Development of clinical risk-prediction models for uterine atony following vaginal and cesarean delivery.

BACKGROUND: Uterine atony is the most common cause of postpartum hemorrhage and is associated with substantial morbidity. Prospectively identifying women at increased risk of atony may reduce the incidence of subsequent adverse events. We sought to develop and evaluate clinical risk-prediction models for uterine atony following vaginal and cesarean delivery, using prespecified risk factors identified from systematic review. METHODS: Using retrospective data from vaginal and cesarean deliveries occurring at a single institution between 2010 and 2019, antepartum and intrapartum risk-prediction models for uterine atony, defined by supplementary uterotonic administration in addition to prophylactic oxytocin infusion, were developed using logistic regression. The C-statistic quantified the ability of the model to discriminate between cases and controls. RESULTS: Data were available for 4773 atony cases and 23 933 controls. The antepartum model included 20 risk factors and exhibited moderate discriminatory ability (C-statistic 0.61, 95% confidence interval 0.60 to 0.62). The intrapartum model included 27 risk factors and showed improved discriminatory ability (C-statistic 0.68, 95% confidence interval 0.67 to 0.69). CONCLUSIONS: We identified antepartum and intrapartum risk-prediction models to quantify patients' risk of uterine atony. Models performed similarly for all delivery modes, races, and ethnic groups. Future work should further improve these models through inclusion of more comprehensive prediction data.

Quantifying the incidence of clinically significant respiratory depression in women with and without obesity class III receiving neuraxial morphine for post-cesarean analgesia: a retrospective cohort study.

BACKGROUND: Obesity is a suspected risk factor for respiratory depression following neuraxial morphine for post-cesarean analgesia, however monitoring guidelines for obese obstetric patients are based on small, limited studies. We tested the hypothesis that clinically significant respiratory depression following neuraxial morphine occurs more commonly in women with body mass index (BMI) ≥40 kg/m2 compared with BMI <40 kg/m2. METHODS: We conducted a single-center, retrospective chart review (2006-2017) of obstetric patients with clinically significant respiratory depression following neuraxial morphine, defined as: (1) opioid antagonist administration; (2) rapid response team activation (initiated in April 2010); or (3) tracheal intubation due to a respiratory event. The incidence of respiratory depression was compared between women with BMI ≥40 kg/m2 and BMI <40 kg/m2. RESULTS: In total, 11 327 women received neuraxial morphine (n=1945 BMI ≥40 kg/m2; n=9382 BMI <40 kg/m2). Women with BMI ≥40 kg/m2 had higher rates of sleep apnea, hypertensive disorders, and magnesium administration. Sixteen cases of clinically significant respiratory depression occurred within seven days postpartum. The incidence did not significantly differ between groups (odds ratio 2.2, 95% CI 0.6 to 6.9, P=0.174). Neuraxial morphine was not deemed causative in any case, however women with BMI ≥40 kg/m2 had higher rates of tracheal intubation unrelated to neuraxial morphine (2/1945 vs. 0/9382, P=0.029). CONCLUSIONS: Respiratory depression in this population is rare. A larger sample (∼75 000) is required to determine whether the incidence is higher with BMI ≥40 kg/m2. Tracheal intubation was higher among the BMI ≥40 kg/m2 cohort, likely due to more comorbidities.

Maternal sedation during scheduled versus unscheduled cesarean delivery: implications for skin-to-skin contact.

BACKGROUND: Early maternal skin-to-skin contact confers numerous benefits to the newborn, but maternal sedation during cesarean delivery could have safety implications for early skin-to-skin contact in the operating room. We compared patient-reported and observer-assessed levels of sedation during unscheduled and scheduled cesarean deliveries. METHODS: Laboring women undergoing unscheduled cesarean delivery with epidural anesthesia, and scheduled cesarean delivery with spinal anesthesia were enrolled. Sedation levels, measured using patient-reported (1=least sedated to 10=most sedated) and observer-assessed (0=most sedated to 5=least sedated) scales, were evaluated at baseline and 15, 30, 45, and 60min following a T4 sensory level. The primary outcomes were patient-reported sedation at 45min and the areas under the sedation curves. RESULTS: Patient-reported levels of sedation were greater at 45min in laboring women undergoing unscheduled (median 7.5, IQR 5-9) versus scheduled cesarean delivery (median 4, IQR 3-6) (difference in medians 3.5, 99% CI 0 to 5). Observer-assessed sedation was not different between groups. The area under the time curve for patient-reported sedation was greater in the unscheduled group, median difference 162 score min (95% CI 52 to 255). The area under the time curve for observer-assessed sedation was greater in the unscheduled group, median difference 26 score min (99% CI 0 to 41). Times to skin-to-skin contact and breastfeeding were not different. CONCLUSIONS: Women undergoing unscheduled cesarean deliveries are more sedated than women undergoing scheduled cesarean deliveries. Skin-to-skin protocols for cesarean deliveries must consider maternal sedation and anesthesiologists should use sedating medications judiciously.

