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To the Editor: Anaphylactic reactions are a common complication of anesthesia, most often related to the use of muscle relaxants.1 The intensity varies from mild clinical manifestations to severe anaphylactic shock and death.2 With increased public awareness and the improvement in the detection and diagnosis of such adverse events, an increased frequency has been reported in most developed countries.3 In France, a recent survey estimated the incidence of anaphylactic reactions to be as high as one amongst 6,500 anesthetic procedures when a muscle relaxant is used.1 Approximately four individuals per 100 population (2.5 million) receive muscle relaxants during anesthesia every year.4 These data allow us to postulate that among the French population alone (60 million people), 350 patients every year will develop a muscle relaxant mediated anaphylactic reaction. Similarly, thousands of patients all over the world will experience similar adverse events. Risk reduction requires that the use of muscle relaxants be limited inasmuch as possible since anaphylaxis may occur in patients with or without a previous history of allergy.1 To date, there are two main indications for muscle relaxants during anesthesia for elective surgery. The first involves the anesthetic procedure itself, i.e., tracheal intubation, while the second relates to the surgical procedure. Muscular relaxation facilitates airway management, access to the surgical site, closure of the abdominal wall and avoids inopportune movements. However, muscle relaxants are no longer mandatory. There is now evidence that the development of new hypnotic drugs has changed airway management and allows tracheal intubation without the need for muscle relaxants in a selected population.5 From a surgical point of view, abdominal and thoracic procedures usually require muscular relaxation but, on the other hand, numerous peripheral surgical procedures such as lower abdominal and limb operations do not require the use of curare. While recent data show that it is possible to intubate the trachea without resorting to muscle relaxants, the topic remains controversial. Intubating habits vary both locally and internationally. It has been suggested that muscle relaxants decrease pharyngeal and laryngeal trauma secondary to intubation.5 As a result, several anesthesiologists are reluctant to curtail muscle relaxation for intubation. In 1996, in France, only 16% of anesthetics requiring tracheal intubation were conducted without the use of muscle relaxants.4 This puts us in a delicate situation. As anesthesiologists, we use a class of drugs, muscle relaxants, known to mediate anaphylaxis with potentially lifethreatening consequences whereas, on the other hand, there is no more doubt that we are able to avoid these drugs in many situations. Should we still widely use muscle relaxants or should we restrict their prescription? Patient safety during anesthesia requires us to take into account all risks, even those that may have been underestimated in the past.

Antiplatelet agents are administered to an increasing number of patients. Preoperative treatment with these agents represents a major problem for the anesthesiologist. The results of a French expert meeting on their perioperative management are reported.Responses to questions formulated by the Organizing Committee were drafted by a group of experts and reviewed by a multidisciplinary. Reading Committee. Recommendations were classified (grade) according to the evidence level of the studies supporting them.First, antiplatelet agents have a variable effect on hemostasis as far as bleeding risk is concerned. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) increase intra- and postoperative bleeding moderately, but not transfusion requirements. Very few data are available on clopidogrel and ticlopidin. Anti-glycoprotein (GP) IIb/IIIa agents may increase bleeding when surgery is required in proximity with their administration. Second, the common practice of withdrawing antiplatelet agents is now challenged because an increased incidence of myocardial infarction has been reported in patients in whom treatment was interrupted. Third, aspirin should not be withdrawn for most vascular procedures and in several additional settings. When a definite increase in intraoperative bleeding is feared, or when surgical hemostasis is difficult, aspirin, clopidogrel or ticlopidine can be replaced by short-acting NSAIDS, given for a ten-day period and interrupted the day before surgery. Platelet transfusion should only be given when overt bleeding is observed. Postoperatively, antiplatelet treatment should be resumed immediately after surgery (first six hours).Anesthesiologists should be aware of the indications, potential complications and means of substitution of these agents.

Oral anticoagulants and low-molecular-weight heparin are both recommended for venous thromboembolism prophylaxis after total hip replacement. To date, these regimens have not been compared by means of clinical end points in the extended prophylaxis setting.We randomly assigned 1279 patients 3 days after total hip replacement surgery to fixed-dose subcutaneous low-molecular-weight heparin (reviparin sodium, 4200 anti-Xa IU) or adjusted-dose oral anticoagulant (international normalized ratio, 2-3; acenocoumarol) for a 6-week period. The primary end point was the failure rate, defined as the combined clinical events of a confirmed symptomatic thromboembolic event, a major hemorrhage, or death. All patients were followed up throughout the study interval. The primary objective was to compare the observed cumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group.In the intent-to-treat population, objectively documented symptomatic thromboembolic events occurred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.30; 95% confidence interval for the difference, -0.8% to 2.8%). Major bleeding occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.001). The failure rate was 24 (3.7%) of 643 patients compared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants (P =.001).A significantly higher benefit-risk ratio was observed for patients undergoing elective hip replacement who received extended out-of-hospital prophylaxis with low-molecular-weight heparin vs acenocoumarol. Low-molecular-weight heparin prophylaxis was at least as effective as oral anticoagulants, but with a marked improvement in safety.

