Extracorporeal membrane oxygenation in obstetric patients: An Israeli nationwide study.

BACKGROUND: The leading causes of maternal mortality include respiratory failure, cardiovascular events, infections, and hemorrhages. The use of extracorporeal membrane oxygenation (ECMO) as rescue therapy in the peripartum period for cardiopulmonary failure is expanding in critical care medicine. METHODS: This retrospective observational study was conducted on a nationwide cohort in Israel. During the 3-year period, between September 1, 2019, and August 31, 2022, all women in the peripartum period who had been supported by ECMO for respiratory or circulatory failure at 10 large Israeli hospitals were identified. Indications for ECMO, maternal and neonatal outcomes, details of ECMO support, and complications were collected. RESULTS: During the 3-year study period, in Israel, there were 540 234 live births, and 28 obstetric patients were supported by ECMO, with an incidence of 5.2 cases per 100 000 or 1 case per 19 000 births (when excluding patients with COVID-19, the incidence will be 2.5 cases per 100 000 births). Of these, 25 were during the postpartum period, of which 16 (64%) were connected in the PPD1, and 3 were during pregnancy. Eighteen patients (64.3%) were supported by V-V ECMO, 9 (32.1%) by V-A ECMO, and one (3.6%) by a VV-A configuration. Hypoxic respiratory failure (ARDS) was the most common indication for ECMO, observed in 21 patients (75%). COVID-19 was the cause of ARDS in 15 (53.7%) patients. The indications for the V-A configuration were cardiomyopathy (3 patients), amniotic fluid embolism (2 patients), sepsis, and pulmonary hypertension. The maternal and fetal survival rates were 89.3% (n = 25) and 100% (n = 28). The average ECMO duration was 17.6 ± 18.6 days and the ICU stay was 29.8 ± 23.8 days. Major bleeding complications requiring surgical intervention were observed in one patient. CONCLUSIONS: The incidence of using ECMO in the peripartum period is low. The maternal and neonatal survival rates in patients treated with ECMO are high. These results show that ECMO remains an important treatment option for obstetric patients with respiratory and/or cardiopulmonary failure.

Cross-talk between Human Spinal Cord µ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates Opioid-induced Scratching Behavior.

BACKGROUND: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between µ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific µ-opioid receptor isoforms which interact with gastrin releasing peptide receptor. METHODS: Reverse transcription polymerase chain reaction was performed on human spinal cord complimentary DNA from two human cadavers. Calcium responses to morphine (1 µM) were examined using calcium imaging microscopy on human cells (HEK293) coexpressing gastrin releasing peptide receptor and different human µ-opioid receptor isoforms. The authors assessed morphine-induced scratching behavior and thermal analgesia in mice following intrathecal injection of morphine (0.3 nmol) and a transactivator of transcription peptide designed from C-terminal sequences of 1Y isoform (0, 0.1, and 0.4 nmol). RESULTS: The authors demonstrated 1Y expression in the spinal cord dorsal horn. Morphine administration evoked a calcium response (mean ± SD) (57 ± 13 nM) in cells coexpressing both gastrin releasing peptide receptor and the 1Y isomer. This was blocked by 10 µM naltrexone (0.7 ± 0.4 nM; P < 0.0001), 1 µM gastrin-releasing peptide receptor antagonist (3 ± 2 nM; P < 0.0001), or 200 µM 1Y-peptide (2 + 2 nM; P < 0.0001). In mice, 0.4 nmol 1Y-peptide significantly attenuated morphine-induced scratching behaviors (scratching bouts, vehicle vs. 1Y-peptide) (92 ± 31 vs. 38 ± 29; P = 0.011; n = 6 to 7 mice per group), without affecting morphine antinociception in warm water tail immersion test (% of maximum possible effect) (70 ± 21 vs. 67 ± 22; P = 0.80; n = 6 mice per group). CONCLUSIONS: Human µ-opioid receptor 1Y isomer is a C-terminal splicing variant of Oprm1 gene identified in human spinal cord. Cross-talk between 1Y and gastrin releasing peptide receptor is required for mediating opioid-induced pruritus. Disrupting the cross talk may have implications for therapeutic uncoupling of desired analgesic effects from side effects of opioids.

