End-ischemic hypothermic oxygenated perfusion for extended criteria donors in liver transplantation: a multicenter, randomized controlled trial-HOPExt.

BACKGROUND: Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury. METHODS: HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage. DISCUSSION: We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.

No Benefit of Adductor Canal Block Compared with Anterior Local Infiltration Analgesia in Primary Total Knee Arthroplasty: A Single-Blinded Randomized Controlled Clinical Trial.

BACKGROUND: An adductor canal block (ACB) performed by an anesthesiologist is an established component of analgesia after total knee arthroplasty. Alternatively, surgeons may perform periarticular local infiltration analgesia (LIA) intraoperatively. We hypothesized that ACB would be superior to anterior LIA in terms of morphine consumption in the first 48 hours after primary total knee arthroplasty under spinal anesthesia. METHODS: This prospective controlled and blinded trial included 98 patients; 48 received an ACB plus sham (saline solution) anterior LIA, and 50 received a sham (saline solution) ACB plus anterior LIA. Both groups received posterior LIA with local anesthetic. The primary outcome was cumulative morphine consumption at 48 hours after surgery. Secondary outcomes were pain while resting, standing, and walking, rehabilitation scores, opioid-related side effects, and patient satisfaction. RESULTS: No difference in the primary outcome was found, and the 48-hour morphine consumption was low in both arms (28.8 ± 17.6 mg with ACB, 26.8 ± 19.2 mg with anterior LIA; p = 0.443). Pain scores were significantly better in the anterior LIA arm, but the differences were not clinically relevant. There were no differences in any other secondary outcome measures. CONCLUSIONS: LIA may be used as the primary option for multimodal postoperative pain management in patients undergoing primary total knee arthroplasty with spinal anesthesia. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Nefopam prescribing preferences in French hospitals: results of a survey.

Introduction: nefopam is a non-opioid, centrally-acting analgesic, frequently prescribed in France for acute pain and postoperatively. Only intravenous (IV) formulation is available, however the off-label oral use is frequent in surgical and medical patients. There is no data on the actual in-hospital prescription preferences in French physicians regarding nefopam. We wish to identify nefopam prescription habits for acute and chronic pain among hospital physicians. Methods: an online survey was sent to physicians via professional emails. Frequency of prescription, indication, preferred and prescribed administration route, dose regimen, and personal perception of the nefopam tolerance and efficiency were examined. Results: a total of 527 responses were analysed. Nefopam was mostly prescribed by senior hospital physicians, for acute pain, orally (85%), 20 mg/6h with 120 mg maximal daily dose. For chronic pain, the oral administration was more frequent. More than half of prescribers considered the efficacy of the oral route was similar to intravenous, and better tolerated compared to intravenous administration. Forty-eight percent of responders would change their prescription attitude in case of oral route approval of nefopam. Conclusion: oral prescription of intravenous formulation of nefopam is frequent, especially for acute pain, and has the same dose and regimen pattern as for intravenous route. Prescribers consider oral nefopam efficient and safe for patients. Regulatory actions regarding the oral nefopam prescription authorization and duration of such prescription are needed.

Adherence to oral antibiotic therapy in patients with bone and joint infection: A pilot study.

OBJECTIVES: The management of bone and joint infections (BJI) is complex and requires prolonged antimicrobial therapy. Few data exist on adherence to anti-infectious treatment other than HIV, and none on BJI, even though compliance is considered as a major determinant of clinical outcome. This work aimed at evaluating adherence to oral antimicrobial treatment in patients with BJI. PATIENTS AND METHODS: This is a prospective observational blinded pilot study evaluating adherence by a 6-item questionnaire at 6 weeks (W6) and 3 months (M3) post-surgery. The primary endpoint was the proportion of patients with high, moderate and poor adherence at W6. Secondary endpoints included change in adherence between W6 and M3, and the exploration of potential variables influencing adherence. RESULTS: Analysis was performed on 65 questionnaires obtained from 43 patients including 35 with device-associated BJI. At W6, 11 out of 34 patients were highly adherent to oral antibiotic therapy, 22 moderately adherent and 1 poorly adherent. There was no significant change in adherence to antibiotic therapy between W6 and M3. The only variable significantly associated with the level of adherence at W6 and M3 was the number of daily doses of antibiotic (P=0.04 and 0.02 at W6 and M3, respectively). CONCLUSIONS: This study provided a snapshot of patients' adherence in BJI. Adherence to antibiotic therapy appeared to be stable up to 3 months and a higher number of daily doses of antibiotic was associated with poorer adherence. These observations need to be confirmed in future large-scale studies using electronic pill monitoring systems.