Reports about anaphylactic and anaphylactoid reactions to rocuronium have increased recently. We report two new cases of documented grade III anaphylaxis, leading to death in one patient. The first case occurred in an 81-year-old ASA II woman scheduled for emergency abdominal surgery. Severe hypotension and tachycardia were observed after rocuronium, without bronchospasm. Neosynephrine allowed rapid resuscitation, and the patient recovered fully. The second patient was a 64-year-old ASA II man scheduled for abdominal surgery. Severe haemodynamic instability and bronchospasm occurred after rocuronium. Despite immediate life support, the postoperative period was complicated by persistent low systolic pressure, acute respiratory distress syndrome, acute renal failure, disseminated intravascular coagulation and pancreatitis, leading to the death of the patient.

Introduction: Direct oral anticoagulants, previously new oral anticoagulants (NOACs) had a favorable risk–benefit profile, both for stroke prevention or systemic embolic events in patients with atrial fibrillation (AF), or for venous thromboembolism (VTE) treatment. Although the rate of intracranial hemorrhage is lower, the risk for major bleeding is similar as for warfarin. Only few data are available for the management of major bleeding in clinical practice. The aim of this study is to present preliminary results regarding characterization and care of major bleeding through a French prospective registry. Methods: The GIHP (French Working group on Perioperative hemostasis) – NACO registry is a prospective observatory started in June 2013 in 32 emergency centers in France and Belgium. Only patients treated by NOACs and hospitalized for major bleeding or urgent surgery were registered. Results: In a midterm analysis in June 2014, 339 patients were included, among which 219 for major bleeding. 75 patients were treated by dabigatran (150 mg bid: 81%), and 142 by rivaroxaban (20 mg od: 54%) (2 patients were treated by Apixaban). The mean age was 76.4 +/- 11y, and mean BMI 26.3. Creatinine clearance was lower than 60 ml/min in 65%. Patients were treated for atrial fibrillation (80%) or VTE (20%). Among patients with AF, 67.2% had CHADS2 at 2 or less. 61.6% of patients received concomitantly at least one drug interfering with CYP or Pgp, and 26.9% received another antithrombotic drug at the time of bleeding. Major hemorrhagic sites were gastrointestinal (25%) and intracranial, either spontaneous (20%) or post-trauma (15%). AOD concentrations were determined in 46% of patients. 20% of the patients with major bleeding had a plasma concentration less than 50 ng/ml. As expected, there is no relationship between drug concentrations and standard hemostatic tests such as PT and aPTT. 38.4% of patients received PCC or aPCC, and 25.7% benefited for any additional procedures (surgery, endoscopy, embolization…). 42.2% of bleeding completely stopped after the administration of clotting factors. At 30d of follow up, 9.1% of patients presented a cardiovascular event, and all-cause mortality was 14.2%. Conclusion: This midterm analysis of the GIHP NACO registry shows consistent results with phase III studies, with some particularities compared to clinical trials, especially in the use of PCC. The registry allows the analysis of specific population such as trauma patients and highlights the care of such major hemorrhages. Disclosures Pernod: LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Off Label Use: PCC and aPCC ro reverse effect of antithrombotic drugs. Albaladejo:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Samama:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Sie:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Bosson:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding.

A patient scheduled for a laparoscopic cholecystectomy had an anaphylactic shock during induction of anesthesia. After the injection of vecuronium, an unusual fall of arterial pressure occurred, with bradycardia, enlargement of the QRS complex, then a circulatory arrest. Chest compressions were initiated, while intravenous epinephrine 1 mg was administered. The cardiac rhythm turned into a ventricular fibrillation (VF). Despite continuous chest compressions with repeated boluses of epinephrine and several external electric shocks, the patient remained in VF. Because of obviously β-adrenergic adverse effects, epinephrine was replaced with norepinephrine. Return of spontaneous circulation was observed, with the recovering of sinusal activity. After staying for several weeks in intensive care unit because of multiorgan failure, the patient recovered without sequelae. Blood samples and cutaneous testing confirmed an allergy to vecuronium. This case report of a cardiac anaphylaxis with prolonged cardiac arrest illustrates the dual activity and adverse effects of epinephrine. Although vasoconstriction is mandated during cardiopulmonary resuscitation to provide an acceptable perfusion pressure to organs, β-adrenergic stimulation seems deleterious to the heart. Experimental studies have shown that blocking the β-adrenergic effects of epinephrine attenuates postresuscitation myocardial dysfunction or helps the return of spontaneous circulation after VF. Norepinephrine, a potent α-adrenergic drug nearly devoid of β-adrenergic properties, could be an interesting alternative to epinephrine. It can improve organ perfusion during cardiopulmonary resuscitation and could be more efficient than epinephrine in case of VF.

