Bupivacaine inhibits the TLR4- and TLR2-Myd88/NF-κB pathways in human leukocytes.

Local anesthetics have anti-inflammatory effects. Because most previous experiments were performed with supra-therapeutic concentrations, we measured the effects of clinically relevant concentrations of bupivacaine on the Toll like receptor 4 (TLR4)- and TLR2-myeloid differentiation primary response 88 (MyD88)-nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathways. We measured tumor necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) release, p38 mitogen-activated protein kinase (MAP-kinase) phosphorylation and translocation of NF-κB in human peripheral blood mononuclear cells (hPBMCs) and human monocytes challenged with lipopolysaccharide (LPS) or tripalmitoylated lipopeptide Pam3CysSerLys4 (Pam3CSK4) in the presence or absence of bupivacaine. Similarly, we measured the effect of bupivacaine on HEK293 cells expressing the hTLR4 and the hTLR2 genes and challenged with LPS or Pam3CSK4. Finally, molecular docking simulations of R(+)- and S(-)-bupivacaine binding to the TLR4-myeloid differentiation protein 2 (MD-2) complex and to the TLR2/TLR1 heterodimer were performed. In PBMCs, bupivacaine from 0.1 to 100 µM inhibited LPS-induced TNF-α and PGE2 secretion, phosphorylation of p38 and nuclear translocation of NF-κB in monocytes. Bupivacaine similarly inhibited the effects of Pam3CSK4 on TNF-α secretion. Bupivacaine inhibited the effect of LPS on HEK293 cells expressing the human TLR4 receptor and the effect of Pam3CSK4 on HEK293 cells expressing the human TLR2 receptor. Molecular docking showed that bupivacaine binds to the MD-2 co-receptor of TLR4 and to the TLR2 receptor. Contrary to numerous experiments performed with supratherapeutic doses, our results were obtained with concentrations of bupivacaine as low as 0.1 µM. We conclude that bupivacaine modulates the inflammatory reactions such as those observed after surgery or trauma, at least partly by inhibiting the TLR4- and TLR2-NF-κB pathways.

Continuous Ropivacaine Peroneal Nerve Infiltration for Fibula Free Flap in Cervicofacial Cancer Surgery: A Randomized Controlled Study.

Introduction: Pain after cervicofacial cancer surgery with free flap reconstruction is both underestimated and undertreated. There is a rational for regional anesthesia at the flap harvest site, but few studies describe it. We assessed the influence of common peroneal nerve infiltration on pain and opioid consumption in patients having oropharyngeal cancer surgery with fibular free flap mandibular reconstruction. Methods: After institutional review board (IRB) approval and written informed consent, fifty-six patients were randomly allocated to perineural catheter with ropivacaine infiltration (ROPI) or systemic analgesia (CONTROL). In the ROPI group, an epidural catheter was placed by the surgeon before closure, and ropivacaine 0.2% 15 mL, followed by 4 mL/h during 48 h, was administered. The primary outcomes were pain scores and morphine consumption during the 48 h postoperative period. We also measured ropivacaine concentration at the end of infusion. Finally, we retrospectively assessed long-term pain up to 10 years using electronic medical charts. Results: Perineural infiltration of ropivacaine significantly reduced pain scores at the harvest site only at day 1, and did not influence overall postoperative opioid consumption. Ropivacaine assay showed a potentially toxic concentration in 50% of patients. Chronic pain was detected at the harvest site in only one patient (ROPI group), and was located in the cervical area in the case of disease progression. Discussion: Although the catheter was visually positioned by the surgeon, continuous ropivacaine infiltration of the common peroneal nerve did not significantly reduce postoperative pain, but induced a blood concentration close to the toxic threshold at day 2. Further studies considering other infiltration locations or other dosing schemes should be tested in this context, both to improve efficacy and reduce potential toxicity.

Antinociceptive properties of losmapimod in two acute pain models in rats: behavioural analysis, immunohistochemistry, dose response, and comparison with usual analgesic drugs.

