Marie-Pierre Bonnet

Analgesic efficacy and adverse effects of epidural morphine compared to parenteral opioids after elective caesarean section: A systematic review

Background: The optimal effective dose of epidural morphine that provides postoperative analgesia after caesarean section with minimal side effects remains debated.

The μ Opioid Receptor Mediates Morphine-induced Tumor Necrosis Factor and Interleukin-6 Inhibition in Toll-like Receptor 2-stimulated Monocytes

BACKGROUND: Morphine possesses immunomodulatory effects but its intrinsic mechanisms, especially in the toll-like receptor 2 (TLR2) signaling pathway, are only partially understood. In this study, we evaluated the effects of morphine on tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-10 (IL-10) production in TLR2-stimulated human monocytes and identified the involvement of the different opioid receptors, and of the lymphocyte-to-monocyte contact. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood by centrifugation on a density gradient. Monocytes were secondarily separated using a high-gradient magnetic cell sorting kit with specific anti-CD14 antibodies. Monocytes or PBMCs were pretreated with opioid receptors antagonists before being cultured with morphine and peptidoglycan (PGN) from Staphylococcus aureus (specific TLR2 agonist). The amount of TNF, IL-6, and IL-10 was measured in the supernatant enzyme-linked immunosorbent assay. RESULTS: Proinflammatory cytokines: Morphine significantly inhibited the production of cytokines in a dose and concentration-dependent manner in PGN-stimulated monocytes. &mgr; Opioid receptor activation specifically mediated this morphine-induced TNF and IL-6 inhibition in monocytes. Morphine significantly inhibited the TNF, but not the IL-6 production, in PGN-stimulated PBMCs. The &mgr; opioid receptor was not involved in this morphine-induced TNF inhibition in PBMCs. Antiinflammatory cytokines: IL-10 was not a factor for the inhibition of TNF and IL-6 production after PGN stimulation in either monocytes or PBMCs cultures. CONCLUSIONS: The &mgr; opioid receptor mediates morphine-induced TNF and IL-6 inhibition in PGN-stimulated monocytes, but not in PBMCs. A direct monocyte-to-lymphocyte contact (PBMCs) alters the inhibitory effects of morphine observed on monocytes alone. IL-10 is not a factor for the inhibition of TNF or for IL-6 production. Interactions between TLR2 and &mgr; opioid intracellular pathways remain to be studied to delineate these morphine immunosuppressive effects.

Critical care and transfusion management in maternal deaths from postpartum haemorrhage

OBJECTIVESnIn postpartum haemorrhage (PPH), as for other causes of acute haemorrhage, management can have a major impact on patient outcomes. The aim of this study was to describe critical care management, particularly transfusion practices, in cases of maternal deaths from PPH.nnnSTUDY DESIGNnThis retrospective study provided a descriptive analysis of all cases of maternal death from PPH in France identified through the systematic French Confidential Enquiry into Maternal Death in 2000-2003.nnnRESULTSnThirty-eight cases of maternal death from PPH were analysed. Twenty-six women (68%) had a caesarean section [21 (55%) emergency, five (13%) elective]. Uterine atony was the most common cause of PPH (n=13, 34%). Women received a median of 9 (range 2-64) units of red blood cells (RBCs) and 9 (range 2-67) units of fresh frozen plasma (FFP). The median delay in starting blood transfusion was 82 (range 0-320)min. RBC and FFP transfusions peaked 2-4h and 12-24h after PPH diagnosis, respectively. The median FFP:RBC ratio was 0.6 (range 0-2). Fibrinogen concentrates and platelets were administered to 18 (47%) and 16 (42%) women, respectively. Three women received no blood products. Coagulation tests were performed in 20 women. The haemoglobin concentration was only measured once in seven of the 22 women who survived for more than 6h. Twenty-four women received vasopressors, a central venous access was placed in 11 women, and an invasive blood pressure device was placed in two women. General anaesthesia was administered in 37 cases, with five patients being extubated during active PPH.nnnCONCLUSIONSnThis descriptive analysis of maternal deaths from PPH suggests that there may be room for improvement of specific aspects of critical care management, including: transfusion procedures, especially administration delays and FFP:RBC ratio; repeated laboratory assessments of haemostasis and haemoglobin concentration; invasive haemodynamic monitoring; and protocols for general anaesthesia.