Introduction Le ticagrelor, inhibiteur reversible des recepteurs P2Y 12 a l’ADP, est un puissant agent antiplaquettaire (AAP) recommande, en association avec l’aspirine, dans le traitement des syndromes coronariens aigus. Comme tout agent antithrombotique, il expose a un risque hemorragique. Aucun antidote specifique n’est disponible. L’efficacite de la transfusion plaquettaire, preconisee dans les hemorragies liees aux AAP est rendue incertaine du fait de son caractere reversible et des concentrations plasmatiques elevees de ticagrelor et de son metabolite actif. Cependant, peu de donnees sont disponibles. L’objectif est d’evaluer, in vitro, si la supplementation en plaquettes permet de restaurer l’agregation plaquettaire inhibee par du ticagrelor. Materiel et methodes Du ticagrelor (3,25 μM soit la concentration plasmatique maximale apres une dose de charge de 180 mg) ou de l’aspirine sont ajoutes a du sang total de volontaires sains ( n = 18). L’aspirine est utilisee comme controle positif. L’agregation plaquettaire est evaluee par impedancemetrie sur sang total et agregometrie optique sur plasma riche en plaquettes (PRP) en utilisant l’ADP et l’acide arachidonique (AA) comme agonistes specifiques du ticagrelor et de l’aspirine, respectivement. La supplementation plaquettaire est definie par l’ajout d’une suspension de plaquettes lavees apportant 60 % de la quantite de plaquettes initiale. Les resultats de l’impedancemetrie sont exprimes en ohms, ceux de l’agregometrie optique, en pourcentage maximal d’agregation. Resultats Le ticagrelor inhibe l’agregation plaquettaire induite a l’ADP, en sang total (1,8 Ω vs. 8,8 Ω, p n = 6) comme en PRP (14 % vs. 77 % p n = 6). L’aspirine inhibe l’agregation induite a l’AA, en sang total (1,3 Ω vs. 6 Ω, p n = 6). L’ajout de plaquettes aux echantillons incubes avec l’aspirine restaure completement l’agregation a l’AA (9,8 Ω vs. 1,3 Ω, p = 0,008). En revanche, la supplementation plaquettaire ne corrige pas les effets du ticagrelor sur l’agregation plaquettaire a l’ADP, en sang total (1,5 Ω vs. 1,3 Ω, p > 0,05) ou en PRP (13 % vs. 14 %, p > 0,05). Discussion Dans cette etude in vitro, l’apport de plaquettes ne restaure pas l’agregation plaquettaire inhibee par une concentration therapeutique de ticagrelor. Ces resultats supportent l’hypothese de l’inefficacite de la transfusion plaquettaire en cas d’hemorragie chez un patient traite par ticagrelor.

Introduction Le ROTEM® a ete associe a une reduction significative des pertes sanguines et des besoins transfusionnels en chirurgie cardiaque, chez les traumatises, en obstetrique, en transplantation hepatique [1] . Mais, chez les patients cirrhotiques, (a) les tests ROTEM® sont correles a la baisse du taux de prothrombine (TP) et du fibrinogene, suggerant une hypocoagulabilite [2] ; (b) les tests de generation de thrombine (TGT) en presence de thrombomoduline (TM) ont revele des potentiels de liberation de thrombine endogene (PTE) identiques chez les cirrhotiques et chez des sujets normaux, suggerant que l’hemostase des cirrhotiques est reequilibree vers la normalite [2] ; (c) le TP n’a jamais ete associe a un risque de saignement chez les cirrhotiques soumis a des procedures invasives [2] . Nous avons mesure et compare (a) les tests ROTEM® appreciant la fermete du caillot, (b) le PTE avant et apres adjonction de TM, (c) les taux de facteur V et de fibrinogene, et la numeration des plaquettes chez des patients cirrhotiques. Patients et methodes Nous avons mesure chez 40 patients dont la cirrhose n’etait pas d’origine infectieuse ou immunologique, (a) le facteur V, le fibrinogene, et la numeration des plaquettes ; (b) la fermete du caillot basee sur les tests MCF en EXTEM, INTEM, FIBTEM, du ROTEM® ; (c) le PTE sur du plasma pauvre en plaquettes, avant et apres adjonction de TM, et le pourcentage de diminution du PTE apres adjonction de TM (δ PTE). Les scores de MELD ont apprecie la gravite de la cirrhose. Le test de Spearman a ete utilise. ρ > 0,5 and p Resultats Des cirrhoses de toutes gravites ont ete inclues. Le PTE etait normal apres adjonction de TM, montrant une coagulation normale. Les tests ROTEM® de fermete du caillot etaient (a) correles au facteur V, au fibrinogene, et a la numeration des plaquettes, suggerant une hypocoagulabilite correlee au degre de l’insuffisance hepatique et une indication a perfuser du plasma frais et des plaquettes avant la chirurgie chez certains patients et (b) predictifs du δ PTE revelant un potentiel de normo coagulation correle au degre de l’insuffisance hepatique. Le test FIBTEM n’est pas dependant des plaquettes et n’est donc pas correle a la numeration des plaquettes ( Tableau 1 ). Discussion Ces resultats sont en accord avec les bases physiologiques de l’hemostase [3] : (a) les tests ROTEM® rendent compte seulement de la fibrinoformation qui represente 5 % de la coagulation globale [3] ; (b) le PTE en presence de TM rend compte de l’ensemble de la coagulation conduisant a la generation de thrombine qui est l’enzyme cle de la coagulation [3] ; (c) le PTE a ete predictif du risque de saignement et de thrombose dans plusieurs situations a risque [3] . En conclusion, les tests ROTEM® ne sont pas appropries pour monitorer la coagulation chez les patients cirrhotiques. Ils indiquent une hypocoagulabilite non confirmee par la generation de thrombine qui est normale.