Background: The p38 protein is a ubiquitous mitogen-activated protein kinase involved in the proinflammatory signalling pathway and in the pain response after various noxious stimuli. Many p38 inhibitors have been developed and shown to provide effective analgesia in animal models. They are, however, mainly administered intrathecally or intravenously. Our study aimed to evaluate losmapimod, a novel oral p38 inhibitor, in two murine acute pain models. Methods: Losmapimod (12 mg kg-1) was compared with paracetamol, ketamine, and morphine using thermal and mechanical stimulation after carrageenan injection. A dose-effect study was also performed with this model. Behavioural testing was also performed in a plantar incision model to confirm the analgesic effect of losmapimod. Expression of activated p38 in neurones, microglia, and astrocytes was also investigated at 2, 15, and 24 h after carrageenan injection. Results: Losmapimod was both antiallodynic and antihyperalgesic in the carrageenan pain model and provided an antinociceptive effect similar to that of morphine. The dose of 12 mg kg-1 was shown to be the ED78 and ED64 after thermal and mechanical stimulation, respectively. After plantar incision, losmapimod provided a significant antinociceptive effect. No life-threatening side-effect was observed in the behavioural study. Losmapimod prevented neurone and microglial activation at 2 and 15 h after carrageenan injection, respectively, but no effect was found on astrocytic activation. Conclusion: Losmapimod appears to be a promising drug in severe acute pain conditions. Losmapimod could also be helpful for postoperative pain control, as suggested by its effect after plantar incision.

Acute Visceral Pain in Rats: Vagal Nerve Block Compared to Bupivacaine Administered Intramuscularly.

BACKGROUND: Visceral and parietal peritoneum layers have different sensory innervations. Most visceral peritoneum sensory information is conveyed via the vagus nerve to the nucleus of the solitary tract (NTS). We already showed in animal models that intramuscular (i.m.) injection of local anesthetics decreases acute somatic and visceral pain and general inflammation induced by aseptic peritonitis. The goal of the study was to compare the effects of parietal block, i.m. bupivacaine, and vagotomy on spinal cord and NTS stimulation induced by a chemical peritonitis. METHODS: We induced peritonitis in rats using carrageenan and measured cellular activation in spinal cord and NTS under the following conditions, that is, a parietal nerve block with bupivacaine, a chemical right vagotomy, and i.m. microspheres loaded with bupivacaine. Proto-oncogene c-Fos (c-Fos), cluster of differentiation protein 11b (CD11b), and tumor necrosis factor alpha (TNF-α) expression in cord and NTS were studied. RESULTS: c-Fos activation in the cord was inhibited by nerve block 2 hours after peritoneal insult. Vagotomy and i.m. bupivacaine similarly inhibited c-Fos activation in NTS. Forty-eight hours after peritoneal insult, the number of cells expressing CD11b significantly increased in the cord (P = .010). The median difference in the effect of peritonitis compared to control was 30 cells (CI95, 13.5-55). TNF-α colocalized with CD11b. Vagotomy inhibited this microglial activation in the NTS, but not in the cord. This activation was inhibited by i.m. bupivacaine both in cord and in NTS. The median difference in the effect of i.m. bupivacaine added to peritonitis was 29 cells (80% increase) in the cord and 18 cells (75% increase) in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli by inhibiting c-Fos and microglia activation. CONCLUSIONS: In rats receiving intraperitoneal carrageenan, i.m. bupivacaine similarly inhibited c-Fos and microglial activation both in cord and in the NTS. Vagal block inhibited activation only in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli. This emphasizes the effects of systemic local anesthetics on inflammation and visceral pain.

Clinical, obstetrical and anaesthesia outcomes in pregnant women during the first COVID-19 surge in France: A prospective multicentre observational cohort study.

