Multicentre, prospective, double-blind, randomised controlled clinical trial comparing different non-opioid analgesic combinations with morphine for postoperative analgesia: the OCTOPUS study.

BACKGROUND: Head-to-head comparisons of combinations of more than one non-opioid analgesic (NOA) with morphine alone, for postoperative analgesia, are lacking. The objective of this multicentre, randomised, double-blind controlled trial was to compare the morphine-sparing effects of different combinations of three NOAs-paracetamol (P), nefopam (N), and ketoprofen (K)-for postoperative analgesia. METHODS: Patients from 10 hospitals were randomised to one of eight groups: control (C) received saline as placebo, P, N, K, PN, PK, NK, and PNK. Treatments were given intravenously four times a day during the first 48 h after surgery, and morphine patient-controlled analgesia was used as rescue analgesia. The outcome measures were morphine consumption, pain scores, and morphine-related side-effects evaluated 24 and 48 h after surgery. RESULTS: Two hundred and thirty-seven patients undergoing a major surgical procedure were included between July 2013 and November 2016. Despite a failure to reach a calculated sample size, 24 h morphine consumption [median (inter-quartile range)] was significantly reduced in the PNK group [5 (1-11) mg] compared with either the C group [27 (11-42) mg; P<0.05] or the N group [21 (12-29) mg; P<0.05]. Results were similar 48 h after surgery. Patients experienced less pain in the PNK group compared with the C, N, and P groups. No difference was observed in the incidence of morphine-related side-effects. CONCLUSIONS: Combining three NOAs with morphine allows a significant morphine sparing for 48 h after surgery associated with superior analgesia the first 24 h when compared with morphine alone. CLINICAL TRIAL REGISTRATION: EudraCT: 2012-004219-30; NCT01882530.

A systematic review of interventions and performance measures for antifungal stewardship programmes.

Objectives: Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures. Methods: We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term 'antifungal stewardship' on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures. Results: A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality. Conclusions: All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP.

Use of analgesics in France, following dextropropoxyphene withdrawal.

BACKGROUND: In 2009, the European Medicines Agency recommended withdrawal of dextropropoxyphene (DXP); in March 2011 it was withdrawn from the market in France. Up until that time the combination dextropropoxyphene-paracetamol (DXP/PC) was widely used for analgesia. At withdrawal, French regulators recommended that DXP/PC be replaced by other step 2 analgesics, i.e. tramadol, codeine, or opium-containing drugs, or by PC for a weak level of pain. To investigate prescribing behaviours after DXP/PC withdrawal, dispensations of analgesics before and after withdrawal were analysed. METHODS: Aggregated dispensation data of analgesics prescribed between January 2009 and December 2012 in the Rhône-Alpes region were obtained from the general health insurance claims data; changes in analgesic dispensation over time were analysed with the ATC/DDD methodology. Pre (Jan-June 2009) and post-withdrawal (Jan-June 2012) changes of DDDs where computed for each analgesic step. RESULTS: The dispensations of DXP/PC experienced a two-step decrease until 2011. Over the withdrawal period 2009-2012, there was a 14% decrease in the overall use of analgesic (from 109 to 94 DDDs), while the use of step 2 analgesics declined by 46% (- 22 DDDs, from 47 to 25 DDDs). This latter decline included a cessation of use of DXP/PC (29 DDDs in 2009) that were only in part (+ 7 DDDs, from 18 to 25 DDDs) compensated by increased use of codeine, tramadol and opium, in monotherapy or combined with PC. For step 1 analgesics, use increased with 9%, mostly PC (+ 8 DDDs, from 31 to 39 DDDs). Step 3 analgesics dispensations remained largely unchanged over this period (around 3 DDDs). CONCLUSIONS: In the Rhône-Alpes region, DXP/PC withdrawal was accompanied in part by an increased use of same level analgesics, and in part by an increased use of PC in monotherapy. The extent of DXP/PC use before withdrawal, and the increased use of PC after DXP withdrawal, underline the complexity of pain management.