Introduction Le memoire de Diplome d’Etudes Specialisees (DES) d’Anesthesie-Reanimation est un travail de recherche qui represente frequemment une epreuve pour les internes et dont les resultats sont souvent inferieurs aux attentes des enseignants et des etudiants. Il apparait donc necessaire de s’interroger sur le fondement de ce memoire, les difficultes rencontrees au cours de sa realisation et les moyens de les surmonter et d’en ameliorer la qualite. Materiel et methodes Une enquete prospective en population par questionnaire a ete realisee aupres des internes d’Anesthesie-Reanimation d’Ile-de-France de 2e, 3eet 4e annees (n = 186, mars–avril 2013). Les internes etaient interroges sur leur opinion vis a vis du memoire, leur satisfaction, leurs attentes concernant le sujet, son choix et l’encadrement existant ou envisage, les formations complementaires suivies ou souhaitees, et leur opinion face a d’autres propositions d’amelioration. Resultats L’exhaustivite des reponses atteint 79 %. Cinquante deux pour cents des repondeurs ont un sujet de memoire au moment de l’enquete. La moitie des internes considere que ce memoire a un interet pour leur formation et leur pratique quotidienne, 63 % d’entre eux pensent que ce memoire represente un enrichissement personnel et 90 % comptent en tirer une satisfaction personnelle. La quasi-totalite des internes souhaite que le sujet corresponde a leur centre d’interet, mais la moitie d’entre eux seulement pense que c’est a eux de proposer le sujet. Dans les faits, le sujet est propose par l’encadrant dans 80 % des cas. L’implication a chaque etape de la recherche est tres variable d’une etudiant a l’autre, sauf pour le recueil de donnees ou l’implication est forte (76 % des internes participent a plus de 50 % de cette etape), et pour l’obtention des autorisations ou, a l’inverse, elle est faible. Chez ceux qui n’ont pas de sujet, l’absence d’encadrant est la premiere raison evoquee (20 %). Entre 70 et 90 % des internes approuvaient les propositions de modification, a l’exception d’une date limite pour le choix du sujet. Les propositions de mise en contact avec des encadrants et de formations complementaires etaient les plus souvent sollicitees. En particulier, les internes souhaitaient plus de formations en statistiques (29 % des internes) et a des logiciels de bureautique (21 % des internes). Discussion Le memoire de DES represente un travail valorise aupres des internes d’Anesthesie-Reanimation et auquel ils sont attaches. L’amelioration de l’encadrement des internes et des formations theoriques complementaires pourrait augmenter leurs competences a realiser leur projet de recherche.

See also Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in clinical investigations of anti-hemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8: 202–4; Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in surgery: an anaesthesiologist's point of view: reply to a rebuttal. This issue, pp 1443–4.

Auteur(s) : Anne Godier, Charles-Marc Samama Hotel-dieu, Service d’anesthesie reanimation, 1 place du parvis de Notre Dame, 75004 Paris Un homme de 68 ans, tabagique non sevre, hypertendu et arteritique, a ete opere d’une lobectomie superieure droite pour un carcinome epidermoide. Les suites operatoires ont ete marquees par une pneumopathie postoperatoire hypoxemiante compliquee d’un choc septique necessitant deux semaines d’hospitalisation en reanimation. [...]

Improve the results of phase II trials of thromboprophylaxis with the new oral anticoagulant drugs

We have investigated residual block after anaesthesia which included the use of the neuromuscular blocking agent vecuronium but no anticholinesterase, in 568 consecutive patients on admission to the recovery room. The ulnar nerve was stimulated submaximally using TOF stimulation (30 mA). Postoperative residual curarization was defined as a TOF ratio0.7. Of the 568 patients, 239 (42%) had a TOF0.7 in the recovery room. These patients had received a larger cumulative dose of vecuronium than patients who had full recovery (mean 7.7 (SD 3.6) mg vs 6.2 (2.7) mg; P0.05) and a shorter time had elapsed since the last vecuronium dose (117 (70) min vs 131 (80) min; P0.05). Of 435 patients whose trachea was extubated, 145 (33%) exhibited inadequate recovery from neuromuscular block. Six of these had one or no response to TOF stimulation and were reintubated. In the remaining 139 patients, neuromuscular block was successfully antagonized. Only 20 patients (3.5%) remembered TOF stimulation when questioned 2 h later in the recovery room, and discomfort associated with it was assessed using a visual analogue scale before discharge. We conclude that it is necessary to antagonize residual block produced by vecuronium.