INTRODUCTION: Clinical outcomes and critical care utilisation associated with Coronavirus Disease 2019 (COVID-19) in obstetric patients remain limited particularly in relation to severe cases. METHODS: A retrospective multicentre cohort study was conducted during the first wave of COVID-19 in France in 18 tertiary referral maternity units. Consecutive women with confirmed or suspected COVID-19 during pregnancy or the delivery hospitalisation were included between March and July 2020 (17-week period). We report clinical, obstetrical and anaesthetic outcomes of pregnant women with COVID-19 and report the prevalence of severe forms and risk factors for respiratory support in this cohort. RESULTS: There were 126 included cases; RT-PCR testing occurred in 82 cases, of which 64 (78%) had a positive test. The caesarean section rate was 52%, and preterm delivery (< 37 weeks) rate was 40%. Neuraxial anaesthesia was performed in 108 (86%) cases with an increasing proportion compared to general anaesthesia over time (p < 0.0002). Twenty-eight cases received oxygen supplementation (nasal oxygen therapy or mechanical ventilation); the SOFAresp score was associated with gestational age at the time of COVID-19 presentation (p = 0.0036) and at delivery (p < 0.0001). Postpartum intensive care unit (ICU) admission occurred in 21 cases (17%) with 17 (13%) receiving invasive or non-invasive ventilation. Pre-delivery factors associated with postpartum ventilation were oxygen support, oxygen saturation and haemoglobin levels. CONCLUSION: In our cohort, COVID-19 was associated with significant maternal morbidity resulting in high ICU admission rates (17%) and invasive or non-invasive ventilation utilisation (10%).

Parietal Block Using Bupivacaine in the Rat: An Anatomical, Behavioral and Histological Study.

PURPOSE: Animal models of regional anaesthesia are useful for studying the effects of blocks and improve their efficacy. The aim of our experiments was to validate a multi-site paravertebral block in the rat. MATERIAL AND METHODS: Dissection and indigo carmine dye injection were performed in five rats (3 rats were dissected and 2 were dye injected). In other groups (n=7rats/group), after inflammation inductive carrageenan injection in the abdominal wall, bupivacaine or saline was injected laterally to the spinal column at the T5, T10, L1, L4 and S1 level. The efficacy of the block on mechanical nociception was measured using von Frey hairs. In addition, we measured c-Fos immunoreactive nuclei in the cord. RESULTS: The multi-site injection showed a perinervous distribution of the injected solution without intra-thoracic, intra-abdominal or epidural diffusion. Bilateral block with a relatively small volume of bupivacaine (0.5 mL) significantly increased the threshold to mechanical pain as compared to control (p=0.007) and significantly decreased the number of c-Fos immunoreactive nuclei in the posterior horn of the spinal cord (p<0.0001). CONCLUSION: This study shows that a parietal abdominal wall block is easy to perform in the rat. This block allows investigators to explore the mechanisms of action of abdominal parietal wall blocks.

Embolization of cerebral arteriovenous shunts in infants weighing less than 5 kg.

OBJECTIVEEndovascular treatment in children, especially neonates, can be more challenging than analogous procedures in adults. This study aimed to describe the clinical and radiological findings, type and timing of endovascular treatment, and early outcomes in children who present with neurovascular malformations, who are treated with embolization, and who weigh less than 5 kg.METHODSThe authors carried out a retrospective review of all consecutively treated children weighing less than 5 kg with neurovascular arteriovenous malformations (AVMs) at a single institution over a 10-year period.RESULTSFifty-two patients were included in the study. Thirty-eight had a vein of Galen aneurysmal malformation, 3 a pial AVM, 6 a pial arteriovenous fistula, and 5 a dural sinus malformation. The endovascular treatment goals were control of cardiac failure or hydrocephalus in cases of nonhemorrhagic malformations or to prevent new bleeding in cases of previous hemorrhage. A hemorrhagic complication occurred in 12 procedures and an ischemic complication in 2. Both complication types were correlated with the age of the infant (age cutoff at 3 months) (p = of 0.015 and 0.049, respectively). No correlation was found with the weight of the infant or the duration of the procedure.CONCLUSIONSThe embolization of AVMs in these patients prevented adverse cardiac effects, hydrovenous disorders, and rebleeding. The risk of major cerebral complications seems mainly correlated with age, with a threshold at 3 months. A multidisciplinary team involved in the treatment of these children may help to improve treatment success and management.

Effective concentration of levobupivacaine and ropivacaine in 80% of patients receiving epidural analgesia (EC80) in the first stage of labour: A study using the Continual Reassessment Method.

