Anti-Factor-Xa and Activated Partial Thromboplastin Time Concordance and Outcomes in Adults Undergoing Extracorporeal Membrane Oxygenation: A Secondary Analysis of the Pilot Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation Randomized Trial.

OBJECTIVES: To determine the concordance between activated partial thromboplastin time (aPTT) and anti-factor-Xa (anti-Xa) in adults undergoing extracorporeal membrane oxygenation (ECMO) and to identify the factors associated with discordant paired aPTT/anti-Xa. DESIGN: Pre-planned secondary analysis of the Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation pilot randomized unblinded, parallel-group controlled trial. SETTING: Two ICUs in two university hospitals. PATIENTS: Thirty-two critically ill patients who underwent ECMO and who had at least one paired aPTT and anti-Xa assay performed at the same time. INTERVENTIONS: We analyzed the concordance between aPTT and anti-Xa and identified factors associated with discordant paired aPTT/anti-Xa based on their respective therapeutic ranges. We also compared biological parameters between heparin resistance episode and no heparin resistance. MEASUREMENTS AND MAIN RESULTS: Of the 32 patients who were included in this study, 24 (75%) had at least one discordant paired aPTT/anti-Xa. Of the 581 paired aPTT/anti-Xa that were analyzed, 202 were discordant. The aPTT was relatively lower than anti-Xa in 66 cases (32.7%) or relatively higher than anti-Xa in 136 cases (67.3%). Thirty-three heparin resistance episodes were identified in six patients (19%). CONCLUSIONS: In these critically ill patients undergoing ECMO, one third of paired aPTT/anti-Xa measures was discordant. Coagulopathy and heparin resistance might be the reasons for discordance. Our results support the potential importance of routinely monitoring both tests in this setting.

Admission ultrasonography as a means of identifying unrecognized fetal compromise in term singleton pregnancies at the onset of labor - a feasibility study.

OBJECTIVES: Apparently uncomplicated low-risk pregnancies, especially first time births, account for a significant proportion of adverse birth outcomes. Improved risk stratification with a simple bedside scan on admission in early labor could potentially reduce adverse intrapartum outcomes. The aim of this feasibility study was to assess a cohort of low-risk subjects with admission ultrasonography at the onset of labor with a view to conducting a future randomized controlled trial (RCT). The objectives were three-fold; i) to determine the logistics of performing a labor admission ultrasound scan ii) to establish whether abnormal ultrasound features can be identified and iii) whether they are associated with emergency delivery and/or poor condition of the neonate at birth. METHODS: We performed a prospective cohort study of 295 participants with term singleton cephalic pregnancies admitted in early labor or for labor induction with non-fetal indications. The setting was a university teaching hospital in Ireland with almost 8000 births annually. A bedside ultrasound scan was performed to assess fetal biometry, amniotic fluid volume and placental maturity. Patients and their babies were followed up until hospital discharge. The outcomes of interest included image quality, time to perform a scan, oligohydramnios (Single Deepest Pool ≤ 2 cm), small for gestational age (SGA; abdominal circumference <10th centile), mature placenta (Grannum 2 or 3), pathological CTG, emergency cesarean section (CS), fetal acidosis (cord arterial pH <7.10 or base excess <-12.0), low Apgar score <7 at 5 min and neonatal unit admission. RESULTS: Image quality was optimal in 274 of the 295 scans (93%) and 271 (92%) were completed in less than 10 min. Of this low-risk population, 67 of 294 (23%) had oligohydramnios, 11 (4%) were small for gestational age and 87 (30%) had a mature placenta (Grannum grade 2). The incidence of pathological CTG and emergency CS was higher among patients with oligohydramnios than those with a normal scan but did not reach statistical significance; Odds Ratio 3.40 (95% Confidence Intervals 0.55 to 20.92) and OR 1.43 (95% CI 0.66 to 3.08) respectively. The mean birthweight was significantly lower in those with oligohydramnios -139 g (95% CI -248 to -30) and admission scan detected SGA -357 g (95% CI -557 to -137). Adverse perinatal outcomes were uncommon with a higher incidence of fetal acidosis (pH < 7.10) in the oligohydramnios group. The incidence of neonatal unit admission >24 h was higher in the oligohydramnios group but not statistically significant; OR 3.75 (95% CI 0.61 to 22.97). Results for SGA alone were non-significant and results for oligohydramnios and SGA combined were similar to those for oligohydramnios alone. CONCLUSIONS: Admission ultrasonography is feasible in a routine clinical setting, but evidence of benefit is weak and does not currently justify a randomized controlled trial.

