Role of recombinant factor VIIa in the clinical management of severe postpartum hemorrhage: consensus among European experts.

OBJECTIVES: There have been significant advances in the medical management of severe postpartum hemorrhage (sPPH) over recent decades, which is reflected in numerous published guidelines. To date, many of the currently available national and international guidelines recommend recombinant factor VIIa (rFVIIa) to be used only at a very late stage in the course of sPPH, as a "last resort", before or after hysterectomy. Based on new safety data, rFVIIa has recently been approved by the European Medicines Agency (EMA) and Swissmedic for use in sPPH, if uterotonics are insufficient to achieve hemostasis, which in fact is significantly earlier in the course of postpartum hemorrhage (PPH). We therefore aimed to develop expert consensus guidance as a step toward standardizing care with the use of rFVIIa for clinicians managing women experiencing life-threatening sPPH. METHODS: The consensus process consisted of one face-to-face meeting with a group of nine experts, including eight obstetrician-gynecologists and a hematologist highly experienced in sPPH care in tertiary care perinatal centers. The panel was representative of multidisciplinary expertise in the European obstetrics community and provided consensus opinion in answer to pre-defined questions around clinical practice with rFVIIa in the management of sPPH. Recommendations have been based on current national and international guidelines, extensive clinical experience, and consensus opinion, as well as the availability of efficacy and new safety data. RESULTS: The expert panel developed 17 consensus statements in response to the 13 pre-defined questions on the use of rFVIIa in the management of sPPH including: available efficacy and safety data and the need for interdisciplinary expertise between obstetricians, anesthesiologists, and hematologists in the management of sPPH. Based on novel data, the experts recommend: (1) earlier administration of rFVIIa in patients with sPPH who do not respond to uterotonic administration to optimize the efficacy of rFVIIa; (2) the importance of hematological parameter prerequisites prior to the administration of rFVIIa to maximize efficacy; and (3) continued evaluation or initiation of further invasive procedures according to standard practice. Furthermore, recommendations on the timing of rFVIIa treatment within the sPPH management algorithm are outlined in a range of specified clinical scenarios and settings, including vaginal delivery, cesarean section, and smaller birthing units before transfer to a tertiary care center. The panel agreed that according to available, and new data, as well as real-world experience, there is no evidence that the use of rFVIIa in patients with sPPH increases the risk of thromboembolism. The authors acknowledge that there is still limited clinical effectiveness data, as well as pharmacoeconomic data, on the use of rFVIIa in sPPH, and recommend further clinical trials and efficacy investigation. CONCLUSIONS: This expert panel provides consensus guidance based on recently available data, clinical experience, and expert opinion, augmented by the recent approval of rFVIIa for use in sPPH by the EMA. These consensus statements are intended to support clinical care for sPPH and may help to provide the impetus and a starting point for updates to existing clinical practice guidelines.

Education in obstetric anesthesiology: an international approach.

Competency-based training and active teaching methods are increasingly becoming accepted and utilized in medical schools and hospitals, and obstetric anesthesiology training is expected to follow this process. This article summarizes current modalities of obstetric anesthesiology training in five countries from various parts of the world. Analysis of these curricula shows that implementation of new educational methods is variable, incomplete, and lacking in data related to patient outcomes. Research in assessments and practical applications are required to avoid wide ranges of educational strategies.

Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial.

