suggest that effects of a-tDCS prevent the summation response induced by r-IH during rCOLDT and the a-tDCS blocked the disengagement of DPMS. Thereby, tDCS could be considered as a new approach to contra-regulate paradoxical mechanisms involved in the r-IH. Clinical trials identification: NCT02432677. URL:https://clinicaltrials.gov/.

Preoperative transcranial direct current stimulation: Exploration of a novel strategy to enhance neuroplasticity before surgery to control postoperative pain. A randomized sham-controlled study

Background An imbalance in the excitatory/inhibitory systems in the pain networks may explain the persistent chronic pain after hallux valgus surgery. Thus, to contra-regulate this dysfunction, the use of transcranial direct current stimulation (tDCS) becomes attractive. Objective We tested the hypothesis that two preoperative active(a)-tDCS sessions compared with sham(s)-tDCS could improve the postoperative pain [as indexed by Visual Analogue Scale (VAS) at rest and during walking (primary outcomes)]. To assess their effect on the change in the Numerical Pain Scale (NPS0-10) during Conditioned Pain Modulation (CPM-task), disability related to pain (DRP) and analgesic consumption (secondary outcomes). Also, we assessed if the brain derived neurotrophic factor (BDNF) in the cerebral spinal fluid (CSF) after tDCS could predict the intervention’s effect on the DRP. Methods It is a prospective, double blind, sham-controlled, randomized single center, 40 women (18–70 years-old) who had undergone hallux valgus surgery were randomized to receive two sessions (20 minutes each) of anodal a-tDCS or s-tDCS on the primary motor cortex at night and in the morning before the surgery. To assess the DRP was used the Brazilian Profile of Chronic Pain: Screen (B-PCP:S). Results A-tDCS group showed lower scores on VAS at rest and during walking (P<0.001). At rest, the difference between groups was 2.13cm (95%CI = 1.59 to 2.68) while during walking was 1.67cm (95%CI = 1.05 to 2.28). A-tDCS, when compared to s-tDCS reduced analgesic doses in 73.25% (P<0.001), produced a greater reduction in B-PCP:S (mean difference of 9.41 points, 95%CI = 0.63 to 18.21) and higher function of descending pain modulatory system (DPMS) during CPM-task. Conclusion A-tDCS improves postoperative pain, the DRP and the function of DPMS. Also, the CSF BDNF after a-tDCS predicted the improvement in the DRP. In overall, these findings suggest that a-tDCS effects may be mediated by top-down regulatory mechanisms associated with the inhibitory cortical control. Trial registration ClinicalTrials.gov NCT02360462