[Medication errors with concentrated potassium intravenous solutions: Data of the literature, context and prevention]. / Erreurs médicamenteuses avec les solutés concentrés de potassium injectable: données de la littérature, état des lieux et prévention.

Accidental direct intravenous injection of a concentrated solution of potassium often leads to patient death. In France, recommendations of healthcare agencies to prevent such accidents cover only preparation and intravenous infusion conditions. Accidents continue to occur in French hospitals. These facts demonstrate that these recommendations are insufficient and ineffective to prevent such deaths, especially those occurring during a catheter flushing. This article reviews the measures able to reduce the number of accidents. Countries which removed concentrated ampoules from ward stocks observed a decrease of the number of accidental deaths. This withdrawal, recommended by the World Health Organization, is now part of standards in studies aimed at determining the safety of care in hospitals. However, removal alone is insufficient to eliminate the risk. The combination with other measures should be considered. These measures are the provision of a combination of diluted intravenous ready to use solutions, the promotion of the oral route with tablets and oral solutions for potassium replenishment and to make available products with safeguards to prevent single shot intravenous injection. Studies aimed at determining the consequences on preventing concentrated potassium accidents of a widespread distribution of isotonic sodium chloride pre-filled ready-to-use syringes for catheter flushing should be performed.

The influence of various reef sounds on coral-fish larvae behaviour.

The swimming behaviour of coral-reef fish larvae from 20 species of 10 different families was tested under natural and artificial sound conditions. Underwater sounds from reef habitats (barrier reef, fringing reef and mangrove) as well as a white noise were broadcasted in a choice chamber experiment. Sixteen of the 20 species tested significantly reacted to at least one of the habitat playback conditions, and a range of responses was observed: fishes were (1) attracted by a single sound but repelled by none (e.g. white-banded triggerfish Rhinecanthus aculeatus was attracted by the barrier-reef sound), (2) repelled by one or more sounds but attracted by none (e.g. bridled cardinalfish Pristiapogon fraenatus was repelled by the mangrove and the bay sounds), (3) attracted by all sounds (e.g. striated surgeonfish Ctenochaetus striatus), (4) attracted and repelled by several sounds (e.g. whitetail dascyllus Dascyllus aruanus was attracted by the barrier-reef sound and repelled by the mangrove sound) and (5) not influenced by any sound (e.g. convict surgeonfish Acanthurus triostegus). Overall, these results highlight two settlement strategies: a direct selection of habitats using sound (45% of the species), or a by-default selection by avoidance of certain sound habitats (35%). These results also clearly demonstrated the need to analyse the influence of sounds at the species-specific level since congeneric and confamilial species can express different behaviours when exposed to the same sounds.

Postoperative intravenous morphine titration.

Relief of acute pain during the immediate postoperative period is an important task for anaesthetists. Morphine is widely used to control moderate-to-severe postoperative pain and the use of small i.v. boluses of morphine in the post-anaesthesia care unit allows a rapid titration of the dose needed for adequate pain relief. The essential principle of a titration regimen must be to adapt the morphine dose to the pain level. Although morphine would not appear to be the most appropriate choice for achieving rapid pain relief, this is the sole opioid assessed in many studies of immediate postoperative pain management using titration. More than 90% of the patients have pain relief using a protocol of morphine titration and the mean dose required to obtain pain relief is 12 (7) mg, after a median of four boluses. Sedation is frequent during i.v. morphine titration and should be considered as a morphine-related adverse event and not evidence of pain relief. The incidence of ventilatory depression is very low when the criteria to limit the dose of i.v. morphine are enforced. Morphine titration can be used with caution in elderly patients, in children, or in obese patients. In practice, i.v. morphine titration allows the physician to meet the needs of individual patients rapidly and limits the risk of overdose making this method the first step in postoperative pain management.

Prescriptions analysis by clinical pharmacists in the post-operative period: a 4-year prospective study.