BACKGROUND: A comparison of the effective dose in 50% of patients (ED50) has suggested that the potency of levobupivacaine lies between that of bupivacaine and ropivacaine. However, for clinical purposes, knowledge and use of doses close to the ED95 are more relevant. This study was designed to determine the EC80 (effective concentration) for both epidural levobupivacaine and ropivacaine using the Continual Reassessment Method (CRM) during obstetric analgesia. METHODS: In this double-blind randomised study, term parturients were included by cohorts of 6 if cervical dilatation was≤5cm and visual analogue pain score (VAPS)>30mm. Efficacy was defined by a decrease of VAPS to a value≤10, thirty minutes after epidural injection of 20mL of levobupivacaine or ropivacaine. The first cohort received the lowest dose. Every next cohort received a dose according to the response's probability calculated using a Bayesian method, incorporating data from all consecutive previous patients. In addition, a logistic equation was fitted a posteriori to the whole data set to determine the whole dose-probability curve. RESULTS: Fifty-four patients were enrolled. Levobupivacaine 0.17% and ropivacaine 0.2% gave probabilities of success of 82% and 72% respectively. By fitting the logistic model to the data, the concentration leading to a probability of 0.8 (EC80) was 0.14% for levobupivacaine and 0.24% for ropivacaine while the EC50 were 0.09% for levobupivacaine and 0.17% for ropivacaine, respectively. CONCLUSION: This study suggests that epidural levobupivacaine used as the sole drug for labour analgesia has an EC80 lower than that of ropivacaine.

The Opiorphin Analog STR-324 Decreases Sensory Hypersensitivity in a Rat Model of Neuropathic Pain.

BACKGROUND: Neuropathic pain represents a therapeutic challenge, and treatments with increased efficacy and tolerability still need to be developed. Opiorphin protects endogenous enkephalins from degradation, potentiating enkephalin-dependent analgesia via the activation of opioid pathways. Enkephalins are natural ligands of opioid receptors, with strong affinity for δ-opioid receptors. Expression of functional δ-opioid receptors increases in sensory neurons after peripheral nerve injury in neuropathic pain models. In a postoperative pain model, opiorphin and its stable analog STR-324 have an analgesic potency comparable to that of morphine, but without adverse opioid-related side effects. Consequently, administration of endogenous opiorphin peptides or STR-324 might be effective in managing peripheral neuropathic pain. METHODS: In this study, STR-324 was administered intravenously over the course of 7 days to rats with mononeuropathy induced by L5-L6 spinal nerve root ligation. The rats exhibited mechanical allodynia, thermal hyperalgesia, and spontaneous pain-related behavior throughout the testing period. RESULTS: Here, we report that the continuous administration of STR-324 significantly reduced mechanical allodynia and spontaneous pain-related behavior from day 2 to day 7 in animals that received 10 or 50 µg/h of STR-324 as compared to placebo-treated animals (P < .00001 and P < .0011, respectively, for mechanical allodynia; P = .028 and P = .0049, respectively, for spontaneous pain-related behavior). In addition, STR-324 reduced the pain-evoked expression of spinal c-Fos in this model, demonstrating that it acts at least in part through inhibition of endogenous nociceptive pathways. CONCLUSIONS: These observations suggested that STR-324 may be an effective addition to the multimodal approach for treating clinical neuropathic pain.

The Cricoid Force Necessary to Occlude the Esophageal Entrance: Is There a Gender Difference?

BACKGROUND: We tested the hypothesis whether gender differences exist in the applied cricoid force necessary to prevent regurgitation. Real-time visual and dynamic means were used to assess the effectiveness of different applied cricoid forces in occluding the esophageal entrance in men (group 1) and in women (group 2). METHODS: In anesthetized and paralyzed patients, the glottis and esophageal entrance were visualized with a Glidescope video laryngoscope. Trained operators performed cricoid pressure (CP) and gastric tube insertion trials. Successful gastric tube insertion in the presence of CP was considered ineffective CP, whereas unsuccessful insertion was considered effective CP. The applied cricoid forces were measured with a novel instrument, the cricometer. The first patient in each group received 20 N. The applied cricoid force in successive patients was determined by the response of the previous patient within the same group, using the up-and-down sequential allocation technique. RESULTS: In the 30 men and 30 women who qualified for the study, the median cricoid force (cricoid force = 50) that occluded the esophageal entrance was 30.8 N (95% confidence interval = 28.15-33.5) in men, and 18.7 N in women (95% confidence interval = 17.1-20.3; P < .0001). Patency of the esophageal entrance was observed when CP was not applied and when inadequate forces that allowed successful esophageal cannulation were used. CONCLUSIONS: The current study provides evidence that the median force necessary to occlude the esophageal entrance to prevent regurgitation is less in women compared with men. Applying the appropriate cricoid force in women should also decrease airway-related problems that tend to occur with the use of excessive forces. The findings of the current study may only be applicable to patients with normal body habitus.