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with hemostasis during the perioperative period, and the combination of NSAID and enoxaparin could increase this effect. The aim of this prospective, blinded experimental study was to assess these effects using a model of arterial thrombosis and bleeding in the rabbit. Methods After anesthesia was induced and monitors placed, the common carotid arteries were exposed, and 60% stenosis of the right common carotid artery was produced. Twenty minutes later, a compression injury of the artery was produced that triggered a series of cyclic episodes of thrombosis and clot lysis. This was manifested as cyclic flow reductions (CFR; measured with an electromagnetic flow meter). After the first flow reduction was noted, the rabbits were immediately and randomly assigned to one of four groups (n = 10 each) that received intravenous infusions: control, ketorolac (2 mg/kg), enoxaparin (0.5 mg/kg), and ketorolac plus enoxaparin (2 mg/kg and 0.5 mg/kg, respectively). The number of CFRs that occurred in the subsequent 20-min period was used as a measure of treatment effect. The contralateral common carotid artery was exposed, and both stenosis and injury were produced. The ability of the administered drug to prevent thrombosis was assessed as the number of CFRs that occurred during the first 20-min period after vessel injury. In addition, both before and after group assignment and drug injection, bleeding times were noted and a platelet aggregation test was performed. Laparotomy was followed by a spleen section, and the extent of the wound and the amount of splenic bleeding were measured. Results The treatment effect was indicated by the median number of CFRs, which was 5.5 in the control group, 1 in the ketorolac group, 2 in the enoxaparin group, and 0 in the ketorolac + enoxaparin group. The prevention effect was indicated by the median number of CFRs, which was 4 in the control group, 0 in the ketorolac group, 2 in the enoxaparin group, and 0.5 in the ketorolac + enoxaparin group. Bleeding time was significantly lengthened in the enoxaparin and in the ketorolac + enoxaparin groups. Splenic and wound bleeding was greater in the ketorolac group. Platelet aggregation was completely inhibited in the ketorolac and the ketorolac + enoxaparin groups. Conclusions Ketorolac had an important antithrombotic activity. The association of enoxaparin with ketorolac seemed to lengthen the bleeding time observed with ketorolac.

Background: As any potent anticoagulant, apixaban, an oral factor Xa inhibitor, exposes to a risk of haemorrhagic complications. Thus in the absence of specific antidote, bleeding management is challenging. Aim: To investigate the efficacy of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and partially activated PCC (aPCC) to compensate, in vitro, the anticoagulant effects of apixaban. Methods: Whole blood (WB) from healthy volunteers was spiked with therapeutic (200 ng.ml-1) or overdose (680 ng.ml-1) amount of apixaban and either rFVIIa (equivalent to 90 and 120 μg.kg-1), PCC (25 and 50 UI.kg-1), or aPCC (80 and 160 UI.kg-1). Reversal was assessed on WB with thromboelastography, and on platelet poor plasma using standard laboratory assays (PT, aPTT) as well as thrombin generation test (TGT). Increase of clot turbidity was also recorded to explore the dynamics of fibrin polymerization. Results: Apixaban concentration dependently lengthened PT, aPTT, and the clotting time (CT) in ROTEM®. It also increased lag time (LT) and decreased endogenous thrombin potential (ETP) as well as peak height in the TGT. Apixaban delayed and slowed down fibrin formation and polymerization with subsequent alteration of the resulting clot. rFVIIa had predominant effects on kinetics parameters. Addition of rFVIIa overcorrected PT, aPTT, and CT at apixaban therapeutic concentration and partly restored them in overdose situation. rFVIIa also decreased LT, and accelerated fibrin polymerization at therapeutic dose. Addition of PCC shortened PT and CT, increased peak height and ETP, but paradoxically lengthened aPTT and little modified the turbidity profile. Addition of aPCC shortened PT, aPTT, and LT in the TGT, whereas it did not affected CT in ROTEM®. aPCC also increased peak high, overcorrected ETP, and induced earlier and faster fibrin polymerization. Conclusions: These non-specific prohaemostatic agents corrected partially or completely several laboratory parameters. In particular aPCC, improving most of them was the most seducing. Further investigation is nevertheless necessary: reversal of aPCC was not confirmed in WB, increasing concentration of the prohaemostatic agents had no additive effect, and putative efficacy was strongly dependent on the observed parameter (rFVIIa was best on CT; PCC on ETP). Overall our observations underline the need for robust endpoints and clinical trials.

The pharmacologic specificity of low-molecular-weight heparins (LMWHs) has enabled multiple attractive developments in the prophylaxis and treatment of arterial thrombosis. Their high antithrombotic potency associated with a potentially lower induced bleeding risk, the lack of platelet interaction, the prevention of myointimal hyperplasia, and the lower incidence of heparin-induced thrombocytopenia, are major advantages. New studies in cardiology and vascular surgery demonstrate a high efficacy for LMWHs associated with a low risk.