Fetal scalp stimulation for assessing fetal well-being during labour.

BACKGROUND: Continuous fetal heart rate monitoring by cardiotocography (CTG) is used in labour for women with complicated pregnancies. Fetal heart rate abnormalities are common and may result in the decision to expedite delivery by caesarean section. Fetal scalp stimulation (FSS) is a second-line test of fetal well-being that may provide reassurance that the labour can continue. OBJECTIVES: To evaluate methods of FSS as second-line tests of intrapartum fetal well-being in cases of non-reassuring CTG. FSS and CTG were compared to CTG alone, and to CTG with fetal blood sampling (FBS). SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (which includes trials from CENTRAL, MEDLINE, Embase, CINAHL, the WHO ICTRP and conference proceedings), ClinicalTrials.gov (18 October 2022), and reference lists of retrieved studies. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) that compared any form of FSS to assess fetal well-being in labour. Quasi-RCTs, cluster-RCTs and studies published in abstract form were also eligible for inclusion, but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Two trials, involving 377 women, met the inclusion criteria for this review. Both trials were conducted in hospital settings and included women with singleton, term (37+0 weeks or more) pregnancies, a cephalic presentation, and abnormal CTG. Follow-up was until hospital discharge after the birth. A pilot trial of 50 women in a high-income country (Ireland) compared CTG and digital fetal scalp stimulation (dFSS) with CTG and fetal blood sampling (FBS). A single-centre trial of 327 women in a lower middle-income country (India) compared CTG and manual fetal stimulation (abdominal or vaginal scalp stimulation) with CTG alone. The two included studies were at moderate or unclear risk of bias. Both trials provided clear information on allocation concealment but it was not possible to blind participants or health professionals in relation to the intervention. Although objective outcome measures were reported, outcome assessment was not blinded or blinding was unclear. dFSS and CTG versus FBS and CTG There were no perinatal deaths and data were not reported for neurodevelopmental disability at >/= 12 months. The risk of caesarean section (CS) may be lower with dFSS compared to FBS (risk ratio (RR) 0.38, 95% confidence interval (CI) 0.16 to 0.92; 1 pilot trial, 50 women; very low-certainty evidence) but the evidence is very uncertain. There were no cases of neonatal encephalopathy reported. The evidence was also very uncertain between dFSS and FBS for assisted vaginal birth (RR 1.44, 95% CI 0.76 to 2.75; very low-certainty evidence) and for the spontaneous vaginal birth rate (RR 2.33, 95% CI 0.68 to 8.01, very low-certainty evidence). Maternal acceptability of the procedures was not reported. FSS and CTG versus CTG alone Manual stimulation of the fetus was performed either abdominally (92/164) or vaginally (72/164). There were no perinatal deaths and data were not reported for neurodevelopmental disability at >/= 12 months. There may be little differences in the risk of CS on comparing manual fetal stimulation and CTG with CTG alone (RR 0.83, 95% CI 0.59 to 1.18; 1 trial, 327 women; very low-certainty evidence), but again the evidence was very uncertain. There were no cases of neonatal encephalopathy reported. There may be no differences in the risk of assisted vaginal birth (RR 1.43, 95% CI 0.78 to 2.60; very low-certainty evidence) or in the rates of spontaneous vaginal birth (RR 1.01, 95% CI 0.85 to 1.21, very low-certainty evidence), but again the evidence is very uncertain. Maternal acceptability of abdominal stimulation/FSS was not reported although 13 women withdrew consent after randomisation due to concerns about fetal well-being. AUTHORS' CONCLUSIONS: There is very low-certainty evidence available which makes it unclear whether stimulating the fetal scalp is a safe and effective way to confirm fetal well-being in labour. Evidence was downgraded based on limitations in study design and imprecision. Further high-quality studies of adequate sample size are required to evaluate this research question. In order to be generalisable, these trials should be conducted in different settings, including broad clinical criteria at both preterm and term gestational ages, and standardising the method of stimulation. There is an ongoing study (FIRSST) that will be incorporated into this review in a subsequent update.

