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.

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.

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.

Mortality related to anaesthesia in France: analysis of deaths related to airway complications.

Death certificates from the French national mortality database for the calendar year 1999 were reviewed to analyse cases in which airway complications had contributed to peri-operative death. Respiratory deaths (and comas) found in a previous national 1978-82 French survey (1:7960; 95% CI 1:12,700 to 1:5400) were compared with the death rate found in the present one: 1:48,200 (95% CI 1:140,000 to 1:27,500). In 1999, deaths associated with failure of the breathing circuit and equipment were no longer encountered and no death was found to be related to undetected hypoxia in the recovery unit. Deaths related to difficult intubation also occurred at a lower rate than in the previous report (1:46,000; 95% CI 1:386,000 to 1:13,000) in 1978-82 vs 1:176,000 (95% CI 1:714,000 to 1:46,000) in 1999, a fourfold reduction. In most cases, there were both inadequate practice and systems failure (inappropriate communication between staff, inadequate supervision, poor organisation). This large French survey shows that deaths associated with respiratory complications during anaesthesia have been strikingly reduced during this 15-year period.

Adaptability of protein A-immunoadsorption allows temporary reduction of anti-VIII antibodies and realisation of high-risk haemorrhagic surgery.

We report the successful treatment by protein A-immunoadsorption (IA) of an hemophilic man with anti-F VIII antibodies (Abs) who needed high-risk bleeding surgery. This patient had developed high levels of anti-F VIII Abs preventing substitution by clotting factor and preventing high-risk bleeding surgery. Because of rebound in Abs levels or complications, IA procedures were modified several times leading to appropriate decrease of anti-F VIII inhibitor Abs allowing bilateral knees surgery. IA procedure is enough adaptable to be modified to prevent complications. Collaboration between clinical, biological, apheresis and surgical teams implied has permitted surgery and prevented life-threatening bleeding complications.

[Changes in transfusion practice for surgery]. / Evolution des pratiques transfusionnelles pour la chirurgie.

The context of transfusion has changed in recent years. Some data could lead to an increased demand: the risk of viral transmission has significantly decreased; a national survey has revealed that the mortality related to an insufficient or delayed transfusion was higher to the side effects of the transfusion itself. Some other data could decrease the demand: the preoperative use of EPO is now easier; the intraoperative use of antifibrinolytic has been shown to be efficient. The number of allogenic red blood cells units (RBCs) transfused each year in France regularly increases, while the transfusion of predeposited autologous blood is in sharp decline. However, in hospitals still using but reducing this technique, the consumption of allogenic RBCs does not increase and the transfusion of any blood (allogenic and/or autologous) decreases. The strategy is based on preoperative evaluation of usual blood loss and tolerable blood loss by accepting a reasonable risk of allogenic blood transfusion. Advances in public health seem to be found above all in the analysis of system failures.

Impact of choice of treatment for bleeding episodes on inhibitor outcome in patients with mild/moderate hemophilia a and inhibitors.

Patients with mild/moderate hemophilia A (MHA) may develop inhibitors to factor VIII (FVIII). In this condition, FVIII clotting activity (FVIII:C) baseline levels may remain stable for some patients, but may be reduced to less than 0.01 U/mL for others. Several risk factors for the development of inhibitors in MHA have been proposed. Genetic factors, such as mutations in the FVIII gene, may play a central role; however, other influences, such as intensive treatment with FVIII products, may also be important. Optimal treatment regimens have yet to be determined, not only for the eradication of inhibitors, but also for the management or surgical prophylaxis of hemorrhages associated with this condition. Several treatment options for the control of bleeding in patients with MHA and inhibitors (MHAI) are currently available, and the choice of therapeutic strategy should be given careful consideration; some treatments may produce an anamnestic response, thus delaying the return to FVIII:C baseline levels and adversely affecting the duration of the severe bleeding phenotype. To increase our knowledge of MHAI, a retrospective collection of data is currently being performed among hemophilia centers in France and Belgium. Based on five examples of patients with MHAI collated from preliminary study data, we illustrate the impact on inhibitor outcome of the therapeutic choices used to treat bleeding episodes in these patients.