Mid-regional pro-adrenomedullin (MR-proADM), a marker of positive fluid balance in critically ill patients: results of the ENVOL study.

BACKGROUND: The optimal control of blood volume without fluid overload is a main challenge in the daily care of intensive care unit (ICU) patients. Accordingly this study focused on the identification of biomarkers to help characterize fluid overload status. METHODS: Sixty-seven patients were studied from ICU admission to day 7 (D7). Blood and urine samples were taken daily and sodium and water balance strictly calculated resulting in a total cumulative assessment of ∆Na+ and ∆H2O. Furthermore, plasmatic biomarkers (cortisol, epinephrine, norepinephrine, renin, angiotensin II, aldosterone, pro-endothelin, copeptine, atrial natriuretic peptide, erythropoietin, mid-regional pro-adrenomedullin (MR-proADM)) and Sequential Organ Failure Assessment (SOFA) scores were measured at D2, D5 and D7. Blood volumes were measured with 51Cr fixed on red blood cells at D2 and D7. RESULTS: The ∆Na+ or ∆H2O were increased in all patients but never related to blood volumes at D2 nor D7. Total blood volumes were at normal values with constantly low red blood cell volumes and normal or decreased plasmatic volume. Weight, plasmatic proteins, and hemoglobin were weakly related to ∆Na+ or ∆H2O. Amongst all tested biomarkers, only MR-proADM was related to sodium and fluid overload. This biomarker was also a predictor of SOFA scores. CONCLUSIONS: Plasmatic concentration in MR-proADM seems to be a good surrogate for evaluation of ∆Na+ or ∆H2O and predicts sodium and extracellular fluid overload. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01858675 in May 13, 2013.

STR-324, a Stable Analog of Opiorphin, Causes Analgesia in Postoperative Pain by Activating Endogenous Opioid Receptor-dependent Pathways.

BACKGROUND: Opiorphin is a naturally occurring potent analgesic human peptide. It protects enkephalins from degradation and inhibits pain perception in various acute pain models via activation of endogenous opioid pathways. However, the efficacy of opiorphin continuous infusion and its chemically stable form, STR-324, in postoperative pain is unknown. METHODS: Using the Brennan model of plantar incision-induced hypersensitivity, the authors examined the postsurgical analgesic response to mechanical and thermal stimuli of 7-day continuously intravenously infused drugs (8 to 10 rats per group). Antinociception from opiorphin with reference to morphine and STR-324 was assessed. Spinal c-Fos expression and the involvement of opioid receptor-dependent pathways were investigated. The occurrence of respiratory and hemodynamic adverse effects of opiorphin was also tested. RESULTS: Intravenous infusion of opiorphin significantly reduced responses to mechanical stimuli from days 1 to 4 post surgical period at 143 to 175-kPa mean ranges compared with 23 to 30-kPa mean ranges for vehicle (P < 0.05). During the 3-day postoperative period, no respiratory rate, oxygen saturation, arterial pressure, or heart rate adverse effects were induced by opiorphin. STR-324 consistently inhibited mechanical and thermal hyperalgesia with similar potency as that of opiorphin. Mechanistic analyses demonstrated that the STR-324 antinociceptive effect was reversed by the opioid antagonist, naloxone. Also, STR-324 significantly reduced the number of pain-evoked spinal cFos-immunoreactive nuclei. CONCLUSION: Intravenous infusion of opiorphin and STR-324 produced significant antinociceptive effect in a postoperative pain model. This study demonstrates that STR-324 is effective in postoperative pain management due to its strong antihyperalgesic effects mediated via opioid-dependent antinociceptive pathways. Opiorphin analog should represent a new class of potent and safe analgesics.

Effect of Intralipid® on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study.