[ADVANCES IN FETAL THERAPY IN COMPLICATED MONOCHORIONIC PREGNANCIES AND IN SEVERE CONGENITAL DIAPHRAGMATIC HERNIA: FIVE YEARS EXPERIENCE].

INTRODUCTION: : Minimally invasive fetal therapeutic procedures reduce the morbidity and mortality in monochorionic (MC) twins and in fetuses with congenital diaphragmatic hernia (CDH). MC pregnancies share their blood systems due to communicating vessels over their single placenta and may develop specific complications: Twin-to-Twin transfusion syndrome (TTTS), Selective intrauterine growth restriction (sIUGR), Twin Anemia-Polycythemia Sequence (TAPS), Twin Reverse Arterial Perfusion Syndrome (TRAP) or anomalies in one. Half of complicated MC require intrauterine interventions. Severe CDH is linked to a high rate of neonatal death due to pulmonary hypoplasia. Fetoscopic tracheal occlusion (FETO) with a balloon improves postnatal outcome. AIMS: A fetal therapy center was established in the Hadassah Medical Centers, Jerusalem in 2011 for intrauterine interventions. We report our 5 years' experience. METHODS: This prospective cohort follows the outcome of MC pregnancies and cases of severe CDH which underwent therapeutic fetal procedures in Hadassah between the years 2011-16. RESULTS: Out of 114 procedures, 95 were in MC: 84 monochorionic diamniotic twins, 7 monochorionic monoamniotic twins, 2 dichorionic triamniotic triplets and 2 monochorionic triplets. We treated 65 TTTS cases with fetoscopy and laser ablation of communicating vessels. The survival rate of both twins was 58.5% and at least one survived in 81.5% of the cases. In 2nd/3rd trimesters selective termination of 15 cases the survival rate of the remaining twin was 87%. In 11 cases of TRAP sequence treated with laser ablation of the feeding vessel the survival of the remaining twin was 91%. In 19 fetoscopies in severe CDH, 12 were for balloon insertion and 7 for removal. Endotracheal balloon was successfully placed in 11 of 12 cases (10 left-sided, 1 right-sided CDH). Balloon removal was prenatally performed by elective fetoscopy (n=7) or by intrapartum urgent puncture. There were no intrauterine fetal deaths. In isolated left-sided CDH the survival was 57%, whereas none survived in non-isolated left-sided CDH and right sided CDH. CONCLUSIONS: In-utero procedures are safe for the mother and increase newborn survival in MC pregnancies, thus specialized clinics are life-saving. FETO is a therapeutic option for severe CDH. Our results meet similar achievements reported by other leading world centers.

A Novel Proliposomal Ropivacaine Oil: Pharmacokinetic-Pharmacodynamic Studies After Subcutaneous Administration in Pigs.