Cervical ripening and labour induction: A critical review of the available methods.

Induction of labour is one of the most common interventions experienced by pregnant women. There are two overlapping components to labour induction, which include cervical ripening and the initiation of regular contractions. A large number of clinical studies have been conducted for evaluating the methods used for induction of labour, their effectiveness and safety, and pregnancy outcomes. Randomised controlled trials (RCTs) provide the strongest form of evidence for clinical practice. These data are brought together in systematic reviews and have been incorporated into national and international guidelines. Despite this, there is considerable variation in the recommendations between guidelines. Heterogeneity between studies, inconsistency in the definitions of trial outcomes, and underpowered sample size contribute to the difficulty in making robust recommendations. There are pharmacological and non-pharmacological approaches that can be compared with each other and with placebo or no treatment. There are also complementary therapies that may appeal to women but lack evidence of their effectiveness. These issues have been addressed in the current chapter, with a critical review of the research evidence presented in clinical trials and systematic reviews.

Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator.

The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aß42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.

Feasibility study protocol of a pragmatic, randomised controlled pilot trial: membrane sweeping to prevent post-term pregnancy-the MILO Study.

BACKGROUND: Post-term pregnancy is associated with an increased risk of maternal complications, respiratory distress and trauma to the neonate. Amniotic membrane sweeping has been recommended as a simple procedure to promote the spontaneous onset of labour. However, despite its widespread use, there is an absence of evidence on (a) its effectiveness and (b) its optimal timing and frequency. The primary aim of the MILO Study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. We will also assess the acceptability and feasibility of the proposed trial interventions to clinicians and women (through focus group interviews). METHODS/DESIGN: Multicentre, pragmatic, parallel-group, pilot randomised controlled trial with an embedded factorial design. Pregnant women with a live, singleton foetus ≥ 38 weeks gestation; cephalic presentation; longitudinal lie; intact membranes; English speaking and ≥ 18 years of age will be randomised in a 2:1 ratio to membrane sweep versus no membrane sweep. Women allocated randomly to a sweep will then be randomised further (factorial component) to early (from 39 weeks) versus late (from 40 weeks) sweep commencement and a single versus weekly sweep. The proposed feasibility study consists of four work packages, i.e. (1) a multicentre, pilot randomised trial; (2) a health economic analysis; (3) a qualitative study; and (4) a study within the host trial (a SWAT). Outcomes to be collected include recruitment and retention rates, compliance with protocol, randomisation and allocation processes, attrition rates and cost-effectiveness. Focus groups will be held with women and clinicians to explore the acceptability and feasibility of the proposed intervention, study procedures and perceived barriers and enablers to recruitment. DISCUSSION: The primary aim of the MILO Study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. Results will inform whether and how the design of the definitive trial as originally envisaged should be delivered or adapted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04307199 . Registered on 12 March 2020.

Peak Serum Chloride and Hyperchloremia in Patients Undergoing Cardiac Surgery Is Not Explained by Chloride-Rich Intravenous Fluid Alone: A Post-Hoc Analysis of the LICRA Trial.