Pregnancy-related ICU admissions in France: trends in rate and severity, 2006-2009.

Objective:To determine the national rate per delivery of pregnancy-related ICU admissions of women in France, the characteristics and severity of these cases, and their trends over the 4-year study period. Design:Descriptive study from the national hospital discharge database. Setting:All ICUs in France. Patients:All women admitted to an ICU during the pregnancy, the delivery, or the postpartum period from January 1, 2006, to December 31, 2009. Interventions:None. Measurements and Main Results:Of 3,262,526 deliveries, 11,824 women had pregnancy-related ICU admissions, for an overall rate of 3.6 per 1,000 deliveries. The conditions reported most frequently were obstetric hemorrhages (34.2%) and hypertensive disorders of pregnancy (22.3%). Case severity was assessed with four markers: case-fatality rate (1.3%), length of ICU stay (mean, 3.0 ± 0.1 d), Simplified Acute Physiology Score II score (mean: 19.7 ± 0.1), and a SUP REA code, which indicates the combination of a Simplified Acute Physiology Score II score more than or equal to 15 and at least one specific procedure related to life support or organ failure (23.0%). The most frequent causes of ICU admission were those associated with the least severity in the ICU. During the study period, the rate of pregnancy-related ICU admissions decreased from 3.9 to 3.4 per 1,000 deliveries (p < 0.001), whereas the overall severity of cases increased with longer stays, higher Simplified Acute Physiology Score II scores, and a greater proportion of SUP REA codes (all p < 0.001). Analysis by principal diagnosis showed that the severity of the condition of women admitted to ICU significantly increased over time for hemorrhages and hypertensive complications. Conclusions:The rate of women with pregnancy-related ICU admissions decreased and the severity of their cases increased. Most ICU admissions remained related to the least severe conditions. This raises the issue of the most appropriate organization of care for women with pregnancy-related conditions who require continuous surveillance but not necessarily intensive care.

In Vitro Plasma-Induced Endothelial Oxidative Stress and Circulating Markers of Endothelial Dysfunction in Preeclampsia: An Observational Study

Objective:u2002To investigate plasma-induced endothelial reactive oxygen species (ROS) production in vitro and its relation to endothelial dysfunction in preeclampsia (PE).u2003Methods:u2002Plasma was drawn from 17 PE patients, 17 matched healthy pregnant (HP) women, 17 matched non-pregnant healthy volunteers (NP), and 10 septic shock (SC) patients. In vitro plasma-induced ROS production was assessed in cultured human endothelial cells. In vivo endothelial activation and injury were assessed through measurements of plasma von Willebrand factor (vWF) and soluble thrombomodulin (sTM) concentrations, respectively.u2003Results:u2002Endothelial ROS production was not induced by PE, HP, and NP plasmas. However, it was significantly increased in SC compared to other groups (p < .005). Pregnancy (PE and HP) was associated with higher vWF compared to NP. Among pregnancies, vWF was higher in PE compared to HP women (p < .05). sTM was unchanged between PE, HP and NP. In SC, vWF and sTM were significantly increased compared to other groups (p < .01). Simultaneously, endothelial ROS production and sTM concentration were correlated (p = .673; p < .05).u2003Conclusion.u2002Plasma does not induce in vitro endothelial ROS production in PE women for which endothelial dysfunction is limited to activation but not injury. By contrast, SC patients demonstrate both endothelial activation and injury, closely related to plasma-induced endothelial oxidative stress.

Anesthetic and Obstetrical Factors Associated With the Effectiveness of Epidural Analgesia for Labor Pain Relief: An Observational Population-Based Study.