Reducing the risk of anaphylaxis during anaesthesia: guidelines for clinical practice.

These guidelines represent a consensus of experts in the field of immediate hypersensitivity reactions occurring during anaesthesia. They were based on international science, and implemented in France under the auspices of the French Society for Anaesthesia and Intensive Care (SFAR: Société Française d'Anesthésie et de Reanimation). Their aim was to provide the most valid, widely accepted, effective and easily teachable guidelines that current knowledge, research and experience can provide. This paper presents the main extracts of these recommendations with the most relevant clinical implications.

Decreased transmission of Enterobacteriaceae with extended-spectrum beta-lactamases in an intensive care unit by nursing reorganization.

In our gastrointestinal surgical intensive care unit (SICU), the large number of patients with multiple enterostomies enhances the risk of nosocomial transmission of gut extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) by health care workers. A control study performed in our SICU from June-August 1992 showed an ESBLE gut colonization rate of 70%. To reduce this rate, nursing procedures were intensified or modified, particularly handwashing, single-use equipment and waste control. To test the efficiency of these procedures, 64 patients hospitalized for more than two days from September 1992-March 1993 were screened for gut acquisition of ESBLE. Rectal samples were taken within 48 h after admission and then weekly. After nursing reorganization, the ESBLE colonization rate dropped significantly to 40% (P < 0.001). Twenty patients (31.7%) acquired a gut ESBLE, after a mean of 24.3 +/- 13.7 days. Each patient was colonized with one, two or three ESBLE (Klebsiella pneumoniae, Escherichia coli and Enterobacter aerogenes). Baseline characteristics of the 20 colonized and 39 non-colonized patients showed no significant difference (Student's t-test, P > 0.05). The nursing workload, estimated as a omega index, was greater in the colonized group (P < 0.001). These findings show that strict observance of nursing procedures can significantly reduce ESBLE acquisition in a high-risk surgical unit.

Overall experience with NovoSeven.

Recombinant activated factor VII (rFVIIa, NovoSeven) was first developed for treating those haemophilia patients with inhibitors who cannot benefit from conventional therapies. Several clinical trials have clearly demonstrated that rFVIIa is a safe and effective therapy for home treatment of mild-to-moderate bleeding episodes. Its theoretical inability to abnormally activate the coagulation system has also prompted many clinicians to use it in elective surgical procedures. Recommended dose ranges for rFVIIa usually vary from 60 to 120 microg/kg, although 90 microg/kg is generally accepted as an initial treatment dose. If necessary, further rFVIIa can be administered as bolus injections every 2 to 6 h or, alternatively, as a continuous infusion. In patients with congenital haemophilia, this treatment is effective in up to 92% of cases. Recombinant FVIIa has also been successfully used in patients with acquired haemophilia where results have shown a wide safety margin, suggesting that rFVIIa should be considered as first-line therapy. The prospect of extending the indication of rFVIIa exists, and preliminary reports suggest that rFVIIa could be useful in patients with congenital or acquired platelet disorders, thrombocytopenia or liver failure. This drug represents a major advance in the treatment and prevention of bleeding in predisposed patients.

Evaluation of coagulation equilibrium at baseline and during factor VIII and factor IX replacement in haemophiliacs.