OBJECTIVES: With the exception of 0.9% saline, little is known about factors that may contribute to increased serum chloride concentration (SCl-) in patients undergoing cardiac surgery. For the present study, the authors sought to characterize the association between administered chloride load from intravenous fluid and other perioperative variables, with peak perioperative SCl-. DESIGN: Secondary analysis of data from a previously published controlled clinical trial in which patients were assigned to a chloride-rich or chloride-limited perioperative fluid strategy (NCT02020538). SETTING: Academic medical center. PARTICIPANTS: The study comprised 1,056 adult patients with normal preoperative SCl- undergoing cardiac surgery. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Peak perioperative SCl- and hyperchloremia, defined as peak SCl- >110 mmol/L, were selected as co-primary endpoints. Regression modeling identified factors independently associated with these endpoints. Mean (standard deviation) peak perioperative SCl- was 114 (5) mmol/L, and hyperchloremia occurred in 824 (78.0%) of the cohort. In addition to administered volume of 0.9% saline, multivariate linear and logistic regression modeling consistently associated preoperative SCl- (regression coefficient 0.5; 95% confidence interval [CI] 0.4-0.6 mmol/L; odds ratio 1.60; 95% CI 1.41-1.82 per 1 mmol/L increase) and cardiopulmonary bypass duration (regression coefficient 0.1; 95% CI 0.1-0.2 mmol/L; odds ratio 1.12; 95% CI 1.06-1.19 per 10 minutes) with both co-primary outcomes. Multivariate modeling only explained approximately 50% of variability in peak SCl-. CONCLUSIONS: The present study's data identified an association for both 0.9% saline administration and other nonfluid variables with peak perioperative SCl- and hyperchloremia. Stand-alone strategies to limit administration of chloride-rich intravenous fluid may have limited ability to prevent hyperchloremia in this setting.

Prospective cohort study of water immersion for labour and birth compared with standard care in an Irish maternity setting.

OBJECTIVE: To examine the birth outcomes for women and babies following water immersion for labour only, or for labour and birth. DESIGN: Prospective cohort study. SETTING: Maternity hospital, Ireland, 2016-2019. PARTICIPANTS: A cohort of 190 low-risk women who used water immersion; 100 gave birth in water and 90 laboured only in water. A control group of 190 low-risk women who received standard care. METHODS: Logistic regression analyses examined associations between water immersion and birth outcomes adjusting for confounders. A validated Childbirth Experience Questionnaire was completed. MAIN OUTCOME MEASURES: Perineal tears, obstetric anal sphincter injuries (OASI), postpartum haemorrhage (PPH), neonatal unit admissions (NNU), breastfeeding and birth experiences. RESULTS: Compared with standard care, women who chose water immersion had no significant difference in perineal tears (71.4% vs 71.4%, adj OR 0.83; 95% CI 0.49 to 1.39) or in OASI (3.3% vs 3.8%, adj OR 0.91; 0.26-2.97). Women who chose water immersion were more likely to have a PPH ≥500 mL (10.5% vs 3.7%, adj OR 2.60; 95% CI 1.03 to 6.57), and to exclusively breastfeed at discharge (71.1% vs 45.8%, adj OR 2.59; 95% CI 1.66 to 4.05). There was no significant difference in NNU admissions (3.7% vs 3.2%, adj OR 1.06; 95% CI 0.33 to 3.42). Women who gave birth in water were no more likely than women who used water for labour only to require perineal suturing (64% vs 80.5%, adj OR 0.63; 95% CI 0.30 to 1.33), to experience OASI (3.0% vs 3.7%, adj OR 1.41; 95% CI 0.23 to 8.79) or PPH (8.0% vs 13.3%, adj OR 0.73; 95% CI 0.26 to 2.09). Women using water immersion reported more positive memories than women receiving standard care (p<0.01). CONCLUSIONS: Women choosing water immersion for labour or birth were no more likely to experience adverse birth outcomes than women receiving standard care and rated their birth experiences more highly.

A preliminary study of intensivist-performed DVT ultrasound screening in trauma ICU patients (APSIT Study).