BACKGROUND: Liposomal local anesthetics are limited by a short liposomal shelf-life, even when under refrigeration. We describe a novel proliposomal ropivacaine that produces liposomes in situ, only after exposure to aqueous media. METHODS: In vitro: Nanoparticles were assessed (particle size distribution analyzer, cryo-transmission electron microscopy) at baseline and after exposure to saline/plasma. TOXICITY: In porcine wound healing study (n = 12), healing was assessed by photography, clinical assessment, and histology. Pharmacodynamics: Seventeen young piglets were randomly assigned to plain 0.5% ropivacaine (n = 5), proliposomal 4% ropivacaine (n = 6), or sham (n = 6). Tactile threshold was assessed using von Frey filaments applied to the surgical wound; the nonoperated skin was used as a control. Tactile threshold over time was determined using area under the curve (AUC) and assessed by 1-way analysis of variance. PHARMACOKINETICS: 8 young piglets were randomly assigned to plain 0.5% (25 mg, n = 4) or proliposomal 4% (200 mg, n = 4) ropivacaine. Plasma ropivacaine was assessed by high-performance liquid chromatography at baseline and at intervals over 36 hours. Paired ropivacaine concentration (from wound exudate and plasma) was obtained at 96 hours. Data were analyzed using noncompartmental and compartmental models. RESULTS: In vitro: On exposure to saline and plasma, the study drug was transformed from a homogenous oil to an emulsion containing liposomes of approximately 1.4-µm diameter; this effect was dilution dependent and stable over time. TOXICITY: All wounds healed well; no effect of drug group was observed. Pharmacodynamics: Plain and proliposomal ropivacaine provided sensory anesthesia for approximately 6 and 30 hours, respectively. There was an approximately 7-fold increase in the AUC of anesthesia for proliposomal ropivacaine compared with plain ropivacaine (mean difference, 1010; 95% confidence interval [CI], 625-1396 g·h/mm; P < 0.0001). PHARMACOKINETICS: There was no difference in Cmax (2.31 ± 0.74 vs 2.32 ± 0.46 mg/L), despite an approximately 8-fold difference in dose. However, proliposomal ropivacaine was associated with a marked prolongation of Tmax (6.50 ± 6.35 vs 0.5 ± 0.0 hours), terminal half-life (16.07 ± 5.38 vs 3.46 ± 0.88 hours; P = 0.0036), and ropivacaine-time AUC (47.72 ± 7.16 vs 6.36 ± 2.07 h·mg/L; P < 0.0001), when compared with plain ropivacaine. The proliposomal formulation provided an approximately 250-fold higher ropivacaine concentration in the surgical wound (mean difference, 3783 ng/mL; 95% CI, 1708-5858; P = 0.001) and an approximately 25-fold higher wound:plasma ropivacaine concentration ratio (mean difference, 126; 95% CI 38-213; P = 0.011). CONCLUSIONS: Proliposomal ropivacaine exerted prolonged anesthesia with delayed elimination, typical for liposomal drugs. The advantage of this novel proliposomal ropivacaine is its ease of preparation and its extended shelf-stability (>2 years) at room temperature.

Proliposomal Ropivacaine Oil: Pharmacokinetic and Pharmacodynamic Data After Subcutaneous Administration in Volunteers.

BACKGROUND: Slow-release liposomal formulations of local anesthetics prolong plasma redistribution and reduce peak plasma drug concentration, allowing safer administration of larger doses and further prolonging sensory effects. However, their clinical applicability is limited by expensive manufacture and liposomal leakage. Previously, we described the simple preparation of a novel proliposomal ropivacaine oil that produces multilamellar liposomal vesicles on exposure to aqueous media and that has a shelf-life of >2 years at room temperature. In this study, we present both pharmacodynamic and pharmacokinetic data in healthy volunteers after subcutaneous injection of this novel proliposomal preparation of ropivacaine. METHODS: In the pharmacodynamic phase of this study, 15 volunteers received 3 separate subcutaneous injections of 2.5 mL containing 1 of the following drugs: proliposomal 4% ropivacaine, plain 0.5% ropivacaine, and the ropivacaine-free proliposomal vehicle. Drugs were administered into the lower back, and their location was randomized and blinded; a separate area was used as an uninjected, open control. Experimental sensory assessment was made at repeated intervals over 72 hours using both pinprick sensation and experimental heat pain tolerance (assessed using quantitative sensory testing). In a separate pharmacokinetic phase of this study, 9 volunteers received subcutaneous injections of 2.5 mL of either proliposomal 4% ropivacaine (n = 6) or plain 0.5% ropivacaine (n = 3); these participants had plasma ropivacaine concentrations assessed at repeated intervals over 72 hours. RESULTS: The mean ± SE duration of pinprick anesthesia after proliposomal and plain ropivacaine administration lasted 28.8 ± 6.0 and 15.9 ± 3.5 hours, respectively (mean difference, 16.8 hours; 95% confidence interval, 10.0-23.7; P = 0.001). For experimental heat pain, the anesthesia duration was approximately 36 and 12 hours, respectively, with mean ± SE area under the curve of the normalized heat pain tolerance over time 55.0 ± 28.8 Δ°C·min for proliposomal ropivacaine and 9.6 ± 26.0 Δ°C·min for plain ropivacaine (mean difference, 64.6 Δ°C·min; 95% confidence interval, 10.2-119.0; P = 0.036). In the pharmacokinetic study, there was no significant difference in peak plasma concentration in the proliposomal ropivacaine group (164 ± 43 ng/mL compared with 100 ± 41 ng/mL in the plain ropivacaine group; P = 0.07) despite an 8-fold increase in ropivacaine dose in the proliposomal group. The 99% upper prediction limit for peak plasma concentrations (351 ng/mL proliposomal; 279 ng/mL plain) was well below the putative toxic plasma concentration for both groups. The mean ± SE terminal half-life and area under the curve for proliposomal ropivacaine versus plain ropivacaine were 13.8 ± 3.6 hours vs 5.9 ± 2.3 hours (P = 0.011) and 5090 ± 1476 h·ng/mL vs 593 ± 168 h·ng/mL (P = 0.0014), respectively. CONCLUSIONS: The prolonged pharmacodynamic effect of proliposomal ropivacaine, together with its delayed elimination and prolonged redistribution to plasma, is compatible to depot-related slow-release and similar to the performance of other liposomal local anesthetics. The advantage of the proliposomal oil is its ease of preparation and its extended shelf-stability at room temperature.