Abstract 2269 Background: In randomized, double-blind, phase III trials, dabigatran etexilate (DE) 220 mg once daily (qd) was as effective as enoxaparin 40 mg qd in preventing venous thromboembolism (VTE) following total hip or knee replacement (THR, TKR), with a favourable safety profile. As patient populations in clinical practice may differ from those in clinical trials, we conducted an international, observational, single-arm study to evaluate the safety and efficacy of DE in a real-world setting. A prespecified secondary objective was to generate epidemiological data on the incidence of co-morbidities and co-medications in TKR and THR patients treated with DE in a routine clinical setting. We present here these epidemiological results as well as the patient characteristics observed in phase III clinical trials of DE and historical population studies. Methods: Patients were recruited at 110 sites in 9 countries in the European Union. The protocol required that patients were aged ≥ 18 years, undergoing elective THR or TKR and eligible for DE 220 mg qd (first dose 110 mg 1–4 hours after surgery) according to the European label (≤ 75 years old with creatinine clearance [CrCL] > 50 mL/min). Baseline data were collected at the screening visit prior to surgery. In the phase III clinical trials of DE, randomization to DE 220 mg qd or 150 mg qd was irrespective of age and renal function. Results: Of the 5292 patients treated in this observational study, 2734 underwent THR and 2558 TKR. Table 1 shows the baseline demographics and medical history and the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA). Patients undergoing TKR were more often female and mean BMI was higher than THR patients. With the exception of diabetes, other co-morbidities and co-medications were comparable between TKR and THR patients. Mean CrCL and mean age at baseline were influenced by the inclusion and exclusion criteria for the study and therefore differed from those in the Phase III DE trials (Table 2). Regarding gender, BMI, diabetes and history of VTE, the data from the observational study are generally comparable to those found in other large observational studies (e.g., White, et al. Arch Intern Med. 1998;158:1525–1531; Andersen, et al. Chest. 2003;124:349–356; Warwick, et al. J Bone Joint Surg Br. 2007;89-B:799–807). The incidences of the primary endpoints for efficacy (symptomatic VTE and all-cause mortality) and safety (major bleeding events) in the observational study are reassuring and supportive of the evidence seen in the clinical trials. Conclusions: Demographic characteristics of the patients included in the observational study are broadly aligned with previously published real-world data sets and add detail on co-morbidities. Patients included in this observational study were in general similar to those of the phase III TKR and THR trials of DE but a valid direct comparison between these data should take into account the differences in age and renal function due to study design. Disclosures: Rosencher: Sanofi (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Pfizer (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; BMS (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Bayer (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; GSK (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees. Frostick:Pfizer (anticoagulant therapy): Speakers Bureau; Bristol-Myers Squibb (anticoagulant therapy): Speakers Bureau; Biomet (product development and education): Speakers Bureau; Boehringer Ingelheim (anticoagulant therapy): Speakers Bureau; DePuy (product development and education): Consultancy; Boehringer Ingelheim (anticoagulant therapy): Consultancy; Biomet (product development and education): Consultancy; DePuy (product development and education): Research Funding; Johnson & Johnson (anticoagulant therapy): Research Funding. Feuring:Boehringer Ingelheim (anticoagulant therapy): Employment. Kleine:Boehringer Ingelheim (anticoagulant therapy): Employment. Brueckmann:Boehringer Ingelheim (anticoagulant therapy): Employment. Clemens:Boehringer Ingelheim (anticoagulant therapy): Employment. Samama:GSK (anticoagulant therapy): Primary Investigator Other; LFB (anticoagulant therapy): Primary Investigator, Primary Investigator Other; Fresenius: Membership on an entity's Board of Directors or advisory committees; Curacyte (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Bayer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Baxter (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Lilly (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; BMS (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; GSK (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; CSL Behring (anticoagulant therapy): Honoraria; Biotest (anticoagulant therapy): Honoraria; Bayer (anticoagulant therapy): Honoraria; Boehringer Ingelheim (anticoagulant therapy): Honoraria; LFB (anticoagulant therapy): Honoraria; Cordis (product development and education): Honoraria; Sanofi (anticoagulant therapy): Primary Investigator, Primary Investigator Other.

Abstract 1160 Background: Dabigatran etexilate (DE) 220 mg once daily (qd) was as effective as enoxaparin 40 mg qd in phase III trials for the prevention of venous thromboembolism (VTE) in orthopaedic surgery patients, with a favourable safety profile. Recommendations from the European Medicines Agency state that DE 110 mg should be administered 1–4 hours after surgery and 220 mg thereafter, in patients ≤ 75 years and without moderate renal impairment or concomitant verapamil, amiodarone or quinidine. The aim of this prospective, international, observational, single-arm study was to evaluate the safety and efficacy of DE in a real-world setting, with a particular focus on pre-specified subgroups that may represent an increased risk of bleeding and/or VTE. We report here a prespecified analysis of the results for additional subgroups with different body mass index (BMI), creatinine clearance (CrCL) and age. Methods: Patients were included if aged ≥ 18 years and undergoing elective total hip or knee replacement (THR, TKR). Patients also had to be eligible for DE 220 mg qd according to the European label. The primary safety endpoint was the incidence of major bleeding events (MBEs) as defined in the pivotal clinical trials of DE; the primary efficacy endpoint was documented symptomatic VTE (sVTE) (the composite of symptomatic proximal and distal deep vein thrombosis and symptomatic non-fatal pulmonary embolism) and all-cause mortality. The observation period was from the first dose to 24 hours after the last dose of DE. We examined the incidence of these endpoints stratified by baseline BMI, CrCL and age, all characteristics with potential influence on bleeding and/or efficacy. Results: 5292 patients were included in the study. Median BMI was 28.4 kg/m2. Median CrCL was 95.4 mL/min, with 70.4% of patients having CrCL ≥ 80 mL/min and 26.0% with CrCL 50 to < 80 mL/min. Median age was 64 years. A small proportion of patients were treated who had moderate renal impairment (1.1%) or were > 75 years old (0.8%); no differences in primary efficacy or safety results were seen in these underpowered groups. The incidence of MBEs for all patients was 0.72% (95% CI: 0.51, 0.98%).Occurrence of MBEs was comparable for subgroups of patients with BMI ≤ 35 kg/m2 and numerically higher for severely obese patients with BMI > 35 kg/m2 (1.47%). The rate of MBE was not affected by age < 65 or ≥ 65 years. There were no differences for patients with CrCL ≥ 80 or those with CrCL 50 to < 80 mL/min. Incidence of sVTE and all-cause mortality in patients treated in the total population was 1.04% (95% CI: 0.78, 1.35%). The rates were comparable in patients stratified according to their BMI, age and CrCL. Overall, the type of surgery, THR or TKR, did not impact on the incidence of MBEs (0.69% [95% CI 0.42%, 1.08%] and 0.74% [95% CI 0.45%, 1.16%], respectively), whereas the composite of sVTE and death was more common in the TKR group (1.56% [95% CI 1.12%, 2.12%]) than the THR group (0.55% [95% CI 0.31%, 0.90%]), as expected. The stratified analysis by surgery type did not show differences in incidence rates of the primary efficacy or safety endpoints across BMI, age or CrCL sugroups. Conclusion: DE 220 mg qd administered to patients undergoing TKR or THR according to the European label showed a favourable safety profile in a real-world clinical setting irrespective of their BMI, renal function and age. Disclosures: Rosencher: BMS (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Pfizer (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Sanofi (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; GSK (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Bayer (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees. Frostick:DePuy: Research Funding; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Biomet: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; DePuy: Consultancy; Boehringer Ingelheim: Consultancy; Biomet: Consultancy; Johnson & Johnson: Research Funding. Feuring:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Kleine:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Brueckmann:Boehringer Ingelheim Pharma GmbH & cO.kg: Employment. Clemens:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Samama:Cordis (product development and education): Honoraria; LFB (anticoagulant therapy): Honoraria; Boehringer Ingelheim (anticoagulant therapy): Honoraria; Bayer (anticoagulant therapy): Honoraria; Biotest (anticoagulant therapy): Honoraria; CSL Behring (anticoagulant therapy): Honoraria; Sanofi-Aventis (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; GSK (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; BMS (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Lilly (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Baxter (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Bayer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Curacyte (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Fresenius: Membership on an entity's Board of Directors or advisory committees; LFB (anticoagulant therapy): Primary Investigator, Primary Investigator Other; GSK (anticoagulant therapy): Primary Investigator Other; Sanofi (anticoagulant therapy): Primary Investigator, Primary Investigator Other.