BACKGROUND: Multiple screening Duplex ultrasound scans (DUS) are performed in trauma patients at high risk of deep vein thrombosis (DVT) in the intensive care unit (ICU). Intensive care physician performed compression ultrasound (IP-CUS) has shown promise as a diagnostic test for DVT in a non-trauma setting. Whether IP-CUS can be used as a screening test in trauma patients is unknown. Our study aimed to assess the agreement between IP-CUS and vascular sonographer performed DUS for proximal lower extremity deep vein thrombosis (PLEDVT) screening in high-risk trauma patients in ICU. METHODS: A prospective observational study was conducted at the ICU of Alfred Hospital, a major trauma center in Melbourne, Australia, between Feb and Nov 2015. All adult major trauma patients admitted with high risk for DVT were eligible for inclusion. IP-CUS was performed immediately before or after DUS for PLEDVT screening. The paired studies were repeated twice weekly until the DVT diagnosis, death or ICU discharge. Written informed consent from the patient, or person responsible, or procedural authorisation, was obtained. The individuals performing the scans were blinded to the others' results. The agreement analysis was performed using Cohen's Kappa statistics and intraclass correlation coefficient for repeated binary measurements. RESULTS: During the study period, 117 patients had 193 pairs of scans, and 45 (39%) patients had more than one pair of scans. The median age (IQR) was 47 (28-68) years with 77% males, mean (SD) injury severity score 27.5 (9.53), and a median (IQR) ICU length of stay 7 (3.2-11.6) days. There were 16 cases (13.6%) of PLEDVT with an incidence rate of 2.6 (1.6-4.2) cases per 100 patient-days in ICU. The overall agreement was 96.7% (95% CI 94.15-99.33). The Cohen's Kappa between the IP-CUS and DUS was 0.77 (95% CI 0.59-0.95), and the intraclass correlation coefficient for repeated binary measures was 0.75 (95% CI 0.67-0.81). CONCLUSIONS: There is a substantial agreement between IP-CUS and DUS for PLEDVT screening in trauma patients in ICU with high risk for DVT. Large multicentre studies are needed to confirm this finding.

Membrane sweeping for induction of labour.