Bone cement usage modalities at a multi-site university hospital centre.

BACKGROUND: Although cements are widely used during arthroplasty procedures, few recommendations exist regarding their optimal usage modalities, which, nevertheless, govern the long-term surgical outcomes. No detailed information is available on how cements are used in French hospitals. The objectives of this questionnaire survey among surgeons working at a multi-site university hospital in France were to describe practices, determine whether these varied with surgeon experience, and look for differences compared to recommendations. HYPOTHESIS: Cementing techniques vary widely among surgeons at a university hospital. MATERIAL AND METHODS: A questionnaire was sent to the five orthopaedic departments of our university hospital to collect data on the surgeons (age, sex, years of experience), their practice (type of implants used, annual number of arthroplasties with each arthroplasty type and each indication, and proportion of cemented arthroplasties), the type of cement used, and the cementing technique. RESULTS: Of the 34 surgeons, 21 completed the questionnaire, 20 males and 1 female with a mean age of 41 years (range, 31-59 years) and a mean of 11 years (range, 1-29 years) of experience. High-viscosity antibiotic-loaded cement was preferred by 20 (95%) surgeons, notably for knee arthroplasties, of which the median annual numbers were 55 (range, 0-218) and 8 (range, 1-40) for primary and revision cemented procedures, respectively. Various cementing techniques in ambient air were used: 12/21 (57%) surgeons used pulsed lavage to prepare the bone before cementation and 18/21 (86%) applied the cement to both the bone cuts and the implant. Of the 18 surgeons who performed knee arthroplasties, 12 used pulsed lavage, including 9 of the 11 surgeons with more than 5 years of experience and only 3 of the 7 less experienced surgeons. Similarly, of the 12 surgeons who used pulsed lavage for cemented arthroplasties, 11 were among the 12 surgeons who performed more than 15 cemented arthroplasties annually and 1 was among the 6 who performed fewer cemented arthroplasties. DISCUSSION: Cementing techniques varied widely, reflecting the dearth of recommendations and controversial results of published studies. In our centre, the use of pulsed lavage to improve bone preparation and cement application to both the bone and the implant should be promoted, as both techniques are universally advocated. Our study demonstrates the need to provide surgeons with opportunities to exchange their experiences about the other aspects of cementing in order to harmonise practices and to optimise the use of cement. LEVEL OF EVIDENCE: IV, questionnaire survey.

Drug incompatibilities in intravenous therapy: evaluation and proposition of preventive tools in intensive care and hematology units.

PURPOSE: Physicochemical incompatibility (PCI) between drugs infused together is frequent, but under-recognized. PCI can lead to drug inactivity, catheter occlusion, embolism or inflammatory reactions. The aims of this work were to identify most frequent and relevant drug incompatibilities and to review and develop strategies for their prevention. METHOD: This was an observational prospective survey conducted between January and March 2015 in an intensive care unit (ICU) and in September 2014 in a hematology sterile unit (HSU). Drugs administered to patients were recorded and their compatibility assessed based on published compatibility data. RESULTS: Drug incompatibilities accounted for 12% (23/189) and 17% (116/686) of drug pairs infused in the ICU and the HSU, respectively. Pantoprazole was the most frequent drug implied in PCI. Regarding drug classes, anti-infective agents and gastrointestinal drugs were the most frequently implied. Among the incompatible pairs, 78% and 61% implicated a drug with extreme pH in the ICU and HSU, respectively. The tools proposed to reduce the frequency of PCI included: compatibility cross-tables, labeling of drugs with extreme pH and optimized administration schedules. CONCLUSIONS: Given the frequency and the potential for severe consequences of PCI, pharmacists have a role to play in raising awareness of nurses and practitioners, and proposing adequate tools and solutions to reduce their incidence.

Sleep Disorders and Therapeutic Management: A Survey in a French Population of Prisoners.

In a French prison, most inmates reported not being satisfied with their sleep. Life habits between good and bad sleepers were not significantly different except for television and smoking. The most frequently reported symptom of insomnia was several awakenings at night, and the most frequently cited etiologies were rumination of thoughts and noise. Most patients reported that their sleeping problems began or worsened after incarceration. A quarter of the inmates were following a hypnotic treatment, and most of these treatments began in prison. Only 42% of patients were satisfied with its effectiveness. These observations enabled us to make recommendations for healthy sleep patterns such as respecting normal night-and-day cycles, encouraging to stop smoking, and promoting appropriate use of hypnotic treatments.