Low-dose ketamine with multimodal postcesarean delivery analgesia: a randomized controlled trial.

BACKGROUND: Ketamine at subanesthetic doses has analgesic properties that have been shown to reduce postoperative pain and morphine consumption. We hypothesized that intravenous ketamine 10mg administered during spinal anesthesia for cesarean delivery, in addition to intrathecal morphine and intravenous ketorolac, would decrease the incidence of breakthrough pain and need for supplemental postoperative analgesia. METHODS: Using a randomized double-blind placebo-controlled design, healthy women scheduled for cesarean delivery receiving hyperbaric spinal bupivacaine, fentanyl and morphine were randomized to intravenous ketamine 10mg or saline following delivery. Postoperative analgesia included scheduled ketorolac and acetaminophen/hydrocodone tablets as needed for breakthrough pain. The primary outcome was the incidence of breakthrough pain in the first 24h. Secondary outcomes included the number of acetaminophen/hydrocodone tablets administered and numeric rating scale for pain (0-10). RESULTS: Group characteristics did not differ. There was no difference in the incidence of breakthrough pain (ketamine 75% VS. saline 74%, P=0.86). There was no difference in 24-h or 72-h use of supplemental acetaminophen/hydrocodone tablets between groups. Pain scores in the first 24h were similar, but lower in the ketamine compared to the saline group 2weeks postpartum (difference -0.6, 95% CI -1.1 to -0.9). CONCLUSIONS: We found no additional postoperative analgesic benefit of low-dose ketamine during cesarean delivery in patients who received intrathecal morphine and intravenous ketorolac. Subjects who received ketamine reported lower pain scores 2weeks postpartum.

A randomized controlled trial of the effect of combined spinal-epidural analgesia on the success of external cephalic version for breech presentation.

BACKGROUND: Improving the success of external cephalic version (ECV) for breech presentation may help avoid some cesarean deliveries. The results of randomized trials comparing the success of ECV with neuraxial analgesia compared to control are inconsistent. We hypothesized that combined spinal-epidural (CSE) analgesia would increase the success of ECV when compared with systemic opioid analgesia. METHODS: Parturients with singleton breech presentation (n=96) were randomized to receive CSE analgesia with bupivacaine 2.5mg and fentanyl 15 microg (CSE group) or intravenous fentanyl 50 microg (SYS group) before ECV attempt. The primary outcome was ECV success. RESULTS: The success rate of ECV was 47% with CSE and 31% in the SYS group (P=0.14). Subsequent vaginal delivery was 36% for CSE and 25% for SYS (P=0.27). Median [IQR] visual analog pain scores (0-100mm scale) were lower with CSE (3 [0-12]) compared to SYS analgesia (36 [16 to 54]) (P<0.005) and patient satisfaction (0-10 scale) was higher (CSE 10 [9 to 10] versus SYS 7 [4 to 9]) (P<0.005). There were no differences in fetal heart rate patterns, but median time to return to fetal heart rate reactivity after analgesia was shorter with CSE (13 [IQR 9-21] min) compared to the SYS group (39 [IQR 23-51] min) (P=0.02). CONCLUSIONS: There was no difference in the rate of successful ECV or vaginal delivery with CSE compared to intravenous fentanyl analgesia. Pain scores were lower and satisfaction higher with CSE analgesia, and median time to fetal heart rate reactivity was shorter in the CSE group.

Biochemical and functional analysis of a conserved IGF-binding protein isolated from rainbow trout (Oncorhynchus mykiss) hepatoma cells.

Rainbow trout (Oncorhynchus mykiss) serum contains several IGF-binding proteins (IGFBPs) that specifically bind to IGFs. The structures of these fish IGFBPs have not been determined and their physiological functions are poorly defined. In this study, we identified a 30 kDa IGFBP present in rainbow trout serum and secreted by cultured trout hepatoma cells. This IGFBP binds to IGFs but not to insulin. This IGFBP was purified to homogeneity using a three-step procedure involving Phenyl-Sepharose chromatography, IGF-I affinity chromatography and reverse-phase HPLC. Affinity cross-linking studies indicated that this IGFBP binds to IGF-I with a higher affinity than to IGF-II. N-terminal sequence analysis of the trout IGFBP suggests that it shares high sequence identity with that of human IGFBP-1 in the N-terminal region. When added to cultured fish and human cells, the trout IGFBP inhibited IGF-I-stimulated DNA synthesis and cell proliferation in a concentration-dependent manner. The inhibitory effect of the fish IGFBP was comparable to those of human IGFBP-1 and -4. These results indicate that the IGFBP molecule is structurally and functionally conserved in evolutionarily ancient vertebrate species such as bony fish.