BACKGROUND: Induction of labour involves stimulating uterine contractions artificially to promote the onset of labour. There are several pharmacological, surgical and mechanical methods used to induce labour. Membrane sweeping is a mechanical technique whereby a clinician inserts one or two fingers into the cervix and using a continuous circular sweeping motion detaches the inferior pole of the membranes from the lower uterine segment. This produces hormones that encourage effacement and dilatation potentially promoting labour. This review is an update to a review first published in 2005. OBJECTIVES: To assess the effects and safety of membrane sweeping for induction of labour in women at or near term (≥ 36 weeks' gestation). SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (25 February 2019), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (25 February 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing membrane sweeping used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed on a predefined list of labour induction methods. Cluster-randomised trials were eligible, but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, risk of bias and extracted data. Data were checked for accuracy. Disagreements were resolved by discussion, or by including a third review author. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included 44 studies (20 new to this update), reporting data for 6940 women and their infants. We used random-effects throughout. Overall, the risk of bias was assessed as low or unclear risk in most domains across studies. Evidence certainty, assessed using GRADE, was found to be generally low, mainly due to study design, inconsistency and imprecision. Six studies (n = 1284) compared membrane sweeping with more than one intervention and were thus included in more than one comparison. No trials reported on the outcomes uterine hyperstimulation with/without fetal heart rate (FHR) change, uterine rupture or neonatal encephalopathy. Forty studies (6548 participants) compared membrane sweeping with no treatment/sham Women randomised to membrane sweeping may be more likely to experience: · spontaneous onset of labour (average risk ratio (aRR) 1.21, 95% confidence interval (CI) 1.08 to 1.34, 17 studies, 3170 participants, low-certainty evidence). but less likely to experience: · induction (aRR 0.73, 95% CI 0.56 to 0.94, 16 studies, 3224 participants, low-certainty evidence); There may be little to no difference between groups for: · caesareans (aRR 0.94, 95% CI 0.85 to 1.04, 32 studies, 5499 participants, moderate-certainty evidence); · spontaneous vaginal birth (aRR 1.03, 95% CI 0.99 to 1.07, 26 studies, 4538 participants, moderate-certainty evidence); · maternal death or serious morbidity (aRR 0.83, 95% CI 0.57 to 1.20, 17 studies, 2749 participants, low-certainty evidence); · neonatal perinatal death or serious morbidity (aRR 0.83, 95% CI 0.59 to 1.17, 18 studies, 3696 participants, low-certainty evidence). Four studies reported data for 480 women comparing membrane sweeping with vaginal/intracervical prostaglandins There may be little to no difference between groups for the outcomes: · spontaneous onset of labour (aRR, 1.24, 95% CI 0.98 to 1.57, 3 studies, 339 participants, low-certainty evidence); · induction (aRR 0.90, 95% CI 0.56 to 1.45, 2 studies, 157 participants, low-certainty evidence); · caesarean (aRR 0.69, 95% CI 0.44 to 1.09, 3 studies, 339 participants, low-certainty evidence); · spontaneous vaginal birth (aRR 1.12, 95% CI 0.95 to 1.32, 2 studies, 252 participants, low-certainty evidence); · maternal death or serious morbidity (aRR 0.93, 95% CI 0.27 to 3.21, 1 study, 87 participants, low-certainty evidence); · neonatal perinatal death or serious morbidity (aRR 0.40, 95% CI 0.12 to 1.33, 2 studies, 269 participants, low-certainty evidence). One study, reported data for 104 women, comparing membrane sweeping with intravenous oxytocin +/- amniotomy There may be little to no difference between groups for: · spontaneous onset of labour (aRR 1.32, 95% CI 88 to 1.96, 1 study, 69 participants, low-certainty evidence); · induction (aRR 0.51, 95% CI 0.05 to 5.42, 1 study, 69 participants, low-certainty evidence); · caesarean (aRR 0.69, 95% CI 0.12 to 3.85, 1 study, 69 participants, low-certainty evidence); · maternal death or serious morbidity was reported on, but there were no events. Two studies providing data for 160 women compared membrane sweeping with vaginal/oral misoprostol There may be little to no difference between groups for: · caesareans (RR 0.82, 95% CI 0.31 to 2.17, 1 study, 96 participants, low-certainty evidence). One study providing data for 355 women which compared once weekly membrane sweep with twice-weekly membrane sweep and a sham procedure There may be little to no difference between groups for: · induction (RR 1.19, 95% CI 0.76 to 1.85, 1 study, 234 participants, low-certainty); · caesareans (RR 0.93, 95% CI 0.60 to 1.46, 1 study, 234 participants, low-certainty evidence); · spontaneous vaginal birth (RR 1.00, 95% CI 0.86 to 1.17, 1 study, 234 participants, moderate-certainty evidence); · maternal death or serious maternal morbidity (RR 0.78, 95% CI 0.30 to 2.02, 1 study, 234 participants, low-certainty evidence); · neonatal death or serious neonatal perinatal morbidity (RR 2.00, 95% CI 0.18 to 21.76, 1 study, 234 participants, low-certainty evidence); We found no studies that compared membrane sweeping with amniotomy only or mechanical methods. Three studies, providing data for 675 women, reported that women indicated favourably on their experience of membrane sweeping with one study reporting that 88% (n = 312) of women questioned in the postnatal period would choose membrane sweeping in the next pregnancy. Two studies reporting data for 290 women reported that membrane sweeping is more cost-effective than using prostaglandins, although more research should be undertaken in this area. AUTHORS' CONCLUSIONS: Membrane sweeping may be effective in achieving a spontaneous onset of labour, but the evidence for this was of low certainty. When compared to expectant management, it potentially reduces the incidence of formal induction of labour. Questions remain as to whether there is an optimal number of membrane sweeps and timings and gestation of these to facilitate induction of labour.

A Protocol that Mandates Postoxygenator and Arterial Blood Gases to Confirm Brain Death on Venoarterial Extracorporeal Membrane Oxygenation.

The apnea test (AT) during clinical brain death (BD) testing does not account for different arterial gas tensions on veno-arterial extracorporeal membrane oxygenation (V-A ECMO). We aimed to develop a protocol and now report our experience with three patients. The protocol was developed and implemented in 2015 at a quaternary center in Australia, measures both right radial and postoxygenator carbon dioxide (CO2) and oxygen (O2) gas tensions during the AT, incorporates regular gas sampling and a gradual reduction in fresh gas flow to ensure patient oxygenation. Patient 1 remained apneic despite both right radial and postoxygenator CO2 gas tensions >60 mmHg. Patient 2, despite having CO2 levels in a right radial arterial sample high enough to diagnose BD, postoxygenator CO2 remained <60 mmHg. Patient 2 did not breathe but radiological tests confirmed BD. Patient 3 showed respiratory effort but only once CO2 levels rose high enough in both right radial and postoxygenator samples. No patient was hypoxic during the AT. Performance of a reliable AT on V-A ECMO requires measurement of both right radial and postoxygenator blood gases. A protocol, which measures both blood gas values, is feasible to implement, while being both safe and easy to perform.