Mathematical modeling and systems pharmacology of tuberculosis: Isoniazid as a case study.

Tuberculosis (TB) treatment needs to be optimized as it is currently long and associated with increasing drug resistance. The antimycobacterial effect of isoniazid (INH) is characterized by a biphasic kill curve, whose causes are still debated. In this work, we developed a complete mathematical model describing the time-course of TB infection and its treatment by INH in human lung. This model was based on a pharmacokinetic model, a pharmacodynamic model and a pathophysiological model. It was used to simulate the antibacterial effect of INH during the first days of therapy. This full model adequately reproduced some qualitative and quantitative properties of the early bactericidal activity of INH observed in TB patients. The kill curves simulated with the model reproduced the biphasic killing effect of INH and the predicted declines in extracellular bacteria were comparable to clinical data. A sensitivity analysis provided interesting insights regarding the biphasic kill curve. The first phase appeared to be essentially driven by the drug effect. In the second phase, while drug pharmacology was the major determinant of the antibacterial effect, a slight influence of the dynamics of infected macrophages was also observed. This work permits to formulate hypotheses for optimizing the efficacy of TB drug candidates and confirms the utility of mathematical modeling to generate new assumptions for TB research.

Evaluation of Safe Infusion Devices for Antineoplastic Administration.

Nurses endure daily low-level exposure to cytotoxic drugs, which can lead to significant absorption with potential harmful consequences. New sterile medical devices called cytotoxic safe infusion systems (CSISs), intended by their manufacturers to improve safety and quality of cytotoxic drug infusions, have been made commercially available. CSISs from 3 manufacturers were tested in 2 cancer units and compared with standard infusion sets. The aim of this study is to evaluate the devices regarding occupational exposure, quality of the infusion, and economic aspects.

Consequences of renal failure on non-renal clearance of drugs.

Kidney disease not only alters the renal elimination but also the non-renal disposition of drugs that are metabolized by the liver. Indeed, modifications in the expression and activity of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Accumulated uremic toxins, inflammatory cytokines, and parathyroid hormones may modulate these proteins either directly or by inhibiting gene expression. This can lead to important unintended variations in exposure and response when drugs are administered without dose adjustment for reduced renal function. This review summarizes our current understanding of non-renal clearance in circumstances of chronic and acute renal failure with experimental but also clinical studies. It also evaluates the clinical impact on drug disposition. Predicting the extent of the drug disposition modification is difficult first because of the complex interplay between metabolic enzymes and transport proteins but also because of the differential effects in the different organs (liver, intestines). Recommendations of the US FDA are presented as they may be potentially helpful tools to predict these modifications when no specific pharmacokinetic studies are available.

Bayesian networks: a new method for the modeling of bibliographic knowledge: application to fall risk assessment in geriatric patients.

Falls in geriatry are associated with important morbidity, mortality and high healthcare costs. Because of the large number of variables related to the risk of falling, determining patients at risk is a difficult challenge. The aim of this work was to validate a tool to detect patients with high risk of fall using only bibliographic knowledge. Thirty articles corresponding to 160 studies were used to modelize fall risk. A retrospective case-control cohort including 288 patients (88 ± 7 years) and a prospective cohort including 106 patients (89 ± 6 years) from two geriatric hospitals were used to validate the performances of our model. We identified 26 variables associated with an increased risk of fall. These variables were split into illnesses, medications, and environment. The combination of the three associated scores gives a global fall score. The sensitivity and the specificity were 31.4, 81.6, 38.5, and 90 %, respectively, for the retrospective and the prospective cohort. The performances of the model are similar to results observed with already existing prediction tools using model adjustment to data from numerous cohort studies. This work demonstrates that knowledge from the literature can be synthesized with Bayesian networks.

Evaluation of safe infusion devices for antineoplastic administration.

Nurses endure daily low-level exposure to cytotoxic drugs, which can lead to significant absorption with potential harmful consequences. New sterile medical devices called cytotoxic safe infusion systems (CSISs), intended by their manufacturers to improve safety and quality of cytotoxic drug infusions, have been made commercially available. CSISs from 3 manufacturers were tested in 2 cancer units and compared with standard infusion sets. The aim of this study is to evaluate the devices regarding occupational exposure, quality of the infusion, and economic aspects.