BACKGROUND: Clinical pharmacists can help prevent medication errors. However, data are scarce on their role in preventing medication prescription errors in the post-operative period, a high-risk period, as at least two prescribers can intervene, the surgeon and the anesthetist. We aimed to describe and quantify clinical pharmacist' intervention (PIs) during validation of drug prescriptions on a computerized physician order entry system in a post-surgical and post-transplantation ward. We illustrate these interventions, focusing on one clearly identified recurrent problem. METHODS: In a prospective study lasting 4 years, we recorded drug-related problems (DRPs) detected by pharmacists and whether the physician accepted the PI when prescription modification was suggested. RESULTS: Among 7005 orders, 1975 DRPs were detected. The frequency of PIs remained constant throughout the study period, with 921 PIs (47%) accepted, 383 (19%) refused and 671 (34%) not assessable. The most frequent DRP concerned improper administration mode (26%), drug interactions (21%) and overdosage (20%). These resulted in a change in the method of administration (25%), dose adjustment (24%) and drug discontinuation (23%) with 307 drugs being concerned by at least one PI. Paracetamol was involved in 26% of overdosage PIs. Erythromycin as prokinetic agent, presented a recurrent risk of potentially severe drug-drug interactions especially with other QT interval-prolonging drugs. Following an educational seminar targeting this problem, the rate of acceptation of PI concerning this DRP increased. CONCLUSION: Pharmacists detected many prescription errors that may have clinical implications and could be the basis for educational measures.

Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.

BACKGROUND: Patients receiving anti-platelet agents for secondary cardiovascular prevention frequently require non-cardiac surgery. A substantial proportion of these patients have their anti-platelet drug discontinued before operation; however, there is uncertainty about the impact of this practice. The aim of this study was to compare the effect of maintenance or interruption of aspirin before surgery, in terms of major thrombotic and bleeding events. METHODS: Patients treated with anti-platelet agents for secondary prevention and undergoing intermediate- or high-risk non-cardiac surgery were included in this multicentre, randomized, placebo-controlled, trial. We substituted non-aspirin anti-platelets with aspirin (75 mg daily) or placebo starting 10 days before surgery. The primary outcome was a composite score evaluating both major thrombotic and bleeding adverse events occurring within the first 30 postoperative days weighted by their severity (weights were established a priori using a Delphi consensus process). Analyses followed the intention-to-treat principle. RESULTS: We randomized 291 patients (n=145, aspirin group, and n=146, placebo group). The most frequent surgical procedures were orthopaedic surgery (52.2%), abdominal surgery (20.6%), and urologic surgery (15.5%). No significant difference was observed neither in the primary outcome score [mean values (SD)=0.67 (2.05) in the aspirin group vs 0.65 (2.04) in the placebo group, P=0.94] nor at day 30 in the number of major complications between groups. CONCLUSIONS: In these at-risk patients undergoing elective non-cardiac surgery, we did not find any difference in terms of occurrence of major thrombotic or bleeding events between preoperative maintenance or interruption of aspirin.

Hepatopulmonary Syndrome and Post-Liver Transplantation Complications: A Case-Control Study.

BACKGROUND: Although liver transplantation (LT) improves survival in cirrhotic patients with hepatopulmonary syndrome (HPS), few data exist concerning post-operative complications in these patients. OBJECTIVE: To compare complications after LT between patients with and without HPS. METHODS: In a case-control study, we retrospectively analyzed all patients who underwent LT in our center from January 2010 to July 2016. We compared cases of identified HPS to controls matched for age, MELD score, comorbidities, red blood cells transfused, and highest dosage of norepinephrine perfused during transplantation. RESULTS: Among 451 transplanted patients, we identified 71 patients with HPS who could be analyzed. We found a significantly (p<0.001) higher number of post-operative complications in patients with HPS (median 5 vs 3), with more occurrence of cardiac, infectious and surgical complications than in the controls: 39.4% vs 12.7% (p<0.001), 81.7% vs 49.3% (p<0.001), and 59.2% vs 40.1% (p<0.029), respectively. There were also more ICU readmissions at 1 month among HPS patients (10 vs 1, p=0.01). There was no significant difference concerning ventilation data, lengths of ICU or hospital stay (8.5 [range 3-232] and 32 [14-276] days, respectively on the whole cohort) and death in the ICU (4.2% on the whole cohort). The 1-year survival was higher in HPS patients (94.4% vs 81.1%, p=0.034); there was no difference in 5-year survival. CONCLUSION: HPS patients seem to have a higher number of complications in the first month following LT.