International audience; ABSTRACT: INTRODUCTION: Prothrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008. METHODS: All consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion. RESULTS: Of 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR. CONCLUSIONS: Severe bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.

C.-M. Samama *, B. Gafsou , T. Jeandel , S. Laporte , A. Steib , E. Marret , P. Albaladejo , P. Mismetti , N. Rosencher a a Service d’anesthesie-reanimation, groupe hospitalier Cochin-Broca Hotel-Dieu, 1, place du Parvis-de-Notre-Dame, 75181 Paris cedex 04, France b Service d’anesthesie-reanimation, hopital Avicenne, Bobigny, 125, rue de Stalingrad, 93006 Bobigny cedex, France c Service de pharmacologie clinique, hopital Bellevue, CHU de Saint-Etienne, 29, boulevard Pasteur, 42055 Saint-Etienne cedex 2, France Departement d’anesthesie-reanimation, CHU, hopitaux universitaires de Strasbourg, 1, place de l’Hopital, 67091 Strasbourg cedex, France Departement d’anesthesie-reanimation, groupe hospitalier Saint-Antoine–Tenon–Trousseau, 4, rue de la Chine, 75020 Paris, France f Pole d’anesthesie-reanimation, CHU de Grenoble, BP 217, 38043 Grenoble cedex 09, France

Because many patients with atherosclerotic disease of the abdominal aorta also have coronary artery disease, assessment of cardiac risk before abdominal aortic surgery has received much attention. Our prospective study was designed to identify predictors of cardiac risk in consecutive patients evaluated preoperatively with dipyridamole-thallium single-photon-emission computed tomography (SPECT) to assess myocardial perfusion and radionuclide angiography to measure left ventricular ejection fraction.Clinical and scintigraphic data were collected prospectively during hospitalization in 457 consecutive patients undergoing elective abdominal aortic surgery. Adverse cardiac outcomes were predicted with multivariate analyses.Eighty-six patients (19 percent) had one or more of the following postoperative complications: prolonged myocardial ischemia (61 patients), myocardial infarction (22), congestive heart failure (20), and severe ventricular tachyarrhythmia (2). Twenty patients died postoperatively (4.4 percent), half of them from cardiac causes. Information about myocardial perfusion obtained from dipyridamole-thallium SPECT did not accurately predict adverse cardiac outcomes. The best correlates of cardiac complications were definite clinical evidence of coronary artery disease (odds ratio, 2.6; 95 percent confidence interval, 1.6 to 4.3) and age greater than 65 years (odds ratio, 2.3; 95 percent confidence interval, 1.4 to 3.6). Measurement of the ejection fraction was useful only in the prediction of left ventricular failure. Age greater than 65 years was the only predictor of death (odds ratio, 26.4; 95 percent confidence interval, 3.5 to 200.0).The presence of definite clinical evidence of coronary artery disease and older age were the most important preoperative predictors of an adverse cardiac outcome after abdominal aortic surgery. These results suggest that the routine use of dipyridamole-thallium SPECT and radionuclide angiography for screening before abdominal aortic surgery may not be justified.