We designed a prospective unicentre study to evaluate the safety and efficacy of continuous infusion of different factor VIII (FVIII) and FIX concentrates in haemophilia A (n = 9) and haemophilia B (n = 4) patients undergoing surgical procedures. This study was designed to assess the potential risk of developing thromboembolic complications during different types of surgery and to provide some comparative data with respect to continuous infusion of clotting factor concentrates. Heparin prophylaxis was not used in most cases. As pointed out by others, we did not find any significant changes in prothrombin fragment F1+2 and D-dimers during a pharmacokinetic study using a bolus dose of 50 U/kg of a very high purity clotting factor concentrate. Moreover, prothrombin F1+2 and D-dimer serial assays were also carried out postoperatively, and compared with levels in control non-haemophilic patients who had undergone similar surgery with heparin prophylaxis. In haemophilia patients, despite (in most cases) an absence of heparin prophylaxis, no thrombotic complications occurred, and neither the coagulation cascade nor the fibrinolytic system were significantly over-activated, compared with the control group. From a clinical standpoint, all patients achieved excellent haemostasis without clinical evidence of thrombosis. This study emphasizes the convenient and safe administration of highly-purified FVIII and FIX concentrates in haemophiliacs undergoing surgical procedures, and constitutes a small comparative database for the evaluation of new products.

Hepatic vascular exclusion (HVE) for major liver resections.

One hundred fifty-three patients underwent hepatic resection. Hepatic venous exclusion (HVE) was utilized in 23%. Aortic clamping was used in 20% of cases with hepatic venous exclusion. The mean duration of liver ischemia was 33 minutes. HVE increases the resectability of massive posterior or hypervascular liver tumors and prevents the risk of massive bleeding or air embolism. The only counterindication is the presence of severe preexisting cardiac dysfunction.

[Heart transplantation. Experience at La Pitié hospital. Apropos of 82 cases]. / La transplantation cardiaque. L'expérience de La Pitié. A propos de 82 cas.

Since 1968, 320 patients with severe irreversible myocardial failure, have been referred to our department for transplantation; 78 p. 100 had dilated cardiomyopathies; 14 p. 100 had ischaemic heart disease and 8 p. 100 had valvular heart disease. One hundred and five patients had absolute contra-indications and were excluded (pulmonary hypertension, diabetes, gastro-duodenal ulcer, age, or other major organic disease). Of the remaining 215 patients, only 82 were transplanted because of the limited number of available donor hearts. The most commonly used technique was orthotopic grafting as described by Lower and Shumway; Barnard's method of heterotopic grafting was used in 1 case and a block heart and lung transplantation by Reitz and Shumway's method was performed in 3 cases. The main postoperative complications, apart from technical problems (7 deaths), were related to rejection (107 episodes, 27 deaths), infection (82 episodes, 13 deaths), atherosclerosis of the graft (4 cases, 2 deaths, 1 retransplantation) and malignant tumours (3 deaths). After transplantation, 82 p. 100 of patients were discharged after an average hospital stay of 2 months; 47 p. 100 survived the first year and lead almost normal socio-professional activities. Thirty patients are still alive, the longest postoperative survival being 9 years. Significant advances have been made in the last 3 years. Classical immuno-suppressor therapy (steroids, azathioprine, horse antilymphocytic serum) has given way to more effective antilymphocytic sera and more powerful immuno-suppressor drugs (cyclosporine A). This treatment has greatly changed the postoperative course of events. Rejection phenomena, though still as common, are much less serious and, above all, more insidious.(ABSTRACT TRUNCATED AT 250 WORDS)

An observational evaluation of the rate of awakening after isoflurane or desflurane used in daily clinical practice.

STUDY OBJECTIVE: To evaluate the rate of awakening after desflurane (D) or isoflurane (I) anesthesia when used during daily clinical practice. DESIGN: Observational prospective study. SETTING: University-affiliated metropolitan hospital. PATIENTS: 68 ASA physical status I and II patients (18-75 yrs) scheduled for abdominal surgeries. INTERVENTIONS: Patients scheduled for abdominal surgery of various duration received either D or I. No time was specified for discontinuation of the inhaled drugs at the end of the surgery. T0 for recovery parameters was stated as the end of the surgery. A p-value < 0.05 was considered as significant. Results are expressed as medians and ranges. MEASUREMENTS AND MAIN RESULTS: 68 patients (32 in D group and 36 in I group) were analyzed. Patient demographic data were similar between the two groups. Duration of surgery was 151 minutes (83-428 min) and 174 minutes (40-552 min) for I and D, respectively. Extubation occurred earlier after D (18 min [9-35 min]) as compared to I (32 min [7-77 min]). Time to reach the Aldrete score at 10 was faster after D (30 min [12-45]) as compared to I (46 min [15-110]). Unlike I, the rate of awakening after D was independent of the duration of surgery. The differences between D and I reached statistical significance in surgical procedures lasting more than 100 minutes. CONCLUSION: Used during routine conditions, D allows for faster recovery than I in surgical procedures lasting more than 100 minutes. The rate of awakening after D remained independent of the duration of the surgical procedure.