Low-Dose Versus Therapeutic Anticoagulation in Patients on Extracorporeal Membrane Oxygenation: A Pilot Randomized Trial.

OBJECTIVES: To determine whether randomization of patients undergoing extracorporeal membrane oxygenation to either therapeutic or a low-dose anticoagulation protocol results in a difference in activated partial thromboplastin time and anti-Xa. DESIGN: Randomized, controlled, unblinded study. SETTING: Two ICUs of two university hospitals. PATIENTS: Patients admitted to the ICU, who required extracorporeal membrane oxygenation (venovenous or venoarterial) and who did not have a preexisting indication for therapeutic anticoagulation. INTERVENTIONS: Therapeutic anticoagulation with heparin (target activated partial thromboplastin time between 50 and 70 s) or lower dose heparin (up to 12,000 U/24 hr aiming for activated partial thromboplastin time < 45 s). MEASUREMENTS AND MAIN RESULTS: Thirty-two patients were randomized into two study groups that were not significantly different in demographics and extracorporeal membrane oxygenation characteristics. There was a significant difference in the daily geometric mean heparin dose (11,742 U [95% CI, 8,601-16,031 U] vs 20,710 U [95% CI, 15,343-27,954 U]; p = 0.004), daily geometric mean activated partial thromboplastin time (48.1 s [95% CI, 43.5-53.2 s] vs 55.5 s [95% CI, 50.4-61.2 s]; p = 0.04), and daily geometric mean anti-Xa (0.11 international units/mL [95% CI, 0.07-0.18] vs 0.27 [95% CI, 0.17-0.42]; p = 0.01). We found similar results when considering only venovenous extracorporeal membrane oxygenation episodes; however, no difference in daily geometric mean activated partial thromboplastin time between groups when considering only venoarterial extracorporeal membrane oxygenation episodes. CONCLUSIONS: Allocating patients on extracorporeal membrane oxygenation to two different anticoagulation protocols led to a significant difference in mean daily activated partial thromboplastin time and anti-Xa levels between groups. When considering subgroups analyses, these results were consistent in patients on venovenous extracorporeal membrane oxygenation. Our results support the feasibility of a larger trial in patients undergoing venovenous extracorporeal membrane oxygenation to compare different anticoagulation protocols; however, this study does not provide evidence on the optimal anticoagulation protocol for patients undergoing extracorporeal membrane oxygenation.

Forceps delivery for non-rotational and rotational operative vaginal delivery.

Forceps are a commonly used instrument for assisting vaginal birth. Accepted indications include prolonged labour, suspected foetal distress and maternal medical conditions that benefit from a shortened second stage of labour. Maternal and offspring outcomes of forceps-assisted birth have been extensively reported in observational studies, but randomised trial evidence is limited. Forceps-assisted delivery has a lower failure rate than vacuum-assisted delivery but is associated with a higher incidence of maternal pelvic floor trauma. Second-stage caesarean section is associated with less foetal-neonatal trauma than forceps-assisted delivery but markedly reduces the chance of a subsequent vaginal birth. This review outlines the existing evidence on prevention, indications and contraindications for forceps-assisted birth (non-rotational and rotational), short- and long-term complications for mother and baby, alternatives to use of forceps and how to manage an abandoned forceps-assisted birth. The essential components of informed consent are also discussed.

Medico-legal considerations and operative vaginal delivery.

Women undergo operative vaginal delivery (OVD) as an alternative to caesarean section when complications arise in the second stage of labour. The perinatal mortality associated with OVD is very low, and most of the perinatal morbidity is minor. However, when serious adverse events occur, such as traumatic birth injury, shoulder dystocia, cerebral palsy and perinatal death, there are medico-legal implications. There is also the potential for litigation in relation to maternal pelvic floor injury, which is increased with OVD. Obstetricians performing and supervising OVDs need to be aware of the potential pitfalls and minimise the risk of adverse outcomes. Given that most obstetricians will be involved in adverse birth-related events, it is important that they are aware of the legal processes that may ensue. It is also important when reviewing adverse OVD-related outcomes that association is differentiated from causation. These issues are addressed in the current chapter with attention drawn to the Montgomery ruling, which redefines the legal standards expected in relation to informed consent.