Introduction L’incidence de la thrombose veineuse postoperatoire apres chirurgie reglee ou non de la jambe et du pied est mal connue. Le role de l’obesite comme facteur de risque est mal precise mais il justifie portant le recours frequent a des posologies d’HBPM augmentees lors d’un traitement preventif. L’objectif de cette etude est de decrire et comparer les strategies de prise en charge (prophylaxie antithrombotique periet postoperatoire) chez des patients obeses (BMI > 30) et nonobeses devant subir une intervention chirurgicale a la jambe ou au pied. Methodes L’etude ENVOL est une etude de cohorte, observationnelle, longitudinale, multicentrique, effectuee en France a partir de decembre 2006 et incluant 2400 patients.- 45 % obeses et 55 % non obeses. La prophylaxie thromboembolique a ete laissee libre selon les protocoles des differents investigateurs. Les donnees pre, peri et postoperatoires ont ete relevees jusqu’a la 12e semaines + 3, comportant notamment le type de chirurgie, le type d’immobilisation eventuelle, le type et la duree du traitement prophylactique, la survenue de complications thromboemboliques, d’infarctus du myocarde, d’angor instable, d’AVC et de complications chirurgicales precoces. Les complications thromboemboliques ont ete validees par un comite d’experts independants. Resultats 2400 patients ont ete inclus (fractures de jambe et de cheville, chirurgie de l’arriere pied et de l’avant pied). L’analyse est en cours et apportera les reponses concernant la pertinence des differentes strategies de prise en charge (absence ou non, duree) en fonction des parametres chirurgicaux et de l’obesite. L’incidence des evenements thromboemboliques sera rapportee et d’eventuels facteurs predictifs de survenue seront identifies.

Background Oral anticoagulants and low-molecular-weight heparin are both recommended for venous thromboembolism prophylaxis after total hip replacement. To date, these regimens have not been compared by means of clinical end points in the extended prophylaxis setting. Methods We randomly assigned 1279 patients 3 days after total hip replacement surgery to fixed-dose subcutaneous low-molecular-weight heparin (reviparin sodium, 4200 anti-Xa IU) or adjusted-dose oral anticoagulant (international normalized ratio, 2-3; acenocoumarol) for a 6-week period. The primary end point was the failure rate, defined as the combined clinical events of a confirmed symptomatic thromboembolic event, a major hemorrhage, or death. All patients were followed up throughout the study interval. The primary objective was to compare the observed cumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group. Results In the intent-to-treat population, objectively documented symptomatic thromboembolic events occurred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively ( P = .30; 95% confidence interval for the difference, −0.8% to 2.8%). Major bleeding occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively ( P = .001). The failure rate was 24 (3.7%) of 643 patients compared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants ( P = .001). Conclusions A significantly higher benefit-risk ratio was observed for patients undergoing elective hip replacement who received extended out-of-hospital prophylaxis with low-molecular-weight heparin vs acenocoumarol. Low-molecular-weight heparin prophylaxis was at least as effective as oral anticoagulants, but with a marked improvement in safety.

The survey of how Canadian intensive care units (ICUs) prevent and diagnose venous thromboembolism (VTE) presented in this issue of Critical Care illustrates considerable variability. Lack of optimal patient care reflects how VTE is rated in ICUs. The discussion should no longer focus on the incidence of thrombosis, but rather on its prevention. Unfractionated heparin remains the most commonly used agent to prevent VTE, despite the recognized efficacy and safety of low-molecular-weight heparins (LMWHs) in the ICU setting. In addition, too few ICU directors consider the use of mechanical prophylactic measures, such as graded elastic stockings and venous foot pump. The present situation calls for large randomized controlled trials in either medical or surgical ICU patients, and for new education programmes in order to modify the care of ICU patients with regard to VTE.

Background Nitric oxide inhibits platelet adhesion and aggregation in vitro. The aim of this prospective study was to assess the platelet antiaggregating activity of nitric oxide administered to patients with acute respiratory distress syndrome (ARDS) at increasing concentrations. Methods In six critically ill patients (mean age 37 +/- 16 yr) with ARDS (lung injury severity score > or = 2.2), the lungs were mechanically ventilated with inhaled nitric oxide (1, 3, 10, 30, and 100 ppm) randomly administered. Patients with cardiac dysrhythmias, septic shock, an underlying hemostasis disorder (constitutive or acquired), a platelet count less than 100 Giga/l, or a decreased platelet aggregation and those treated with antiplatelet or anticoagulant agents were excluded. Platelet aggregation was measured without nitric oxide and at each nitric oxide concentration in platelet-rich plasma issued from radial artery. Ivy bleeding time using a horizontal incision was simultaneously performed. Results After nitric oxide, a non-dose-dependent but statistically significant decrease in ex vivo platelet aggregation induced by three aggregating agents was observed: adenosine diphosphate = -56 +/- 18%, collagen = -37 +/- 18%, and ristocetin = -45 +/- 18% (P < 0.05). In each individual, Ivy bleeding time remained within normal values measured in healthy volunteers, and variations after nitric oxide did not correlate with changes in platelet aggregation. Simultaneously, arterial oxygenation improved significantly and pulmonary artery pressure decreased significantly. Conclusions In patients with ARDS and without preexisting coagulation disorders, the beneficial effects of inhaled nitric oxide on arterial oxygenation and pulmonary circulation are associated with a significant inhibition of platelet aggregation. This antithrombotic effect is not associated with a significant prolongation of the bleeding time.