Minocycline Effectively Protects the Rabbit's Spinal Cord From Aortic Occlusion-Related Ischemia.

OBJECTIVES: To identify the minocycline anti-inflammatory and antiapoptotic mechanisms through which it is believed to exert spinal cord protection during aortic occlusion in the rabbit model. DESIGN: An animal model of aortic occlusion-related spinal cord ischemia. Randomized study with a control group and pre-ischemia and post-ischemia escalating doses of minocycline to high-dose minocycline in the presence of either hyperglycemia, a pro-apoptotic maneuver, or wortmannin, a specific phosphatidylinositol 3-kinase antagonist. SETTING: Tertiary medical center and school of medicine laboratory. PARTICIPANTS: Laboratory animals-rabbits. INTERVENTIONS: Balloon obstruction of infrarenal aorta introduced via femoral artery incision. RESULTS: Severe hindlimb paralysis (mean Tarlov score 0.36±0.81 out of 3) was observed in all the control group animals (9 of 11 with paraplegia and 2 of 11 with paraparesis) compared with 11 of 12 neurologically intact animals (mean Tarlov score 2.58±0.90 [p = 0.001 compared with control]) in the high-dose minocycline group. This protective effect was observed partially during a state of hyperglycemia and was completely abrogated by wortmannin. Minocycline administration resulted in higher neurologic scores (p = 0.003) and a shift to viable neurons and more apoptotic-stained nuclei resulting from reduced necrosis (p = 0.001). CONCLUSIONS: In a rabbit model of infrarenal aortic occlusion, minocycline effectively reduced paraplegia by increasing the number of viable neurons in a dose-dependent manner. Its action was completely abrogated by inhibiting the phosphatidylinositol 3-kinase pathway and was inhibited partially by the pro-apoptotic hyperglycemia maneuver, indicating that the activation of cell salvage pathways and mitochondrial sites are possible targets of minocycline action in an ischemic spinal cord.

Anesthetic management of prophylactic cervical cerclage: a retrospective multicenter cohort study.

OBJECTIVES: Cervical incompetence complicates approximately 1 in 500 pregnancies and is the most common cause of second-trimester spontaneous abortion and preterm labor. No prospective or large retrospective studies have compared regional and general anesthesia for cervical cerclage. STUDY DESIGN: Following IRB approval, we performed a retrospective study in the two main medical centers over an 8-year period to assess the association of anesthesia choice with anesthetic and obstetric outcomes. Anesthetic and perioperative details were retrospectively collected from fails of all patients undergoing cervical cerclage from 01/01/2005 until 31/12/2012. Details included demographic data, anesthetic technique, PACU data and perioperative complications. RESULTS: We identified 487 cases of cervical cerclage in 327 women during the study period. The most commonly used anesthetic technique was general anesthesia (GA) (402/487; 82.5%) compared with regional anesthesia (RA) (85/487; 17.5%). When GA was performed, facemask was the most commonly used technique (275/402; 68.4%), followed by intravenous deep sedation (61/402; 15.2%); LMA (51/402; 12.7%) and tracheal intubation (13/402; 3.2%). There were no significant differences in demographic characteristics between women receiving general and regional anesthesia. Average duration of suturing the cervix among the GA group was 9.8 ± 1.6 and 10.6 ± 2.1 min in the RA group (p < 0.001). Average length of stay in the operating room in the GA group was 20.5 ± 3.9 and 23 ± 4.6 min in the RA group (p < 0.001). Patients receiving GA received in the PACU more opioids (6.2 versus 1.2%; p < 0.05) and more non-opioids analgesics (36.8 versus 9.4%; p < 0.001). Duration of PACU stay was shorter after GA (49.5 ± 18 min) than after RA (62.4 ± 28 min; p < 0.001). There were no other differences in anesthetic or perioperative outcome between groups. This study was not designed to provide evidence that RA reduces the risk of pulmonary aspiration, airway complications or adverse fetal neurological effects from maternal anesthetic exposure. CONCLUSIONS: Both regional and general anesthesia were safely used for the performance of cerclage. Patients after general anesthesia had a shorter recovery time but a higher demand for opioids and non-opioids analgesia.