Pre-induction skin-surface warming minimizes intraoperative core hypothermia.

STUDY OBJECTIVE: To test the hypothesis that only one hour of preinduction skin-surface warming decreases the rate at which core hypothermia develops during the first hour of anesthesia. DESIGN: Randomized, prospective study. SETTING: Operating theater of a university hospital. PATIENTS: 16 ASA status I and II adult patients scheduled for laparoscopic cholecystectomy under general anesthesia. INTERVENTIONS: Eight patients were assigned to receive forced-air warming for one hour before induction of anesthesia (prewarmed group); the other eight patients were covered only with a wool blanket during a similar preinduction period (control group). MEASUREMENTS AND MAIN RESULTS: Tympanic membrane (core) and mean skin-surface temperatures were measured at 15-minutes intervals, starting one hour before induction of anesthesia. Mean skin temperature increased from 34.0 +/- 0.1 C to 37.0 +/- 0.2 degrees C in the pre-warmed group (p < 0.05), but remained unchanged at 34.7 +/- 0.3 degrees C in the control group. Core temperature during the preinduction period did not change significantly in either group. Following induction of anesthesia, core temperature decreased at a rate of 1.1 +/- 0.1 degrees C/hr in the control group, but only 0.6 +/- 0.1 degrees C/hr in the pre-warmed group (p < 0.05). After one hour of anesthesia, six of eight pre-warmed patients had core temperatures of at least 36.5 degrees C, whereas only one of the eight control patients did (p < 0.05). CONCLUSIONS: A single hour of preoperative skin-surface warming reduced the rate at which core hypothermia developed during the first hour of anesthesia. Preoperative skin surface warming is particularly helpful during short procedures because redistribution hypothermia is otherwise difficult to treat.

Clinical reliability of measured and calculated oxygen parameters in surgical patients: influence of hyperventilation.

The acid-base and oxygen status were assessed in patients undergoing abdominal surgery. We determined the measured and calculated parameters described by Siggaard-Andersen in arterial and mixed venous blood before, during and after a controlled hyperventilation. In these dynamic conditions, the mixed venous calculated p50 showed the most interesting variations. Derived values in arterial blood were unreliable since: 1) fitting to hyperbolic tangent function is not possible when SaO2 greater than 0.98; 2) in these patients, the arterio-venous difference in CtO2 is different from 2.3 mmol/L. The acute changes in calculated p50 are in agreement with the effect of hyperventilation on oxygen status.

[Measurement of multiregional blood volumes: a cerebral vascular autoregulatory phenomenon (author's transl)]. / Mesure du volume sanguin multi-régional: phénomène d'autorégulation vasculaire cérébral.

The variations in regional cerebral blood volume (RCBV) during controlled severe hypotension induced by sodium nitroprusside were studied in a series of 29 patients with aneurysms (14), meningiomas (6) and arteriovenous malformations. Two characteristic variations were noted. The RCBV and mean blood pressure (MPB) vary inversely, this type of variation being known as "Active variation". When pathological lesions are present the RCBV and MBP are modified in the same direction in the regions affected and this is called "Passive variation". A quantitative study in 21 patients showed that in the healthy regions there was a change from the active to the passive mode of variation for a MBP situated between 44 and 52 mm of mercury.