Association of postoperative blood pressure and bleeding after cardiac surgery.

OBJECTIVE: We sought to characterize the relationship between postoperative blood pressure on the day of surgery and metrics of bleeding. METHODS: In a preplanned secondary analysis of prospectively collected data from the Limiting IV Chloride to Reduce AKI trial (NCT02020538), univariate and multivariable regression analyses explored the association between peak systolic blood pressure, peak mean arterial pressure, and peak central venous pressure recorded postoperatively on the day of surgery and multiple metrics of bleeding. Patients at increased bleeding risk due to specific criteria were excluded from analysis. The primary outcome was chest tube drainage (milliliters per hour) on the day of surgery. Secondary outcomes included red blood cell transfusion, surgical re-exploration for bleeding, and hospital mortality. RESULTS: The study cohort comprised 793 patients. Mean ± standard deviation peak systolic blood pressure, mean arterial pressure, and central venous pressure were 125 ± 15 mm Hg, 83 ± 9 mm Hg, and 12 ± 4 mm Hg, respectively. Median (interquartile range) chest tube drainage on the day of surgery was 33 mL/hour (interquartile range, 23 mL/hour-51 mL/hour). Adjusted for prespecified variables, there was no positive association between peak systolic blood pressure and bleeding outcomes, including chest tube drainage (-2.2 mL/10 mm Hg; 95% confidence interval, -3.9 to -0.5 mL/h/10 mm Hg; P = .01) or volume of transfusion (-15 mL/10 mm Hg; 95% confidence interval, -29 to -1 mL/h/10 mm Hg; P = .04). Results remained broadly consistent across multiple secondary outcomes and regardless of whether systolic blood pressure or mean arterial pressure was the explanatory variable. CONCLUSIONS: The lack of positive association between peak systolic blood pressure or peak mean arterial pressure with metrics of bleeding after cardiac surgery promotes equipoise for testing the influence of higher blood pressure targets during the early postoperative period.

PARROT Ireland: Placental growth factor in Assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a Stepped Wedge Cluster Randomised Control Trial Research Study Protocol.

INTRODUCTION: Women presenting with suspected pre-eclampsia are currently triaged on the basis of hypertension and dipstick proteinuria. This may result in significant false positive and negative diagnoses resulting in increased morbidity or unnecessary intervention. Recent data suggest that placental growth factor testing may be a useful adjunct in the management of women presenting with preterm pre-eclampsia. The primary objective of this trial is to determine if the addition of placental growth factor testing to the current clinical assessment of women with suspected preterm pre-eclampsia, is beneficial for both mothers and babies. METHODS AND ANALYSIS: This is a multicentre, stepped wedge cluster, randomised trial aiming to recruit 4000 women presenting with symptoms suggestive of preterm pre-eclampsia between 20 and 36+6 weeks' gestation. The intervention of an unblinded point of care test, performed at enrolment, will quantify maternal levels of circulating plasma placental growth factor. The intervention will be rolled out sequentially, based on randomisation, in the seven largest maternity units on the island of Ireland. Primary outcome is a composite outcome of maternal morbidity (derived from the modified fullPIERS model). To ensure we are not reducing maternal morbidity at the expense of earlier delivery and worse neonatal outcomes, we have established a co-primary outcome which will examine the effect of the intervention on neonatal morbidity, assessed using a composite neonatal score. Secondary analyses will examine further clinical outcomes (such as mode of delivery, antenatal detection of growth restriction and use of antihypertensive agents) as well as a health economic analysis, of incorporation of placental growth factor testing into routine care. ETHICS AND DISSEMINATION: Ethical approval has been granted from each of the seven maternity hospitals involved in the trial. The results of the trial will be presented both nationally and internationally at conference and published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02881073.