Defining Predictors of Weight Loss Response to Lorcaserin.

CONTEXT: Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive. OBJECTIVE: We investigated biomarkers associated with use of lorcaserin (LOR), a 5HT2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, to identify predictors of clinical efficacy. METHODS: Thirty individuals with obesity were treated with 7 days of placebo and LOR in a randomized crossover study. Nineteen participants continued on LOR for 6 months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin, and food intake during a meal were also studied. RESULTS: LOR induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide ß-endorphin after 7 days; ß-endorphin/POMC increased by 30% (P < .001). This was accompanied by a substantial decrease in insulin, glucose, and homeostasis model assessment of insulin resistance before WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6 months that were distinct from prior reports after diet alone. Changes in POMC, food intake, or other hormones did not predict WL. However, baseline CSF POMC correlated negatively with WL (P = .07) and a cutoff level of CSF POMC was identified that predicted more than 10% WL. CONCLUSION: Our results provide evidence that LOR affects the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT2cR agonists.

Randomized trial of transversus abdominis plane block with liposomal bupivacaine after cesarean delivery with or without intrathecal morphine.

STUDY OBJECTIVE: To investigate efficacy and safety of liposomal bupivacaine (LB) transversus abdominis plane (TAP) block with or without intrathecal morphine (ITM) compared with ITM alone for postsurgical analgesia after cesarean delivery (CD). DESIGN: Multicenter, open-label, randomized trial (NCT03853694). SETTING: Operating room. PATIENTS: Women with term pregnancy of 37 to 42 weeks scheduled for elective CD under spinal anesthesia. INTERVENTION: Patients were randomized 1:1:1 to LB 266 mg TAP block alone (LB group), ITM 50 µg followed by LB 266 mg TAP block (LB + ITM group), or ITM 150 µg alone (ITM group). All groups received the same postsurgical multimodal analgesic regimen. MEASUREMENTS: The LB and LB + ITM groups were compared with the ITM group for all efficacy outcomes. Postsurgical opioid consumption in morphine milligram equivalents (MMEs) through 72 h was compared by assessing noninferiority before testing superiority. Postsurgical pruritus severity was assessed on an 11-point numerical rating scale. MAIN RESULTS: Between March 4, 2019, and January 10, 2020, 153 patients (LB, n = 52; LB + ITM, n = 48; ITM, n = 53) were enrolled. Baseline characteristics were comparable across groups. The LB group had statistically noninferior postsurgical opioid consumption through 72 h compared with the ITM group (least squares mean [LSM], 19.2 vs 16.4 MMEs; LSM treatment ratio, 1.17 [95% confidence interval (CI), 0.74-1.86]; noninferiority P < 0.0034) as did the LB + ITM group (LSM, 14.6 vs 16.4 MMEs; LSM treatment ratio, 0.89 [95% CI, 0.55-1.44]; noninferiority P < 0.0001). The LB and LB + ITM groups had significantly reduced pruritus severity scores through 12, 24, 48, and 72 h compared with the ITM group (P ≤ 0.0121). Adverse events occurred in 58%, 85%, and 81% of the LB, LB + ITM, and ITM groups, respectively. CONCLUSIONS: LB TAP block with or without ITM resulted in statistically noninferior postsurgical opioid consumption through 72 h, reduced pruritus, and favorable safety compared with ITM in women undergoing CD.

Pregnancy-specific Adaptations in Leptin and Melanocortin Neuropeptides in Early Human Gestation.

INTRODUCTION: Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and cerebrospinal fluid (CSF) leptin and Agouti-related peptide (AgRP) as well as CSF proopiomelanocortin (POMC) as surrogates for brain melanocortin activity. METHODS: Plasma leptin, soluble leptin receptor, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women before cerclage placement (16.6 ±â€…1.1 weeks; N = 24), scheduled cesarean section (39.2 ±â€…0.2 weeks; N = 24), and from nonpregnant controls (N = 24), matched for age and body mass index. RESULTS: Plasma leptin was 1.5 times higher in pregnancy vs controls (P = 0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs controls (0.8 ±â€…0.1 vs 1.7 ±â€…0.2; P < 0.0001) and remained unchanged at term (0.9 ±â€…0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs controls (95.0 ±â€…7.8 vs 67.5 ±â€…5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P = 0.006). In contrast, at term, CSF AgRP was 42% higher vs controls (P = 0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs controls, reflecting a decrease in melanocortin tone favoring appetitive drive. CONCLUSIONS: Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.

Obstetric venous thromboembolism prophylaxis: What obstetricians should know about anesthesia guidelines.