Background and Objectives The effectiveness of labor epidural analgesia is difficult to explore, as it includes the maternal satisfaction with analgesia as well as the overall childbirth experience. In this population-based study, we sought to identify factors associated with the effectiveness of epidural analgesia for labor pain relief. Methods We performed a secondary analysis of the 2010 French National Perinatal Survey, a cross-sectional study of a representative sample of births in France. All participants who gave birth with an epidural analgesia were included. Effectiveness of epidural analgesia was assessed 2 to 3 days after delivery and intended to include analgesic efficacy and maternal satisfaction together. The factors analyzed were anesthetic management and maternal, obstetrical, and organizational characteristics, using a logistic regression with random effects model. Results Among the 9337 women who gave birth with an epidural analgesia and were included, 8377 (89.3%; 95% confidence interval [CI] = 88.7–89.9) considered their epidural to be very or fairly effective. In the multivariate analysis, effectiveness was significantly associated with the use of patient-controlled epidural analgesia (adjusted odds ratio [aOR] = 1.2 [1.0–1.5]; P = 0.02) and delivery in private maternity facilities (aOR = 1.3 [1.1–1.6]); it was significantly less effective in obese women (aOR = 0.6 [0.5–0.8]) and multiparous women not receiving oxytocin during labor (aOR = 0.4 [0.4–0.6]) as compared with nonobese and nulliparous women with oxytocin, respectively. Conclusions At the population level, most women found epidural analgesia effective for labor pain relief, but specific attention should be paid to obese parturients and multiparous women not receiving oxytocin. High epidural effectiveness with patient-controlled analgesia should promote an increased use of this method.

What Is the True Incidence of Postpartum Hemorrhage

i i l i i i i i i l i i i November 2015 • Volume 121 • Number 5 www.anesthesia-analgesia.org 1397 In Response We thank Bonnet et al.1 for their interest in our work. They raise several interesting points. First, they express concern that the frequency of use of second-line uterotonics (7%) reported in our study2 overestimates the true incidence of postpartum hemorrhage (PPH) in the United States.3,4 Our study aim was to investigate hospital-level patterns in second-line uterotonic use. We did not suggest that the administration of a secondline uterotonic indicated PPH due to uterine atony. Secondline uterotonics are commonly administered in the United States either as a treatment for atonic PPH or for prophylaxis against the progression to PPH in patients who have poor uterine tone after treatment with oxytocin. Therefore, one would expect the frequency of second-line uterotonic use to be higher than national estimates of PPH frequency. Second, Bonnet et al. suggest that we did not exclude women from our sample who received second-line uterotonics for induction of labor. In the United States, the second-line uterotonics, methylergonovine maleate and carboprost, are not used for the indication of induction of labor. Although misoprostol can be used to induce labor at low dose, we took great care to limit misclassification of misoprostol as a uterotonic. Specifically, misoprostol was only considered as a second-line uterotonic in our analysis if the total dose was in excess of 400 μg with the absence of an International Classification of Diseases, Ninth Revision, Clinical Modification code indicating medical induction of labor. Finally, they propose that research investigating the use of second-line uterotonics would best be undertaken by using a prospective design. We would like to clarify that our study would be considered prospective in the context of epidemiologic study designs, given the prospective recording of exposures, To the Editor Bateman et al. 1 recently reviewed second-line uterotonic use in a large nationwide sample of delivery admissions and expressed concern about the scarcity of articles on this topic. We would like to add information that was not mentioned by Bateman et al. A large prospective study in France recently documented the use and tolerability of sulprostone, a secondline prostaglandin E2 analog uterotonic, in women with atonic postpartum hemorrhage.2 In this study, 1.2% of all parturients were treated with sulprostone, accounting for 34% of women with atonic postpartum hemorrhage. This proportion seems more likely to reflect reality than the 7.1% of deliveries reported by Bateman et al., because the incidence of all postpartum hemorrhage is approximately 3% of deliveries in American studies using national databases.3,4 This probable overestimation of postpartum hemorrhage reported by Bateman et al. might have been avoided if information on second-line uterotonics had been combined with specific International Classification of Diseases, Ninth Revision, Clinical Modification codes for postpartum hemorrhage. This would have eliminated the bias caused by the use of uterotonics used as labor induction drugs. Bateman et al. observed a wide interhospital variation in second-line uterotonic use that was attributable to womenor hospital-level characteristics. In the French populationbased study, the authors reported that sulprostone use in severe atonic postpartum hemorrhage was less frequent after vaginal delivery, as well as less frequent in units performing <1500 annual deliveries, in public nonuniversity hospitals, and in units where the obstetricians or the anesthesiologists were not continually present.2 This highlights the inherent limits of administrative databases to study specific components of care. Prospective population-based studies are better suited to explore patterns of postpartum hemorrhage management.

