Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery.

INTRODUCTION: Recombinant factor IX fusion protein (rIX-FP) has been developed to improve the pharmacokinetic (PK) profile of factor IX (FIX), allowing maintenance of desired FIX activity between injections at extended intervals, ultimately optimizing haemophilia B treatment. AIM: To determine the efficacy and safety of rIX-FP in the perioperative setting. METHODS: Subjects were adult and paediatric patients with severe to moderately severe haemophilia B (FIX ≤ 2%) participating in three Phase III clinical trials and undergoing a surgical procedure. PK profiles were established prior to surgery for each patient. Haemostatic efficacy was assessed by the investigator for up to 72 h after surgery. Safety measurements during the study included adverse events and inhibitors to FIX. FIX activity was monitored during and after surgery to determine if repeat dosing was required. RESULTS: Twenty-one, both major and minor, surgeries were performed in 19 patients. Haemostatic efficacy was rated as excellent (n = 17) or good (n = 4) in all surgeries. A single preoperative dose maintained intraoperative haemostasis in 20 of 21 surgeries. Nine major orthopaedic surgeries were conducted in eight patients with a mean of 7 (range: 6-12) rIX-FP injections during surgery and the 14-day postoperative period. Median rIX-FP consumption for orthopaedic surgeries was 87 IU kg(-1) preoperatively and 375 IU kg(-1) overall. No subject developed inhibitors to FIX or antibodies to rIX-FP. CONCLUSION: Recombinant factor IX fusion protein was well tolerated and effectively maintained haemostasis during and after surgery. Stable FIX activity was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available long-acting recombinant FIX.

Diagnosis and management challenges in patients with mild haemophilia A and discrepant FVIII measurements.

Thirty per cent of patients with mild haemophilia A (MHA) present markedly different FVIII: C level when assayed by one-stage clotting and two-stage chromogenic assays. It is, therefore, a real clinical challenge to predict the individual bleeding risk of these patients. The aim of the present work was to study the relationship between the bleeding tendency of these patients with the results of a panel of phenotypic and genotypic tools. Thirty-six patients with MHA were included in this multicentre prospective clinical study. The severity of bleeding symptoms was evaluated using the ISTH/SSC score. FVIII:C levels were measured using an activated partial thromboplastin time-based one-stage FVIII assay (FVIII: C1) and three commercial chromogenic kits (FVIII:CR). FVIII antigen levels, thrombin generation measurement and FVIII gene mutation analysis were also performed. Our results showed that a one-stage FVIII: C assay cannot rule out the diagnosis of MHA, a combined use of FVIII:C1 with a FVIII:CR is suitable for detecting MHA. We observed that FVIII:CR results better reflected the clinical bleeding tendency of patients compared to FVIII:C1. We also observed a relationship between thrombin generation (TG) capacity and FVIII:CR of these patients. FVIII gene mutation analysis showed mutations previously reported in MHA patients with discrepant FVIII:C measurements, but with no predictive value of the individual bleeding phenotype of patients. Overall, we observed a relationship between chromogenic FVIII:C results, TG assay and bleeding tendency of patients with discrepant FVIII:C measurements, while FVIII:C1 was not well correlated with clinical bleeding phenotype in this particular population.

Critical appraisal of organ procurement under Maastricht 3 condition.

The ethics committee of the French Society of Anesthesia and Intensive Care (Sfar) has been requested by the French Biomedical Agency to consider the issue of organ donation in patients after the decision to withdraw life-supportive therapies has been taken. This type of organ donation is performed in the USA, Canada, the United Kingdom, the Netherlands and Belgium. The three former countries have published recommendations formalizing procedures and operations. The French Society of Anesthesia and Intensive Care (Société française d'anesthésie et de reanimation [Sfar]) ethics committee has considered this issue and envisioned the different aspects of the whole process. Consequently, it sounded a note of caution regarding the applicability of this type of organ procurement in unselected patients following a decision to withdraw life-supportive therapies. According to French regulations concerning organ procurement in brain-dead patients, the committee stresses the need to restrict this specific way of procurement to severely brain-injured patients, once confirmatory investigations predicting a catastrophic prognosis have been performed. This suggests that the nature of the confirmatory investigation required should be formalized by the French Biomedical Agency on behalf of the French parliamentarians, which should help preserve population trust regarding organ procurement and provide a framework for medical decision. This text has been endorsed by the Sfar.

SURgical interventions with FEIBA (SURF): international registry of surgery in haemophilia patients with inhibitory antibodies.