OBJECTIVE: To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management. DESIGN: Multicentre, double-blind, randomised placebo-controlled trial. SETTING: 30 French hospitals. POPULATION: Patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins. METHODS: Within 30 minutes after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo. MAIN OUTCOME MEASURES: Failure as composite primary efficacy endpoint: at least 4 g/dl of haemoglobin decrease and/or transfusion of at least two units of packed red blood cells within 48 hours following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures and maternal morbidity-mortality within 6 ± 2 weeks after delivery. RESULTS: 437 patients were included: 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346 ml) and plasma fibrinogen (4.1 ± 0.9 g/l) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the fibrinogen and placebo groups, respectively (odds ratio [OR] = 0.99) after adjustment for centre and baseline plasma fibrinogen; (95% CI 0.66-1.47; P = 0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged in the Fibrinogen group and decreased by 0.56 g/l in the placebo group. No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group versus two in the placebo group. CONCLUSIONS: As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs or postpartum anaemia, but did prevent plasma fibrinogen decrease without any subsequent thromboembolic events. TWEETABLE ABSTRACT: Early systematic blind 3 g fibrinogen infusion in PPH did not reduce anaemia or transfusion rate, reduced hypofibrinogenaemia and was safe.

A systematic review of phenylephrine vs. noradrenaline for the management of hypotension associated with neuraxial anaesthesia in women undergoing caesarean section.

Phenylephrine is recommended for the management of hypotension after spinal anaesthesia in women undergoing caesarean section. Noradrenaline, an adrenergic agonist with weak ß-adrenergic activity, has been reported to have a more favourable haemodynamic profile than phenylephrine. However, there are concerns that noradrenaline may be associated with a higher risk of fetal acidosis, defined as an umbilical artery pH < 7.20. We performed a systematic review of trials comparing noradrenaline with phenylephrine, concentrating on primary outcomes of fetal acidosis and maternal hypotension. We identified 13 randomised controlled trials including 2002 patients. Heterogeneity among the studies was high, and there were too few data to calculate a pooled effect estimate. Fetal acidosis was assessed in four studies that had a low risk of bias and a low risk of confounding, that is, studies which used a prophylactic vasopressor and where women received the allocated vasopressor only. There were no significant differences between these studies. No significant differences were observed for hypotension. Two trials found a significantly lower incidence of bradycardia when using noradrenaline. Cardiac output was significantly higher after noradrenaline in two of three studies. For other secondary outcomes including nausea, vomiting and Apgar scores at 1 and 5 min, no studies found significant differences. The evidence so far is too limited to support an advantage of noradrenaline over phenylephrine. Concerns of a deleterious effect of noradrenaline on fetal blood gas status cannot currently be assuaged by the available data from randomised controlled studies.

Major obstetric hemorrhage.

Major obstetric hemorrhage is a challenge for anesthesiologists because it remains responsible for over 10% of maternal deaths in high-income countries. A standardized multidisciplinary management, described in locally validated protocols and based on international guidelines is mandatory to prevent these deaths. The first difficulty relies on the systematic underestimation of the bleeding. Collection bags must be used to facilitate the diagnosis and therefore rapid management. The etiologies in antenatal or postpartum must be well-known in order to be treated adequately. A rapid recourse to prostaglandins (sulprostone in France) may reverse uterine atony. Invasive approach with surgery or radiology should be promptly implemented (uterine artery or internal iliac artery ligations±uterus plication) and hysterectomy should then be timely considered. Simultaneously, early and aggressive resuscitation with large-bore venous accesses should be implemented for rapid and massive transfusion (4:4:1 RBC:FFP:platelets ratio), along with an early use of fibrinogen concentrates and tranexamic acid. This transfusion strategy may be then guided by thromboelastography or thromboelastometry and bedside hemoglobin measurements. Activated factor VII remains indicated only before or after hysterectomy in case of uncontrolled bleeding. Management of placentation abnormalities (placenta previa, accreta, increta, percreta) must be well mastered as these etiologies may generate cataclysmic hemorrhages that can be and have to be anticipated.

[Study of the 21 cases of thromboembolism from the 4th report of national confidential enquiry into maternal death in France in 2007-2009]. / Analyse des 21 cas de thromboembolie du 4(e) rapport de l'enquête nationale confidentielle sur la mortalité maternelle en France en 2007-2009.