Effective concentration of levobupivacaine and ropivacaine in 80% of patients receiving epidural analgesia (EC80) in the first stage of labour: A study using the Continual Reassessment Method

BACKGROUNDnA comparison of the effective dose in 50% of patients (ED50) has suggested that the potency of levobupivacaine lies between that of bupivacaine and ropivacaine. However, for clinical purposes, knowledge and use of doses close to the ED95 are more relevant. This study was designed to determine the EC80 (effective concentration) for both epidural levobupivacaine and ropivacaine using the Continual Reassessment Method (CRM) during obstetric analgesia.nnnMETHODSnIn this double-blind randomised study, term parturients were included by cohorts of 6 if cervical dilatation was≤5cm and visual analogue pain score (VAPS)>30mm. Efficacy was defined by a decrease of VAPS to a value≤10, thirty minutes after epidural injection of 20mL of levobupivacaine or ropivacaine. The first cohort received the lowest dose. Every next cohort received a dose according to the responses probability calculated using a Bayesian method, incorporating data from all consecutive previous patients. In addition, a logistic equation was fitted a posteriori to the whole data set to determine the whole dose-probability curve.nnnRESULTSnFifty-four patients were enrolled. Levobupivacaine 0.17% and ropivacaine 0.2% gave probabilities of success of 82% and 72% respectively. By fitting the logistic model to the data, the concentration leading to a probability of 0.8 (EC80) was 0.14% for levobupivacaine and 0.24% for ropivacaine while the EC50 were 0.09% for levobupivacaine and 0.17% for ropivacaine, respectively.nnnCONCLUSIONnThis study suggests that epidural levobupivacaine used as the sole drug for labour analgesia has an EC80 lower than that of ropivacaine.

Effective dose of levobupivacaine and ropivacaine in 80% of patients (ED80) receiving epidural analgesia in labour using the continual reassessment method (CRM): 11AP1–1

Background and Goal of Study: The effective dose in 50% of patients (ED50) obtained from the MLAC studies suggested that levobupivacaine (levo) potency is between bupivacaine and ropivacaine (ropi) potencies. CRM is used to determine the effective dose for 80% of patients (ED80), which is more relevant than ED50 for clinical purposes. Our goal was to determine ED80 for levo and ropi in labour epidural analgesia. Materials and Methods: The parturients were included after ethics committee approval in first stage of eutocic labour, with visual analog pain score (VAPS) > 30 mm. They were randomised into cohorts of 6, and received in a double blind manner 20 mL of levo or ropi epidurally. The efficacy (i.e., VAPS ≤ 10) was assessed 30 minutes later. The first cohort received the lowest concentration. Every new cohort received a concentration according to the response’s probability calculated with the specific software BPCT [1], incorporating data from all consecutive previous patients. The concentrations chosen were 0.04, 0.08, 0.11, 0.14, 0.17, and 0.2% with the following a-priori chosen probability of success: 0.2, 0.45, 0.65, 0.75, 0.85, 0.95 for levo and 0.15, 0.4, 0.6, 0.7, 0.8, 0.9 for ropi. Patients were included until the probability for the concentration administered to remain unchanged becomes > 0.99 for both groups. A logistic equation was fitted a-posteriori to the whole data set to determine the whole dose-probability curve. Results and Discussion: 54 patients were enrolled. The two groups were similar. A levo concentration of 0.17% gave a probability of success of 82% (95% credibility interval: 0.63-0.94). A ropi concentration of 0.2% gave a probability of success of 72% (95% credibility interval: 0.5-0.88). By fitting a logistic model to the data, we determined an ED50 of 0.085% for levo vs. 0.17% for ropi and an ED80 of 0.14% for levo vs. 0.24% for ropi. There was no difference in side effects between the two groups.