A randomized controlled trial of the efficacy and respiratory effects of patient-controlled intravenous remifentanil analgesia and patient-controlled epidural analgesia in laboring women.

BACKGROUND: Safe and effective alternatives are required in labor when epidural analgesia is not appropriate. We hypothesized that patient-controlled IV remifentanil labor analgesia would not be inferior to patient-controlled epidural labor analgesia. METHODS: This randomized nonblinded controlled noninferiority study in healthy women with a singleton fetus and vertex presentation was performed at 1 site. Women were randomized to receive patient-controlled IV analgesia titrated from 20 mcg up to a maximum bolus dose of 60 mcg with a lockout interval of 1 to 2 minutes, or patient-controlled epidural analgesia 0.1% bupivacaine with 2 mcg/mL fentanyl (initiation bolus 15 mL; maintenance bolus 10 mL, lockout interval 20 minutes, basal infusion 5 mL/h). Crossover was permitted after 30 minutes. The primary study outcome was efficacy (assessed as hourly numerical rating scale [NRS] pain score [11-point NRS] and maternal satisfaction [11-point NRS]); the secondary outcome was safety (maternal apnea). Supplementary oxygen was administered continuously during the respiratory monitoring period. During the first hour of analgesia, the heart rate, respiratory rate, pulse oximetry (SpO2), and end-tidal CO2, as an indication of apnea, were compared. Apnea lasting >40 seconds was managed by light stimulation by the attending anesthesiologist. RESULTS: Forty women were recruited to the following groups: remifentanil n = 19 (1 exclusion), epidural n = 20. Four crossed over: 3 from the remifentanil to epidural group and 1 from the epidural to remifentanil group. Mean (± SD) baseline NRS pain scores were similar, 8.4 ± 1.5 for remifentanil and 8.7 ± 1.2 for epidural analgesia, P = 0.52. Baseline adjusted mean NRS reduction at 30 minutes for remifentanil was -4.5 (± 0.6) vs -7.1(± 0.6) for epidural analgesia, P < 0.0001 for both. Pain score at 30 minutes was 3.7 ± 2.8 for remifentanil and 1.5 ± 2.2 for epidural analgesia, P = 0.009. Remifentanil was inferior to epidural analgesia with respect to the NRS at all time points, because the observed difference in NRS was greater than the expected -1.5 units. Maternal satisfaction was 8.6 ± 1.4 for the remifentanil group and 9.1 ± 1.5 for epidural group, P = 0.26. Mean respiratory rate was lower in the remifentanil group, 18 ± 4 vs 21 ± 4 breaths/min in the epidural group, P = 0.03. Mean SpO2 was lower in the remifentanil group 96.8% ± 1.4 vs 98.4 ± 1.2 for epidural group, P < 0.0001. There were 9 apnea events; all occurred in 5 women receiving remifentanil (5/19 [26.3%], P = 0.046). Apgar scores and neonatal respiratory outcomes were similar. CONCLUSION: IV remifentanil is inferior to epidural analgesia for provision of labor analgesia; however, remifentanil does provide a satisfactory level of labor analgesia. Laboring women receiving remifentanil require suitable monitoring to detect and alert for apnea.

Peripartum anesthetic management of patients with Factor XI deficiency.