OBJECTIVES: The Confidential National Enquiry on Maternal Mortality identified 254 deaths in France from 2007 to 2009. Thromboembolism venous disease led to 31 deaths, becoming the 3rd cause of maternal mortality. This study analyses the 21 enquiry files obtained by the National Expert Committee on Maternal Mortality (CNEMM). MATERIALS AND METHODS: Clinical characteristics, arising circumstances and imaging exams were collected in the 20 patients deceased by pulmonary embolism (PE). After excluding two incomplete files, we looked for the PE Risk Factors (RF) in order to sort patients out according to 4 levels of risk (low, moderate, high and major). RESULTS: The main RF were: non-Caucasian ethnic origin (n=8), age over 35years (n=7), diabetes (n=6) and emergency or unplanned caesarean section (n=6). The average number of RF was 3.7: 73% were low, 18% moderate. Among 7 autopsies performed, 6 resulted in PE diagnostic. Only 67% of eligible patients had an imaging exam. CONCLUSION: The search for the RF of thromboembolism accidents, in particular the low RF, should be improved to establish an adapted prophylactic therapy. Autopsy or even post-mortem imaging should be implemented when diagnosis is uncertain in order to avoid over-/under-estimating death incidence caused by PE.

Recombinant human FVIIa for reducing the need for invasive second-line therapies in severe refractory postpartum hemorrhage: a multicenter, randomized, open controlled trial.

BACKGROUND: Case reports on recombinant human factor VIIa (rhuFVIIa) use in women with severe postpartum hemorrhage (PPH) showed encouraging results, but no randomized controlled trial (RCT) is available. PATIENTS AND METHODS: Eighty-four women with severe PPH unresponsive to uterotonics were randomized to receive one early single rhuFVIIa infusion (n = 42) or standard care (no rhuFVIIa; n = 42). The primary efficacy outcome measure was the reduction of the need for specific second-line therapies, such as interventional hemostatic procedures, for blood loss and transfusions. The primary safety outcome measure was the number of deaths and thrombotic events during the 5 days following rhuFVIIa infusion. RESULTS: rhuFVIIa was associated with a reduction in the number of patients who needed second-line therapies compared with controls (standard care). Specifically, 39/42 (93%) patients in the standard care arm received second-line therapies and 22/42 (52%) patients in the rhuFVIIa arm (absolute difference, 41%; range, 18-63%; relative risk RR, 0.56 [0.42-0.76]). The delivery mode (vaginal or Cesarean section) did not affect the primary outcome. No death occurred. Two venous thrombotic events were recorded in the rhuFVIIa arm: one ovarian vein thrombosis and one deep vein thrombosis with a non-severe pulmonary embolism. CONCLUSION: This open RCT in women with severe PPH refractory to uterotonics shows that rhuFVIIa reduces the need for specific second-line therapies in about one in three patients, with the occurrence of non-fatal venous thrombotic events in one in 20 patients.

[Epidural bleeding after labor epidural analgesia]. / Saignement péridural suite à une analgésie péridurale obstétricale.

Anaesthetists often stand in the front line to manage postpartum neurological deficits, although epidural analgesia is rarely responsible for these complications. An epidural analgesia was performed to relieve pain during spontaneous labor in a 34-year-old parturient. An emergency C-section was subsequently required due to fetal heart rate abnormalities. Twelve hours after catheter removal, the parturient developed a severe right leg motor and sensory neurological deficit, predominant on L5 and S1 roots and diagnosed by a neurologist as a central nerve root injury. Lumbar MRI identified a non-compressive epidural bleeding in front of the L5 vertebral body. Epidural bleeding after labor epidural analgesia is a rare complication that may jeopardize the functional prognosis. It may be difficult in some cases to differentiate an upper plexus injury due to labor and delivery from a central epidural analgesia-related nerve root lesion. Fetal head compression at the pelvic brim may induce neurological deficits in several well-differentiated nervous territories, thus mimicking an anaesthetic-induced perimedullar radiculopathy.

6% Hydroxyethyl starch (130/0.4) vs Ringer's lactate preloading before spinal anaesthesia for Caesarean delivery: the randomized, double-blind, multicentre CAESAR trial.