Phosphatidylinositol 3-kinase is required for insulin-like growth factor-I-induced vascular smooth muscle cell proliferation and migration.

Insulin-like growth factor-I (IGF-I) plays an important role in regulating vascular smooth muscle cell (VSMC) proliferation and directed migration. The mitogenic and chemotactic actions of IGF-I are mediated through the IGF-I receptor, but how the activation of the IGF-I receptor leads to these biological responses is poorly understood. In this study, we examined the role of phosphatidylinositol 3-kinase (PI3 kinase) in mediating the mitogenic and chemotactic signals of IGF-I. IGF-I treatment resulted in a significant increase in phosphotyrosine-associated PI3 kinase activity in cultured primary VSMCs. To determine whether insulin receptor substrate (IRS)-1, -2, or both are involved in IGF-I signaling in VSMCs, cell lysates were immunoprecipitated with either an anti-IRS-1 or an anti-IRS-2 antibody, and the associated PI3 kinase activity was determined. IGF-I stimulation resulted in a significant increase in IRS-1- but not IRS-2-associated PI3 kinase activity, suggesting that IGF-I primarily utilizes IRS-1 to transmit its signal in VSMCs. The IGF-I-induced increase in IRS-I-associated PI3 kinase activity was concentration dependent. At the maximum concentration (50 ng/mL), IGF-I induced a 60-fold increase. This activation occurred within 5 minutes and was sustained at high levels for at least 6 hours. IGF-I also caused a concentration-dependent and long-lasting activation of protein kinase B (PKB/Akt). Inhibition of PI3 kinase activation by LY294002 or wortmannin abolished IGF-I-stimulated VSMC proliferation and reduced IGF-I-directed VSMC migration by approximately 60%. These results indicate that activation of PI3 kinase is required for both IGF-I-induced VSMC proliferation and migration.

Down-regulation of protein kinase C inhibits insulin-like growth factor I-induced vascular smooth muscle cell proliferation, migration, and gene expression.

Insulin-like growth factor-I (IGF-I) plays an important role in regulating vascular smooth muscle cell (VSMC) proliferation, directed migration, differentiation, and apoptosis. The signaling mechanisms used by IGF-I to elicit these actions, however, are not well defined. In this study, we examined the role(s) of protein kinase C (PKC) in mediating the IGF-I actions in cultured porcine VSMCs. Out of the eleven known members of PKC family, PKC-alpha, -betaI, -epsilon, -eta, -lambda, -theta, and -zeta, were detectable by Western immunoblot analysis in these cells. Further analysis indicated that the subcellular distribution of several PKC isoforms is regulated by IGF-I. While IGF-I stimulated membrane translocation of PKC-eta, -epsilon, and -zeta and regulated the cytosolic levels of PKC-betaI, it had no such effect on PKC-alpha and -lambda. To examine whether PKC activation is required for the IGF-I-regulated biological responses, phorbol myristate acetate (PMA) and GF109203X were used to down-regulate or inhibit PKC activity. Both PMA (1 microM) and GF109203X (20 microM) nearly completely suppressed the total PKC activity after a 30-min incubation (> 90%), and this inhibition lasted for at least 24 h. Down-regulation or inhibition of PKC activity abolished the IGF-I-induced DNA synthesis, migration and IGFBP-5 gene expression. In contrast, the IGFBP-5 expression induced by forskolin was unaffected by PKC down-regulation or inhibition, suggesting that PKC activation is required for the IGF-regulated but not the cAMP-regulated events. Because the actions of IGF-I on DNA synthesis and IGFBP-5 gene expression in VSMCs have been shown to be mediated through the phosphatidylinositol 3-kinase (PI3 kinase) signaling pathway in porcine VSMCs, the potential role of PKC in IGF-I-induced activation of PI3 kinase and PKB/Akt were examined. Treatment with either PMA or GF109203X did not significantly affect the effects of IGF-I on PI3 kinase activation or PKB/Akt phosphorylation. These results indicated that PKC-betaI, -eta, -epsilon, and -zeta may play an essential role(s) in IGF-I regulation of VSMC migration, DNA synthesis and gene expression, and that these PKC isoforms may either act independently of the PI3 kinase pathway or act further downstream of PKB/Akt in the IGF signaling network.