INTRODUCTION: Factor XI deficiency is predominantly found in the Ashkenazi Jewish population with a prevalence of 9%, but also seen in other ethnicities. Little information is available on obstetric anesthesia management in women with Factor XI deficiency. Therefore, we undertook a study to evaluate obstetric, anesthetic and perinatal outcomes in parturients with Factor XI deficiency. METHODS: A retrospective study was conducted with chart reviews from 1996 to 2011 resulted in 74 women with Factor XI level deficiency. We compared anesthetic and obstetric management in parturients with low (≤30%) level of Factor XI to those with higher levels. RESULTS: Ninety-one pregnancy outcomes were reviewed in these 74 women with Factor XI deficiency. Forty-three women had levels ≤30% in 46 labors while 31 women had levels >30% in 45 labors. Women with low levels of Factor XI were significantly more likely to receive FFP and less likely to receive neuroaxial anesthesia. There were no anesthetic complications and no difference in mode of delivery or neonatal outcomes. DISCUSSION: This study is the first step in building a national database for anesthetic cases and outcomes of parturients with Factor XI deficiency. Further efforts must be made to provide safe analgesia for these women.

When policy meets reality: the new 18-hour on-call shift policy and the Israeli anesthesia workforce crisis.

BACKGROUND: The Israeli physician workforce faces multiple challenges. These include planned policies reducing physician on-call from 26 to 18 h and, from 2026, allowing only graduates of Ministry of Health approved foreign medical schools to take the Israeli licensing examination and an ongoing physician shortage (2019: Israel had 3.19 physicians/1000 persons vs. OECD average of 3.49 physicians/1000 persons). This study examines the potential impact of these planned policies on the Israeli anesthesiology workforce. METHODS: Surveys conducted among 34 public and private Israeli hospital anesthesiology department chairs collected data on their department's number of weekday on-call anesthesiologists and current shortage of anesthesiologists. A subsequent survey collected data on each anesthesiologist in the workforce, including the country where they studied medicine. RESULTS: Each weekday night there were 114 on-call anesthesiologists; 72 residents and 42 attendings. Using productive work coefficients, this translates to 104 resident and 51 attending anesthesiologists. Furthermore, 21 departments had existing anesthesia workforce shortages totaling 110 anesthesiologists. There were 873 anesthesiologists from non-OECD countries whose medical schools are not accredited by the World Federation for Medical Education, of whom 332 were residents (61.9% of residents). Only 20.1% of anesthesiology residents were Israeli medical school graduates. CONCLUSIONS: Descriptive survey data assessed the immediate and long-term consequences for the healthcare system and anesthesiology workforce of two new Health Ministry policies. Implementing the 18-h policy will immediately remove from the daytime workforce 155 anesthesiologists and who will be unavailable to staff elective surgery operating rooms. This will compound the current national shortage of 110 anesthesiologists. It is unclear how to replace this shortfall since there are no surplus Israeli physicians and very few Israeli graduates choose anesthesiology as a specialty. This situation will be exacerbated after 2026 when graduates of certain foreign medical schools will be unable to enter the medical workforce, further reducing the pool of potential anesthesiology residents. Both policies were promulgated without adequate operational and budgetary planning or fiscal or workforce resources; implementation of the 18-h on-call policy has already been postponed. Therefore, new or updated policies must be accompanied by specific operational plans, budgetary allocations and funds for additional workforce.

Outcome predictors and patient progress following delivery in pregnant and postpartum patients with severe COVID-19 pneumonitis in intensive care units in Israel (OB-COVICU): a nationwide cohort study.