Factor VIII Inhibitor Bypassing Activity (FEIBA) can effectively achieve haemostasis in haemophilia patients with inhibitors. Further evaluation of FEIBA in surgical settings is of significant interest considering the relatively limited prospective data published to date. The aim of the study is to evaluate the perioperative efficacy and safety of FEIBA in haemophilia patients with inhibitors. Haemophilia patients with inhibitors who underwent surgical procedures and received FEIBA for perioperative haemostatic control were prospectively enrolled in an open-label, noninterventional, postauthorization study [SURgical interventions with FEIBA (SURF)]. Outcome measures included haemostatic efficacy, safety, FEIBA exposure and blood loss associated with the perioperative use of FEIBA. Thirty-five surgical procedures were performed at 19 centres worldwide in patients with congenital haemophilia A, congenital haemophilia B, or acquired haemophilia A. Haemorrhagic risk was severe in 37.1% (13 of 35) of the procedures, moderate in 25.7% (9 of 35) and mild in 37.1% (13 of 35). One moderate risk surgery was excluded from the efficacy analyses because it did not meet all protocol requirements. Haemostasis was judged to be 'good' or 'excellent' in 91.2% (31 of 34) of surgical procedures and 'fair' in 8.8% (3 of 34). Among the 12 adverse events, three were serious adverse events (SAEs), two of which were unrelated to FEIBA therapy; one SAE, a clot in an arteriovenous fistula, was deemed to be possibly related to therapy. This prospective investigation confirms that FEIBA can be safely and effectively used when performing surgical procedures in haemophilia patients with inhibitors.

Seventy-two total knee arthroplasties performed in patients with haemophilia using continuous infusion.

BACKGROUND AND OBJECTIVES: Total knee replacement (TKR) is the treatment of choice in case of end-stage knee arthropathy, the main complication of haemophilia. We report here a retrospective evaluation of 72 total knee replacement in 51 haemophilia A and B patients using continuous infusion of factor concentrates (CIFC). MATERIALS AND METHODS: Patients were evaluated on the basis of the following efficacy and safety criteria: range of motion, surgery-related blood loss by three different methods, factor consumption and occurrence of short and long term complications. RESULTS: Kaplan-Meier analysis showed a removal-free survival of TKRs of 88.4% 10years after surgery. Most patients were satisfied with their prosthesis and described pain relief and improved mobility and better quality of life after surgery. The long term follow-up showed a mean range of motion at 86° with a flexion deformity of 4°. The blood loss differed significantly according to the method used for measurement. No life-threatening bleeding occurred. Twenty six haematomas (36.1%) and 2 haemarthroses (2.7%) occurred in 38.8% of cases during the first three postoperative weeks, with no significant impact on the orthopaedic outcome. The average factor consumption during hospitalization was 79IU/kg/day for patients with haemophilia A and 99IU/kg/day for patients with haemophilia B. Infections occurred in 4.1% of patients. One patient with severe haemophilia A developed an inhibitor. CONCLUSIONS: The multidisciplinary approach and the homogeneous management of our large cohort allowed the achievement of excellent functional results. Our results confirmed previously reported data on the safety and efficacy of CIFC in situations requiring intensive factor replacement, such as TKR surgery.

[Errors of red cell concentrates recipients: method of analysis using the adverse events notified to the hemovigilance network in 2009]. / Erreurs de destinataire de concentrés de globules rouges : méthode d'analyse à partir de déclarations d'incidents de la chaîne transfusionnelle en 2009.

CONTEXT: Among the adverse events in the blood transfusion process, transfusion to a "wrong" patient is potentially dangerous, as it can lead to an adverse reaction at least in case of ABO incompatible red cell concentrate. MATERIAL AND METHODS: The "Root Cause Analysis" working party of the National Hemovigilance Commission developed a tool to collect this type of adverse event, and tested it on a sample of 43 cases involving red cell concentrates notified between March, 2009 and February, 2010. RESULTS: One hundred and nine failures of a step in the transfusion process were observed, i.e. 2.5 failures per adverse event. Failures may occur early in the process. However, they are mainly found at the time of issuing of the blood component, and further, in the clinical ward. How the failure is eventually detected is not always described when the blood component has been fully transfused, in contrast with the cases where actual transfusion to the wrong patient has been prevented. Knowing the way of failure detection enables an objective approach of the efficacy of the numerous existing safety measures. In this sample, bedside controls (documents check as well as the use of anti-A and anti-B reagents with patient's blood and red cell concentrates) detected the failure in three cases out of 34, which were not detected before, showing an efficacy similar to the administrative control done at reception in the clinical ward. CONCLUSION: The document, set up to analyse step by step these cases of patient errors, will be used in the future to analyse all similar cases, not only with red cell concentrates, but also with platelet concentrates and fresh frozen plasma, ultimately in order to improve their prevention.