BACKGROUND: Rapid intravenous administration of lipid emulsion has become the standard treatment of severe local anesthetic systemic toxicity. This experiment in volunteers aimed at determining the effect of Intralipid® administration on the time to neurologic symptoms. METHODS: Ropivacaine or levobupivacaine was infused intravenously in 16 volunteers (8 mg/min up to 120 mg) with 120 ml Intralipid® 20% (Fresenius, Paris France) or placebo infused at T + 2 min). Each subject received all four treatments in a crossover manner. The infusion was stopped after the intended dose had been administered or on occurrence of incipient neurologic signs of toxicity. The primary outcome was time-to-event. In addition, blood ropivacaine and levobupivacaine concentrations were measured. RESULTS: The dose infused was not different whether volunteers received placebo (81.7 ± 22.3 vs. 80.8 ± 31.7 mg, ropivacaine vs. levobupivacaine) or Intralipid® (75.7 ± 29.1 vs. 69.4 ± 26.2 mg, ropivacaine vs. levobupivacaine), P = 0.755, Intralipid® versus placebo groups. Plasma concentrations were best modeled with an additional volume of distribution associated with Intralipid®. Simulations suggested that decreased peak concentrations would be seen if Intralipid® was given during a period of increasing concentrations after extravascular administration. CONCLUSIONS: At modestly toxic doses of ropivacaine or levobupivacaine, we were unable to find any effect of the infusion of Intralipid® on the time to early signs of neurologic toxicity in volunteers. Peak concentration was decreased by 26 to 30% in the subjects receiving Intralipid®. Simulations showed that Intralipid® might prevent the rapid increase of local anesthetic concentration after extravascular administration.

A Comparison of Photoplethysmography Versus Esophageal Doppler for the Assessment of Cardiac Index During Major Noncardiac Surgery.

BACKGROUND: In this prospective observational study, we compared changes in cardiac index (CI) during fluid challenge using photoplethysmography (PPG; Nexfin™) (CIPPG) versus esophageal Doppler (ED) (CIED) in major noncardiac surgery patients. METHODS: Measurements were obtained when the attending anesthesiologist decided to perform a fluid challenge. Correlations with linear regression, Bland-Altman analysis, and analysis of covariance were performed. Trending ability was studied using 2 different methods: a 4-quadrant plot and a polar plot. RESULTS: Forty-three patients were analyzed with a total of 111 fluid challenges. There was a significant linear relationship between CI PPG and CI ED (r2 = 0.34; P < 0.001). The bias between the ED and the PPG measurements of CI was -0.114 (95% confidence interval [CI95], -1.9 to 1.7) L/min/m2, with a mean percentage error of 55%. The correlation between the changes in CI during a fluid challenge was significant (r2 = 0.25; P = 0.002). The concordance rate of directional changes (increase or decrease) of CI PPG and CI ED during fluid challenge was 67% (CI95, 57-75) for the whole data set and 85% (CI95, 70-94) with an exclusion zone of 15%. When considering ED as a reference, the sensitivity and specificity to give an additional bolus with PPG (increase in CI PPG ≥ 15%) were 35% (CI95, 19-55) and 90% (CI95, 81-96), respectively, with a positive predictive value of 58% (CI95, 33-80) and a negative predictive value of 78% (CI95, 68-86). CONCLUSIONS: In major noncardiac surgery patients, the evaluation of CI using PPG is not interchangeable with the evaluation of CI using ED. When considering the ED as an accurate device to assess changes in CI, PPG is not appropriate to assess the need for additional fluid administration. These results clearly indicate the limitations of PPG as an accurate device to track changes in CI compared with ED.

Modelling of vitamin K half-life in patients treated with vitamin K antagonists before hip fracture surgery.

BACKGROUND: Guidelines recommend treatment with vitamin K in patients requiring reversal of the effect of vitamin K antagonists (VKA) before semi-urgent surgery. In clinical practice, the time for reversal of the international normalized ratio (INR) to values adequate for surgery is often reported longer than the expected 12-24 hours, which may delay surgery and increase the risk of complications. METHODS: In order to optimize the management of elderly patients treated with VKA and undergoing hip fracture surgery, we aimed to model the vitamin K half-life in this specific population. Files for patients admitted between 2006 and 2008 for hip fracture surgery and chronically treated with VKA were retrospectively studied. Only patients with an INR superior to 1.5 upon arrival were included in the study. The effect of vitamin K on the decrease in INR was modelled after a PK/PD analysis using NONMEM. Thirty-one patients' files were analysed. RESULTS: Despite management in accordance with guidelines, 31% of the patients had a delayed return to INR values<1.5 resulting in delayed surgery. Time to INR<1.5 was longer than 24 hours in 50% of the patients. The calculated half-life of vitamin K was 24.7 hours in this population. CONCLUSION: The vitamin K half-life in elderly patients treated with VKA and undergoing hip fracture surgery was prolonged. The use of vitamin K or of a more rapid acting alternative should be discussed, depending on the urgency of the surgery.