BACKGROUND: A key unresolved controversy in severe COVID-19 pneumonitis in pregnancy is the optimum timing of delivery and whether delivery improves or worsens maternal outcomes. We aimed to assess clinical data on every intensive care unit (ICU) day for pregnant and postpartum women admitted to the ICU with COVID-19, with a particular focus on the days preceding and following delivery. METHODS: In this multicentre, nationwide, prospective and retrospective cohort study, we evaluated all pregnant women who were admitted to an ICU in Israel with severe COVID-19 pneumonitis from the 13th week of gestation to the 1st week postpartum. We excluded pregnant patients in which the ICU admission was unrelated to severe COVID-19 pneumonitis. We assessed maternal and neonatal outcomes and longitudinal clinical and laboratory ICU data. The primary overall outcome was maternal outcome (worst of the following: no invasive positive pressure ventilation [IPPV], use of IPPV, use of extracorporeal membrane oxygenation [ECMO], or death). The primary longitudinal outcome was Sequential Organ Failure Assessment (SOFA) score, and the secondary longitudinal outcome was the novel PORCH (positive end-expiratory pressure [PEEP], oxygenation, respiratory support, chest x-ray, haemodynamic support) score. Patients were classified into four groups: no-delivery (pregnant at admission and no delivery during the ICU stay), postpartum (ICU admission ≥1 day after delivery), delivery-critical (pregnant at admission and receiving or at high risk of requiring IPPV at the time of delivery), or delivery-non-critical (pregnant at admission and not critically ill at the time of delivery). FINDINGS: From Feb 1, 2020, to Jan 31, 2022, 84 patients were analysed: 34 patients in the no-delivery group, four in postpartum, 32 in delivery-critical, and 14 in delivery-non-critical. The delivery-critical and postpartum groups had worse outcomes than the other groups: 26 (81%) of 32 patients in the delivery-critical group and four (100%) of four patients in the postpartum group required IPPV; 12 (38%) and three (75%) patients required ECMO, and one (3%) and two (50%) patients died, respectively. The delivery-non-critical and no-delivery groups had far better outcomes than other groups: six (18%) of 34 patients and two (14%) of 14 patients required IPPV, respectively; no patients required ECMO or died. Oxygen saturation (SpO2), SpO2 to fraction of inspired oxygen (FiO2) ratio (S/F ratio), partial pressure of arterial oxygen to FiO2 ratio (P/F ratio), ROX index (S/F ratio divided by respiratory rate), and SOFA and PORCH scores were all highly predictive for adverse maternal outcome (p<0·0001). The delivery-critical group deteriorated on the day of delivery, continued to deteriorate throughout the ICU stay, and took longer to recover (ICU duration, Mantel-Cox p<0·0001), whereas the delivery-non-critical group improved rapidly following delivery. The day of delivery was a significant covariate for PORCH (p<0·0001) but not SOFA (p=0·09) scores. INTERPRETATION: In patients who underwent delivery during their ICU stay, maternal outcome deteriorated following delivery among those defined as critical compared with non-critical patients, who improved following delivery. Interventional delivery should be considered for maternal indications before patients deteriorate and require mechanical ventilation. FUNDING: None.

Partner's presence during initiation of epidural labor analgesia does not decrease maternal stress: a prospective randomized controlled trial.

BACKGROUND: Epidural analgesia reduces pain and anxiety during childbirth. In this randomized controlled trial, we sought to determine whether partner presence during the initiation of epidural analgesia reduces stress of both the mother and her partner and their perception of maternal pain. METHODS: Healthy, nulliparous women who were accompanied by their partners and requested neuraxial analgesia were enrolled into the study. The study took place in the Labor and Delivery Unit of a large tertiary hospital in Israel. Upon request for epidural analgesia, both partners were assessed for baseline anxiety (numerical rating scale, 0 to 10), systolic blood pressure, heart rate, estimated contraction pain of parturient (verbal rating scale for pain, 0 to 10), and salivary amylase. After measurements, couples were randomized into 1 of 2 groups: "partner in" and "partner out." Immediately after epidural catheter insertion, anxiety, arterial blood pressure, heart rate, and salivary amylase were measured again in both partners. Both partners were asked to complete the State Anxiety Inventory questionnaire measuring current anxiety. The parturient was asked to rate the pain of epidural catheter insertion. The primary outcome measurement was parturient and partner anxiety as assessed by the numerical rating scale. RESULTS: Eighty-four couples were randomized (partner in 41, partner out 42, protocol violation 1). At baseline there was no difference in self-reported anxiety of parturients between the partner-in and partner-out groups (median interquartile range 7.5 [6.0 to 9.0] versus 7.0 [3.5 to 8.5]; P = 0.26, difference in medians = -1.0; 95% confidence interval [CI] of difference -2.0 to 1.0). After epidural catheter insertion, parturients in the partner-in group had a higher level of anxiety than those in the partner-out group (8.0 [7.0 to 10.0] versus 7.0 [5.0 to 9.0]; P = 0.03, difference in medians -1.0; 95% CI of difference -2.0 to 0.0). Pain scores during epidural catheter placement were higher in partner-in than in partner-out groups (7.0 [4.0 to 8.0] versus 4.0 [3.0 to 6.0]; P = 0.004, difference in medians = -2.0; 95% CI of difference -3.0 to -1.0). CONCLUSION: Partner presence during epidural catheter insertion for labor analgesia did not decrease anxiety levels. To the contrary, anxiety and pain of epidural catheter placement were greater if the partner remained in the room.