BACKGROUND: Vasopressor administration is recommended to prevent hypotension during spinal anaesthesia (SA) for elective Caesarean delivery. We aimed to test the superior efficacy and ensure safety of a hydroxyethyl starch (HES) vs a Ringer's lactate (RL) preloading, when combined with a phenylephrine-based prophylaxis. METHODS: A total of 167 healthy parturients undergoing elective Caesarean delivery under SA were included in this multicentre, randomized, double-blind study. Patients received 500 ml of 6% HES (130/0.4)+500 ml of RL (HES group) or 1000 ml of RL (RL group) i.v. before SA. After SA, i.v. phenylephrine boluses were titrated when systolic arterial pressure (SAP) was below 95% of baseline. The primary outcome was the incidence of maternal hypotension (SAP <80% of baseline). RESULTS: The incidence of both hypotension and symptomatic hypotension (i.e. with dizziness, nausea/vomiting, or both) was significantly lower in the HES group vs the RL group: 36.6% vs 55.3% (one-sided P=0.025) and 3.7% vs 14.1%. There was no significant difference in total phenylephrine requirements [median (range): 350 (50-1800) vs 350 (50-1250) µg]. The decrease in maternal haemoglobin value the day after surgery was similar in the two groups [1.2 (1.0) vs 1.0 (0.9) g dl(-1)]. There was no detectable placental transfer of HES in six umbilical cord blood samples analysed in the HES group. Neonatal outcomes were comparable between the groups. CONCLUSIONS: Compared with a pure RL preloading, a mixed HES-RL preloading significantly improved prevention of both hypotension and symptomatic hypotension based on early phenylephrine bolus administration and did not induce adverse effects. CLINICAL TRIAL REGISTRATION: NCT00694343 (http://clinicaltrials.gov).

Combined factor V and VIII deficiency and pregnancy--need for an early protocol-based multidisciplinary management.

We report the medical management of a 32-year-old primigravida, after she was found to have a combined factor V (FV) and factor VIII (FVIII) deficiency during pregnancy. A routine coagulation profile performed during the 6th month of pregnancy showed a prolonged activated partial thromboplastin time (aPTT) of 78 seconds, giving a patient/control ratio of 2.29, combined with a prothrombin time (PT) of 28 seconds. An investigation of the coagulation factors showed a combined FV and FVIII deficiency of 29% and 21% respectively. The bleeding risk was considered to be high. A multidisciplinary approach permitted a specific and individualized FVIII substitution protocol. At 39 weeks of amenorrhea, the patient was admitted to the labor room. An infusion of 2000IU of FVIII was implemented over 5 minutes; soon thereafter, PT was 17 seconds, aPTT patient/control ratio had decreased to 1.9 and FV and FVIII reached 38% and 36% respectively. Six hours later, the patient delivered an infant weighing 2850g who had an Apgar score of 10. No bleeding was detected. The patient was then closely monitored for 2 hours in the recovery room. Twelve hours after administration of the first dose of FVIII, another infusion of 2000IU of FVIII was administered. This substitution treatment was continued every 12 hours in ever-decreasing doses, allowing maintenance of FVIII level >50% for 5days. At D7 post-partum, the patient was discharged uneventfully.

[Parkes-Weber syndrome and pregnancy: anaesthetic implications]. / Syndrome de Parkes-Weber et grossesse : implications anesthésiques.

We report two deliveries in a patient with a Parkes-Weber syndrome. This parturient had a complex angiodysplasia including a soft tissue hypertrophy of a lower limb, a cutaneous angioma and arteriovenous malformations. The risk of perimedullar arteriovenous malformations was ruled out by angiographic magnetic resonance imaging of the spinal cord. We also describe other aspects of the management, including prepartum cardiovascular assessment, mode of delivery, the use of epidural analgesia and the prevention of haemorrhagia and thromboembolism.