In 2018 two documents were released from major anesthesia societies, the American Society for Regional Anesthesia (ASRA) and the Society for Obstetric Anesthesia and Perinatology (SOAP), to aid anesthesiologists in decision making regarding neuraxial procedures for obstetric patients receiving anticoagulation. For obstetrical providers seeking to provide appropriate inpatient thromboprophylaxis while also maximizing access to neuraxial anesthesia, awareness of these recommendations may be critically important. In comparison to anesthesiologists in other medical and surgical scenarios, obstetric anesthesiologists are more likely to be called upon to administer anesthesia urgently or emergently. Approximately one-third of women in the United States deliver by cesarean, and while many of these procedures will be scheduled, many others will be performed for an urgent indication where timing of delivery cannot be anticipated precisely. The purpose of this review is to summarize key clinical obstetric anesthesia management points related to anticoagulation for the obstetrician so that both VTE prophylaxis and access to neuraxial anesthesia can be optimized.

Left Lateral Table Tilt for Elective Cesarean Delivery under Spinal Anesthesia Has No Effect on Neonatal Acid-Base Status: A Randomized Controlled Trial.

BACKGROUND: Current recommendations for women undergoing cesarean delivery include 15° left tilt for uterine displacement to prevent aortocaval compression, although this degree of tilt is practically never achieved. We hypothesized that under contemporary clinical practice, including a crystalloid coload and phenylephrine infusion targeted at maintaining baseline systolic blood pressure, there would be no effect of maternal position on neonatal acid base status in women undergoing elective cesarean delivery with spinal anesthesia. METHODS: Healthy women undergoing elective cesarean delivery were randomized (nonblinded) to supine horizontal (supine, n = 50) or 15° left tilt of the surgical table (tilt, n = 50) after spinal anesthesia (hyperbaric bupivacaine 12 mg, fentanyl 15 µg, preservative-free morphine 150 µg). Lactated Ringer's 10 ml/kg and a phenylephrine infusion titrated to 100% baseline systolic blood pressure were initiated with intrathecal injection. The primary outcome was umbilical artery base excess. RESULTS: There were no differences in umbilical artery base excess or pH between groups. The mean umbilical artery base excess (± SD) was -0.5 mM (± 1.6) in the supine group (n = 50) versus -0.6 mM (± 1.5) in the tilt group (n = 47) (P = 0.64). During 15 min after spinal anesthesia, mean phenylephrine requirement was greater (P = 0.002), and mean cardiac output was lower (P = 0.014) in the supine group. CONCLUSIONS: Maternal supine position during elective cesarean delivery with spinal anesthesia in healthy term women does not impair neonatal acid-base status compared to 15° left tilt, when maternal systolic blood pressure is maintained with a coload and phenylephrine infusion. These findings may not be generalized to emergency situations or nonreassuring fetal status.

National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism.

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into four domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism.

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into four domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism.

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into four domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

Proposed diagnostic criteria for the case definition of amniotic fluid embolism in research studies.

Amniotic fluid embolism is a leading cause of maternal mortality in developed countries. Our understanding of risk factors, diagnosis, treatment, and prognosis is hampered by a lack of uniform clinical case definition; neither histologic nor laboratory findings have been identified unique to this condition. Amniotic fluid embolism is often overdiagnosed in critically ill peripartum women, particularly when an element of coagulopathy is involved. Previously proposed case definitions for amniotic fluid embolism are nonspecific, and when viewed through the eyes of individuals with experience in critical care obstetrics, would include women with a number of medical conditions much more common than amniotic fluid embolism. We convened a working group under the auspices of a committee of the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation whose task was to develop uniform diagnostic criteria for the research reporting of amniotic fluid embolism. These criteria rely on the presence of the classic triad of hemodynamic and respiratory compromise accompanied by strictly defined disseminated intravascular coagulopathy. It is anticipated that limiting research reports involving amniotic fluid embolism to women who meet these criteria will enhance the validity of published data and assist in the identification of risk factors, effective treatments, and possibly useful biomarkers for this condition. A registry has been established in conjunction with the Perinatal Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to collect both clinical information and laboratory specimens of women with suspected amniotic fluid embolism in the hopes of identifying unique biomarkers of this condition.

National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism.

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into 4 domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

The Effect of ß2-Adrenoceptor Genotype on Phenylephrine Dose Administered During Spinal Anesthesia for Cesarean Delivery.