[Circumcision in children: an organizational or an ethical challenge?]. / Circoncision chez l'enfant : une simple question d'organisation des soins ou un enjeu éthique ?

OBJECTIVES: To review society, ethical and anaesthesiological issues related to circumcision in children. STUDY DESIGN: Review. METHODS: Pubmed search and expert opinion RESULTS: Circumcision concerns 30 of male world population. Reasons are ritual, medical and hygienic. In Muslims, circumcision is usual performed before the age of six. Surgery is performed at best under sevoflurane general anaesthesia and a penile bloc. Level 1 and level 2 antalgics are used for 72 hours, once the bloc has elapsed. In Jews, circumcision is performed soon after birth, in the community. Emla is the most convenient antalgics in this case. Except in case of emergency, circumcision under general anaesthesia should be delayed after 3 months as general anaesthesia is suspect to exert cerebral toxicity. Before the age of one year, there is a risk of increased respiratory problems following general anesthesia. Therefore, circumcision under general anaesthesia should be performed after one year of age. Circumcision may represent an adjunct to limit AIDS transmission in endemic countries. CONCLUSION: The ethical point associated with circumcision is to allow best analgesia, in a way matching child's age. Analgesia, is achievable by both the surgeon and the anesthesiologist.

[Neurological complications of the regional anesthesia: analysis of the expertises and conclusions of the Regional Commissions for Conciliation and Compensation]. / Complications neurologiques de l'anesthésie locorégionale : analyse des expertises et conclusions des CRCI.

All the files of complications of regional anaesthesias requiring an expertise for a Regional Commission for Conciliation and Compensation for medical accidents (CRCI) between 2003 and 2008 were analyzed. The objective was to estimate the homogeneity of the appointed experts, their opinions and the opinions of the CRCI. Querying the database, shared by the National Office for Compensation for Medical Accidents (ONIAM) and the CRCI, and identified 40 files corresponding to the selection criteria. The expertise carried out involved an anaesthetist in 27 cases, always registered, either on the national list of the experts in medical accidents, or on one list of court-appointed experts. Conversely, in 13 cases, no specialist performing himself the technique in question was involved in the expertise, and sometimes the expert was registered on any list. Mostly, the non-specialists do not conclude to medical malpractice. This was not the case in a single file, where the anaesthetist sought and obtained the addition of an anaesthetist in a new expertise, which concluded differently. Damages assessed were highly variable, but the given evidence provided to understand why. The CRCI have generally followed the opinions of the experts, except in a few cases where the evidence allowed a different opinion without requiring a new expertise. In conclusion, the abnormalities in the appointment of experts do not seem to have had consequences in terms of damage assessment, but may alter the balance between causes faulty and not faulty, in favour of the latter.

[Critical appraisal of organ procurement under Maastricht 3 condition]. / Analyse critique du prélèvement en condition M3 de Maastricht.

The ethics committee of the French Society of Anesthesia and Intensive Care (Sfar) has been requested by the French Biomedical Agency to consider the issue of organ donation in patients after a decision of withdrawing life supporting therapies has been taken. This category of organ donation is performed in the USA, Canada, United Kingdom, the Netherlands and Belgium. The three former countries have published recommendations, which formalize procedures and operations. The Sfar ethics committee has considered this issue and envisioned the different aspects of the whole process. Consequently, it sounds a note of caution regarding the applicability of this type of organ procurement in unselected patient following a decision to withdraw life supporting therapies. According to the French regulation concerning organ procurement in brain dead patients, the committee stresses the need to restrict this specific way of procurement to severely brain injured patients, once confirmatory investigations predicting a catastrophic prognosis have been performed. It suggests that the nature of the confirmatory investigation required should be formalized by the French Biomedical Agency on behalf of the French parliamentarians. This should help preserving population trust regarding organ procurement and provide a framework to medical decision. This text has been endorsed by the Sfar.

Evaluation of the overall haemostatic effect of recombinant factor VIIa by measuring thrombin generation and stability of fibrin clots.