Surgical activity during the Covid-19 pandemic: Results for 112 patients in a French tertiary care center, a quality improvement study.

BACKGROUND: After the emergence of Covid-19 in China, Hubei Province, the epidemic quickly spread to Europe. France was quickly hit and our institution was one of the first French university to receive patients infected with Sars-COV2. The predicted massive influx of patients motivated the cancellation of all elective surgical procedures planned to free hospitalization beds and to free intensive care beds. Nevertheless, we should properly select patients who will be canceled to avoid life-threatening. The retained surgical indications are surgical emergencies, oncologic surgery, and organ transplantation. MATERIAL AND METHODS: We describe the organization of our institution which allows the continuation of these surgical activities while limiting the exposure of our patients to the Sars Cov2. RESULTS: After 4 weeks of implementation of intra-hospital protocols for the control of the Covid-19 epidemic, 112 patients were operated on (104 oncology or emergency surgeries and 8 liver transplants). Only one case of post-operative contamination was observed. No mortality related to Covid-19 was noted. No cases of contamination of surgical care personnel have been reported. CONCLUSION: We found that the performance of oncological or emergency surgery is possible, safe for both patients and caregivers.

Effect of a low-dose ketamine regimen on pain, mood, cognitive function and memory after major gynaecological surgery: a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Major gynaecological abdominal surgery is associated with moderate to severe postoperative pain, hyperalgesia and the need for multimodal analgesia to reduce high morphine consumption. A low-dose ketamine regimen appears to prevent postoperative hyperalgesia. We examined the potential beneficial effect of ketamine on postoperative pain management and cognitive function. METHODS: Ninety patients were included in this double-blind, randomized, placebo-controlled study to test the efficacy and adverse effects of ketamine (as an intraoperative bolus of 0.15 mg kg-1, followed postoperatively by ketamine 0.5 mg per morphine 1 mg in a patient-controlled analgesia device). All patients received additionally ketoprofen. The main end-point was morphine consumption over the first 24 h. Secondary efficacy and safety end-points were morphine consumption during the titration period and during the patient-controlled analgesia period (48 h), the number of morphine-related adverse effects and the results of psychometric tests. RESULTS: Ketamine, in combination with morphine and ketoprofen, did not improve postoperative pain scales and did not reduce morphine consumption and the incidence of morphine-related adverse effects. Ketamine did not modify mood, cognitive and memory functioning. CONCLUSION: Adding a low dose of ketamine to an efficacious multimodal analgesic regimen did not improve analgesia after gynaecological surgery. Although this combination appears to be safe, the lack of benefit suggests that a low dose of ketamine should not be used for routine care.

[Prevention and relief of pain induced by otolaryngological and cervicofacial surgery]. / Prévention et soulagement des douleurs induites par la chirurgie ORL et cervico-faciale.

Pain after otolaryngological and cervicofacial surgery varies greatly because of the wide variety of procedures. Preventing this pain stems from the administration of paracetamol, nonsteroid anti-inflammatory drugs, nefopam, and systematic recourse to morphine when remifentanil is used. Postoperatively, the most painful surgical procedures are an indication for multimodal anesthesia and patient-controlled morphinic analgesic after titration in the postoperative postanesthesia care unit. Applying antalgic protocols, also including locoregional anesthesia, depending on the type of procedure and the patient, can improve the quality of care.

What are the therapeutic alternatives to dextropropoxyphene in France? A prescribers' survey.