BACKGROUND: The ß2-adrenoceptor (ADRB2 gene) possesses several polymorphic sites that have physiologic and/or pharmacologic significance. Previous work has demonstrated that the ADRB2 genotype affects the amount of ephedrine administered to maintain blood pressure during cesarean delivery with spinal anesthesia. This study investigated whether the ADRB2 genotype affected phenylephrine dose requirements during cesarean delivery. Our hypothesis was that the ADRB2 genotype altered the ephedrine dose-response and that we would not see this effect if phenylephrine was the vasopressor used to maintain blood pressure because phenylephrine does not act via the ß2-adrenoceptor. METHODS: Women undergoing elective cesarean delivery were studied. Baseline systolic blood pressure (SBP) was determined, and spinal anesthesia was initiated with hyperbaric bupivacaine 12 mg, fentanyl 20 µg, and morphine 200 µg. Hypotension was treated with a phenylephrine infusion using a standardized algorithm (50 µg/min if SBP was 90%-99% of baseline, 100 µg/min for SBP 80%-89% baseline, and 200 µg/min plus boluses for SBP <80% baseline) for 15 minutes after the administration of spinal anesthesia. ADRB2 genotype at codons 16 and 27 was determined. The effect of genotype on administered phenylephrine was compared by analysis of variance and linear regression. RESULTS: Ninety-six women completed the protocol with full data available for analysis. In the unadjusted analysis, there were no significant differences in phenylephrine dose administered among different genotypes at codons 16 and 27. When adjusted for covariates (maternal body mass index, baseline systolic and diastolic blood pressure, neonatal weight, and ethnicity), there was an increase of 200 µg (95% confidence interval, 4-396; P = 0.04) in phenylephrine administered to Arg16 homozygous genotype subjects compared with Gly16 homozygous genotype subjects. CONCLUSIONS: Phenylephrine dose requirements to maintain SBP after spinal anesthesia are affected by ADRB2 genotype but to a lesser extent than ephedrine. This suggests that previous work demonstrating a large effect of ADRB2 genotype on ephedrine dose requirements may be explained, at least in part, by a differential response to ephedrine based on ADRB2 genotype. It also suggests that there may be ADRB2-mediated differences in the physiologic response to spinal anesthesia.

Serious complications related to obstetric anesthesia: the serious complication repository project of the Society for Obstetric Anesthesia and Perinatology.

BACKGROUND: Because of the lack of large obstetric anesthesia databases, the incidences of serious complications related to obstetric anesthesia remain unknown. The Society for Obstetric Anesthesia and Perinatology developed the Serious Complication Repository Project to establish the incidence of serious complications related to obstetric anesthesia and to identify risk factors associated with each. METHODS: Serious complications were defined by the Society for Obstetric Anesthesia and Perinatology Research Committee which also coordinated the study. Thirty institutions participated in the approximately 5-yr study period. Data were collected as part of institutional quality assurance and sent to the central project coordinator quarterly. RESULTS: Data were captured on more than 257,000 anesthetics, including 5,000 general anesthetics for cesarean delivery. There were 157 total serious complications reported, 85 of which were anesthesia related. High neuraxial block, respiratory arrest in labor and delivery, and unrecognized spinal catheter were the most frequent complications encountered. A serious complication occurs in approximately 1:3,000 (1:2,443 to 1:3,782) obstetric anesthetics. CONCLUSIONS: The Serious Complication Repository Project establishes the incidence of serious complications in obstetric anesthesia. Because serious complications related to obstetric anesthesia are rare, there were too few complications in each category to identify risk factors associated with each. However, because many of these complications can lead to catastrophic outcomes, it is recommended that the anesthesia provider remains vigilant and be prepared to rapidly diagnose and treat any complication.

Impact of cervical effacement and fetal station on progress during the first stage of labor: a biexponential model.

OBJECTIVE: To develop a model that uses cervical effacement, fetal station, and parity to predict progress during the first stage of labor. STUDY DESIGN: This was a secondary analysis of a cohort of 1,128 parturients delivering after 34 weeks. Timed cervical exams from each patient were fit with a biexponential model. Methods for consideration of fetal station, cervical effacement and parity were developed and validated. RESULTS: The biexponential model fit the data in an unbiased manner with a median absolute prediction error of 1.1 cm. Although nulliparous women had slower active labor, they did not differ from multiparous women in their rate of latent labor or the cervical dilation at which they transitioned to active labor. In addition, nulliparous women began laboring with a more effaced cervix (45 vs. 31%) and lower fetal station (-2.8 vs. -3.2). CONCLUSION: We validated a biexponential model for labor progress using a large mixed parity cohort. We demonstrated that parity and initial fetal station add important clinical information that can be used to make a labor model more accurate. As such, parity and fetal station can be utilized in such structural models to predict normal labor progress and potentially identify abnormalities in labor progress.