The median effective analgesic dose (ED50) of ropivacaine in ultrasound-guided transversus abdominis plane block for analgesia in reversal of ileostomy: A double-blind up-down dose-finding study.

BACKGROUND: The transversus abdominis plane block has become popular since it has been combined with ultrasound-guided techniques. In abdominal surgery, and especially in subumbilical surgery, it improves postoperative analgesia and reduces morphine consumption. Although it has been shown to be an effective technique, there are wide variations in reported doses and volumes of local anaesthetic used. OBJECTIVE: The primary objective was to assess the median effective analgesic dose (ED50 = effective dose in 50% of patients) of ropivacaine in TAP blocks for patients undergoing reversal of ileostomy. DESIGN: A double-blind up-down dose-finding study. SETTING: French Teaching Hospital. PATIENTS: Twenty-six colorectal patients were included. INTERVENTIONS: After standardised general anaesthesia, a unilateral ultrasound-guided TAP block was performed on patients undergoing elective reversal of ileostomy using 20 ml of ropivacaine. Doses were predefined according to the up-and-down method. The first patient received a dose of 1.6 mg kg(-1). The dose adjustment interval was 0.2 ml kg(-1). The potentially toxic dose of 3 mg kg(-1) was never exceeded. MAIN OUTCOME MEASURE: The primary endpoint was pain (defined as 3 or higher on a numerical pain scale of 0 to 10) at rest 6 h after TAP block. RESULTS: Out of the twenty-six patients who were included in the study, the ED50 of ropivacaine in TAP block for patients undergoing reversal of ileostomy was 2.70 mg kg(-1) [95% confidence interval (95% CI) 2.37 to 3.03 mg kg(-1)]. CONCLUSION: The ED50 of ropivacaine in TAP blocks in reversal of ileostomy is close to the toxic threshold. Anaesthesiologists should always be aware of the systemic toxicity risk and use weight-based doses when performing a TAP block.

The effectiveness of cricoid pressure for occluding the esophageal entrance in anesthetized and paralyzed patients: an experimental and observational glidescope study.

BACKGROUND: In the last 2 decades, the effectiveness of cricoid pressure (CP) in occluding the esophageal entrance has been questioned. Recent magnetic resonance imaging studies yielded conflicting conclusions. We used real-time visual and mechanical means to assess the patency of the esophageal entrance with and without CP in anesthetized and paralyzed adult patients. METHODS: One hundred seven, nonobese ASA physical status I and II patients were recruited for the study. A cricoid force of 30 N was used. This force was standardized by using a weighing scale before application of CP in each patient. After oxygen administration, anesthetic induction, neuromuscular blockade, and establishment of manual ventilation with FIO2 = 1.0, the view of the glottis and esophageal entrance was visualized, and video recordings were obtained by using a Glidescope video laryngoscope. Attempts to insert 2 gastric tubes (GTs), size 12 and 20 F, into the esophagus were made by a "blinded" operator without and with CP, the timing of which was randomized. A successful insertion of a GT in the presence of CP was considered evidence of a patent esophageal entrance (ineffective CP), whereas an unsuccessful insertion of a GT was considered evidence of an occluded esophageal entrance (effective CP). After the attempts to insert the GTs were completed, tracheal intubation was performed while CP was applied. The position of the esophageal entrance in relation to the glottis (midline versus lateral) was assessed from the video recordings, with and without CP. RESULTS: We stopped the study when 79 patients (41 men and 38 women) qualified for and completed the study (2-sided Clopper-Pearson confidence interval (CI) 95% to 100%, n = 72). Advancement of either size GT into the esophagus could not be accomplished during CP in any patient but was easily done in all subjects when CP was not applied. This occurred whether the esophageal entrance was in a midline position or in a left or right lateral position relative to the glottis. Esophageal patency was visually observed in the absence of CP, whereas occlusion of the esophageal entrance was observed during CP in all patients. Without CP, the esophageal entrance was in a left lateral position in relation to the glottis in 57% ([95 % CI, 45%-68%)] of patients, at midline in 32% (CI, 22%-43%), and in a right lateral position in 11% (CI, 5%-21%). The position did not change with CP. CONCLUSIONS: The current study provides additional visual and mechanical evidence supporting a success rate of at least 95% by using a cricoid force of 30 N to occlude the esophageal entrance in anesthetized and paralyzed normal adult patients. The efficacy of the maneuver was independent of the position of the esophageal entrance relative to the glottis, whether midline or lateral.