About a year after dextropropoxyphene (DXP) withdrawal from the French market, we conducted a survey among members of the French Society of Anesthesia & Intensive Care Medicine (Sfar) and of the French Society of the Study and Treatment of Pain (SFETD) to identify the indications for which this WHO level II analgesic had been prescribed, the prescriber's feedback following withdrawal, and the substitutive analgesics prescribed. DXP had been prescribed by more than 75% of the 430 anaesthesiologists and 230 pain specialists interviewed, mainly for acute and chronic non-cancer pain of moderate intensity. While two thirds of pain specialists were not satisfied with DXP withdrawal, this decision did not affect the majority of anaesthesiologists. In both groups, the main substitutive analgesic was tramadol combined with acetaminophen, while only 24% of prescribers considered acetaminophen alone as a substitute.

Evaluation of early motor and sensory evoked potentials in cervical spinal cord injury.

To determine the efficacy of motor evoked potentials (MEP) and sensory evoked potentials (SEP) in the assessment of severe cervical injury, 17 subjects with severe cervical injury were studied. During the 1st week post-injury and post-surgical treatment, all subjects were submitted to electromyogram (EMG) recordings, dermatomal somatosensory evoked potentials (D.SEP), posterior tibial nerve somatosensory evoked potentials (PTN.SEP), MEP and bilateral cervical electrical stimulations with recording of the diaphragm. For the D.SEP, the latencies of the N9 and N20 responses and the conduction time (N9-N20) were measured in the upper limbs; the latencies of the P40 and P60 responses were measured in the lower limbs. MEP were recorded from distal upper and lower limb muscles following transcranial electrical stimulation of the cortex. (Magnetic stimulation was not indicated because of implanted metallic material in the cervical skull of many patients.) A SEP and MEP grading system was used to improve the assessment of different root neurological levels. In patients with incomplete lesions PTN.SEP, D.SEP and MEP responses could be recorded in territories that were clinically deficient. Patients with complete lesions and absent SEP and MEP responses had a poor outcome. A good correlation was found between the severity of the spinal cord injury and SEP grading. For MEP, the presence or absence of intercostal responses (C4) to cervical and cortical stimulation was the best prognostic indicator. The combined electrophysiological exploration of MEP and SEP proved to be a useful tool for monitoring patients with severe spinal cord injury.

[How is postoperative pain evaluated?]. / Comment évaluer la douleur postopératoire?

The assessment of postoperative pain and analgesic efficacy is essential as pain levels and morphine requirements are not predictable. Self-assessment with unidimensional methods (such as the visual analogue pain scale, the numerical rating scale and the verbal rating scale) is the rule for adults and children more than 5 years of age. The former is a validated method and the most accurate and reproducible scale. Assessment of pain is difficult in children less than 5 years old. Only the scales for hetero-assessment with behavioural assessment (CHEOPS and OPS) are used. Finally, morphine consumption with PCA is also an indirect pain assessment method. Postoperative pain should be assessed several times a day in every patient, starting in the recovery room and prolonged during hospital stay. Pain should be measured at rest and in dynamic conditions by the medical and paramedical team.

[Intravenous morphine titration]. / La titration intraveineuse de morphine.

OBJECTIVES: To describe principles of intravenous (i.v.) morphine titration. To analyse current knowledge based on the experimental and clinical studies. To describe clinical implications in the operating room, postanaesthesia care unit (PACU), prehospital care, emergency and intensive care units (ICU), and cancerology. To provide recommendations for clinical practice. DATA SOURCES: Search in the Medline database without limitation, using the following keywords: morphine titration. STUDY SELECTION: All types of articles were selected including prospective randomised (or not randomised) studies in adults and children, practice guidelines, reviews, editorials and case reports. DATA SYNTHESIS: Intravenous (i.v.) morphine titration is a pharmacological method which involves morphine boluses administration until pain relief, allowing a limitation in morphine side effects which are mainly dose dependent. I.v. morphine titration is widely used in prehospital care, emergency unit, PACU, ICU, and cancerology, in young and elderly patients. In the PACU, when the VAS (visual analogue scale) increases to more than 30 mm, i.v. morphine titration every five minutes with an unlimited number of 2 or 3 mg boluses provides an efficient analgesic regimen in adults. Titration is performed until pain relief (VAS < or =30), sedation that is the most frequent side effect during i.v. morphine titration (Ramsay score >1), severe side effects (like respiratory depression). CONCLUSION: Because of important pharmacological variability in morphine need, iv morphine titration is a simple method which allows a rapid and efficient pain relief notably in the postoperative care.