It has been reported that thrombin generation test (TGT) may be a useful tool to monitor recombinant factor VIIa (rFVIIa). However, TGT does not reflect the stability of fibrin clot and its resistance to fibrinolysis which are crucial. Using whole-blood thromboelastography (TEG) and tissue plasminogen activator (tPA), we developed an in-vitro model to assess fibrin clot stability. Fibrin fibres were thicker in haemophiliacs compared with controls (P < 0.0001). After addition of rFVIIa 90 µg kg(-1), the diameter of fibrin fibres was dramatically decreased (P = 0.006). TEG-tPA assay showed a dose-dependent improvement of clot stability in the presence of rFVIIa. These data demonstrate a significant correlation between fibrin clot structure and its stability (P = 0.001). We also showed a correlation between thrombin generating capacity and clot resistance to fibrinolysis. Despite this overall correlation, a relatively large spreading around a general trend was observed, suggesting that the two assays bring complementary information on the haemostatic effect of rFVIIa.

[Citation errors: Uplavici (for Hlava) and William the Silent (for Jules Verne and Mignet)]. / Références erronées: Uplavici (pour Hlava) et Guillaume le Taciturne (pour Jules Verne et Mignet).

A certain 'O Uplavici' was cited for more than fifty years, although he had never existed. This error probably came from a misinterpretation of the Czech language, in which the real author's name--Hlava--can mean 'Title'. It was finally recognized, which was not the case for the author of the sentence: 'I have no need of hope to take action, nor of success to persevere', it is still regularly attributed in France to William I, Prince of Orange, called the Silent. It is a mistake, and no serious reference certifies that an historical figure would have pronounced this sentence. It was written by the historian Mignet in 1841, to describe the character of William III, Prince of Orange and King of England. It was then used in 1875 by Jules Verne, to describe a character in 'The Mysterious Island'.

[Acute pancreatitis and bradycardia]. / Pancréatite aiguë et bradycardie.

Acute pancreatitis is frequently associated with electrocardiographic abnormalities, including arrhythmias and repolarization. We briefly describe a male patient with a severe acute pancreatitis who presented several bradycardias during his hospitalization in our intensive care unit. The aim of this case report is to underline the probability of severe arrhythmias during acute pancreatitis, which can increase morbidity of this pathology. Despite many publications or reports, causes of increased EKG abnormalities during severe pancreatitis remained unclear and are probably multifactorial. To prevent accidents or complications, patients with severe acute pancreatitis should have a continuous EKG monitoring.

[Autopsy of a common error: the introduction of curare in Europe by W. Raleigh]. / Autopsie d'une erreur commune: l'introduction du curare en Europe par W. Raleigh.

One of the most erroneous and repeated assertion in the history of pharmacology for anaesthetists is to say that "the curare was introduced in Europe by Sir Walter Raleigh under the name of ourari". On the contrary, the names to be reminded are: Lawrence Keymis for the first citation of the word ourari, José Gumilla for the word curare and the description of its effects, Charles-Marie de La Condamine for the import of the first known samples. The mistake was initiated by Alexander von Humboldt and developed by the physiologist Münter, a student of Johannes Müller, quoted by Claude Bernard. The repetition of this error was facilitated by the world diffusion of Claude Bernard's work.

[Survey of anaesthesia-related mortality in France: the role of aspiration of gastric contents]. / Enquête mortalité Sfar-Inserm: analyse secondaire des décès par inhalation de liquide gastrique.

Aspiration of gastric contents is a major complication in relation with the practice of anaesthesia. The present article is aimed at describing detailed data related to aspiration which were obtained during the French national survey on anaesthesia-related mortality conducted by both Sfar and CépiDC-Inserm. Information regarding methods of the survey and the main results has been previously published. In brief, the first part of the survey described the number and characteristics of anaesthetic procedures performed in 1996 (denominator). The second survey analysed deaths related to anaesthesia which were identified from death certificates of the calendar year 1999. Because of the numerical importance of aspiration among the causes of deaths, a secondary analysis was undertaken to assess into details factors leading to the occurrence of this complication. Eighty-three cases of death were found related to aspiration, i.e. one-fifth of deaths related completely or partially to anaesthesia, implying a death rate of one for 221,368 general anaesthetic procedures or 4.5 x 10(-6) (95% IC: 0.8 x 10(-6)-14 x 10(-6)). Patients involved were all in a severe clinical condition (ASA> or =3: 92%), very old and often scheduled for urgent abdominal surgery. Two cases of death occurred during colonoscopy but none in obstetric patients. Aspiration almost always occurred during induction of anaesthesia. Analysis of practice patterns disclosed significant deviations from recommendations. French anaesthetists should voluntarily move through a personal and active process toward an improvement of their practice to reduce the incidence of aspiration.