Comparison of the potency of different propofol formulations: a randomized, double-blind trial using closed-loop administration.

BACKGROUND: Several commercial formulations of propofol are available. The primary outcome of this study was the required dose of propofol alone or combined with lidocaine to achieve induction of general anesthesia. METHODS: This multicenter, double-blinded trial randomized patients (American Society of Anesthesiologists physical status I-III) just before elective surgery with the use of a computer-generated list. Three different propofol 1% formulations-Diprivan (Astra-Zeneca, Cheshire, United Kingdom), Propoven (Fresenius-Kabi AG, Bad Homburg, Germany), and Lipuro (B-Braun, Melshungen AG, Germany)-were compared with either placebo (saline solution) or lidocaine 1% mixed to the propofol solution. Depth of anesthesia was automatically guided by bispectral index and by a computerized closed-loop system for induction, thus avoiding dosing bias. The authors recorded the total dose of propofol and duration of induction and the patient's discomfort through a behavioral scale (facial expression, verbal response, and arm withdrawal) ranging from 0 to 6. The authors further evaluated postoperative recall of pain using a Visual Analog Scale. RESULTS: Of the 227 patients enrolled, 217 were available for analysis. Demographic characteristics were similar in each group. Propoven required a higher dose for induction (2.2 ± 0.1 mg/kg) than Diprivan (1.8 ± 0.1 mg/kg) or Lipuro (1.7 ± 0.1 mg/kg; P = 0.02). However, induction doses were similar when propofol formulations were mixed with lidocaine. Patient discomfort during injection was significantly reduced with lidocaine for every formulation: Diprivan (0.5 ± 0.3 vs. 2.3 ± 0.3), Propoven (0.4 ± 0.3 vs. 2.4 ± 0.3), and Lipuro (1.1 ± 0.3 vs. 1.4 ± 0.3), all differences significant, with P < 0.0001. No adverse effect was reported. CONCLUSION: Plain propofol formulations are not equipotent, but comparable doses were required when lidocaine was concomitantly administered.

Comparison of two doses of ketoprofen to treat pain: a double-blind, randomized, noninferiority trial.

The aim of our study was to compare the efficacy and safety of two doses of ketoprofen (200 mg vs. 300 mg/day) in ambulatory emergency patients with pain related to traumatic and nontraumatic bone and joint diseases. We tested the hypothesis that the efficacy of the lower dose was not lower than that of the higher dose in a double-blind, randomized, noninferiority trial. Patients included in the study were aged 18-65 years with closed benign trauma of the motor system or acute noninfectious rheumatologic conditions, with a resting pain intensity ≥3/10 on a numeric pain scale (NPS), requiring ketoprofen for 5 days. The main end-point was based on two efficacy co-criteria: (i) mean change from baseline of resting pain intensity at the end of the day over 5 days and (ii) total intake of concomitant analgesics. We included 409 patients: 200 in the 200-mg group and 209 in the 300-mg group. The mean change in pain intensity at rest (difference between groups: 0.0, 95% CI -0.4 to 0.4; P = 1.00) and in analgesic consumption (difference between groups: -0.6, 95% CI -1.9 to 0.6; P = 0.33) was not significantly different between the two groups, and the differences were lower than the predefined inferiority margins (0.5 and 1.5, respectively), thus demonstrating noninferiority. No significant difference was noted in the incidence of adverse events (21% vs. 20%, P = 0.71). The efficacy of the 200-mg daily dose of ketoprofen in relieving pain in emergency cases was not inferior to that of the 300-mg dose.