[Assessment of a new light guide (Trachlight) for tracheal intubation]. / Evaluation de l'apprentissage d'un nouveau guide lumineux (Trachlight pour l'intubation trachéale.

OBJECTIVE: To assess the learning curve of a new lighwand device, Trachlight (Laerdal), for blind orotracheal intubation in patients without foreseen difficulty in airway management. STUDY DESIGN: Open, prospective, clinical study. USERS: Twelve persons practicing anaesthesia (specialists, trainees, nurses) underwent videotape learning and manikin training with ten successful intubation manoeuvres required with the device. METHODS: Each person had to carry out a tracheal intubation in ten consecutive patients undergoing scheduled surgery and without history or clinical sign of difficults airway management. RESULTS: One hundred and twenty patients were included. The overall success rate with the Trachlight was 87%. An easy learning curve was obtained as demonstrated by the low failure rate in the first three patients, and by the success rate on the first or second attempt in the last four patients. There was no significant difference in failure rate with or without muscle relaxation (10 vs 20%, NS). Finally, all failures with the Trachlight were followed by successful intubation using direct laryngoscopy, and no traumatic complications were recorded with the device. CONCLUSION: Trachlight is a new lightwand device enabling blind tracheal intubation with a easy learning curve in patients without difficulty in airway management, even for non-selected operators.

[Cerebral aspergillosis and liver transplantation: about one case]. / Aspergillose cérébrale et transplantation hépatique: discussion autour d'un cas.

Cerebral invasive aspergillosis is a rare but serious infection. Mortality is still high despite appropriate treatment. We report the case of a patient with liver transplantation in the context of alcoholic cirrhosis and transplanted back seven years later consequently to an ischemic cholangitis. Following an acquired active viral infection by HCV and treated by antiviral combination therapy the patient presented six months after this second operation a cerebral aspergillosis of tumour-like presentation. It rapidly evolved to an unfavourable outcome with intracranial hypertension state. If the therapeutic management is well established, the diagnosis is difficult. This observation allows us to discuss the various diagnostic criteria of cerebral aspergillosis.

[Peripartum period and hemophilia carriers]. / Gestion du péri-partum de la patiente conductrice d'une hémophilie.

Women who are carriers for hemophilia are usually considered as safe carriers. However, they can present hemorragic symptoms associated with low factor VIII or IX levels. During pregancy, factor VIII increases whereas factor IX does not. The peripartum period is at risk of increased bleeding in these women. Here are presented reports of clinical data concerning two hemophilia carriers with low factor VIII or IX (30-40%) during the peripartum period. They received remifentanil and ketamine for labor pain management because of contraindication of epidural and spinal analgesia. Delivery occured quickly but they presented immediate moderate postpartum haemorrage. They did not necessitate blood transfusion. The one with hemophilia A received desmopressin just after delivery and the other one received factor IX when she arrived in delivery room. Blood factor VIII or IX has to be assessed in these women with familial history of hemophilia and bleeding. During pregnancy, factor VIII increases and can be assessed many times during pregnancy expecting a level over 50%. Factor IX does not really increase during pregancy and hemorrage can occur. Epidural and spinal anesthesia seem to be contraindicated as far as recommandations are concerned. Coagulation factor substitution is a mean of increasing factor level before these anaesthesias and can be discussed for each case.