Peripartum anesthetic management of women with SARS-CoV-2 infection in eight medical centers across three European countries: prospective cohort observation study.

OBJECTIVE: Several reports of obstetric anesthesia management have been published since the onset of the COVID-19 pandemic. We aimed to collect high-quality broad and detailed data from different university medical centers in several European Society of Anesthesiologist countries. METHODS: This prospective observational survey was performed in eight medical centers in Spain, Israel and Portugal from 1st April to 31st July 2020. Institutional review board approval was received at each participating center. Inclusion criteria: all women with a positive test for COVID-19. Retrieved data included maternal, delivery, anesthetic, postpartum details, and neonatal outcomes. Descriptive data are presented, and outcomes were compared for women with versus without respiratory signs and symptoms. RESULTS: Women with respiratory symptoms (20/12.1%) had significantly higher mean (standard deviation) temperature (37.2 °C (0.8) versus 36.8 °C (0.6)), were older (34.1 (6.7) years versus 30.5 (6.6)) and had higher body mass index kg m-2 - (29.5 (7.5) versus 28.2 (5.1)). Women with respiratory symptoms delivered at a significantly earlier gestational age (50% < 37 weeks) with a 65% cesarean delivery rate (versus 22.1% in the group without respiratory symptoms) and 5-fold increased rate of emergency cesarean delivery, 30% performed under general anesthesia. A higher rate of intrauterine fetal death (3%) was observed than expected from the literature (0.2-0.3%) in developed countries. There was no evidence of viral vertical transmission. CONCLUSION: Well-functioning neuraxial analgesia should be available to manage laboring women with respiratory symptoms, as there is a higher frequency of emergency cesarean delivery. We report a higher rate of undiagnosed parturient and intrauterine fetal death.

Hemodynamic consequences of incomplete uterine spiral artery transformation in human pregnancy, with implications for placental dysfunction and preeclampsia.

Normal human pregnancy requires a dramatic increase in uteroplacental blood flow, which is achieved by a transformation in the geometry of uterine spiral arteries, a key element in this blood supply system. The transformation is mediated by trophoblast invasion directed at converting a portion of the spiral artery into an open funnel, thereby greatly reducing resistance to flow. The converted portion lies within the depth of the decidua and part of the myometrium. Insufficient depth of trophoblast invasion in early pregnancy predisposes to inadequate perfusion of the developing placenta and fetus and may lead to preeclampsia, fetal growth restriction, and preterm delivery, sometimes referred to as the "Great Obstetrical Syndromes." We examine the hemodynamic consequences of spiral artery transformation in human pregnancy and the relationship between the degree of transformation and the corresponding change in flow rate and resistance to flow. We identify two key variables in determining the hemodynamic change: the longitudinal converted fraction of the spiral artery and the relative downstream diameter of the open funnel. Our results indicate that there is a critical threshold in the value of the converted fraction required to achieve the marked increase in uteroplacental blood flow in normal pregnancy. This finding validates common clinical observations that the depth of trophoblast invasion reflects the "adequacy" of the increase in uteroplacental blood supply required in normal human pregnancy. Our results provide a quantitative measure of that adequacy and may serve as a future diagnostic marker for high-risk pregnancy.NEW & NOTEWORTHY Human pregnancy requires dramatic increase in uteroplacental blood supply achieved by geometric transformation of uterine spiral arteries and facilitated by trophoblast invasion of these arteries to greatly reduce resistance to flow. Incomplete transformation has been associated with failed pregnancies, preeclampsia, and other pathologies, but a quantitative measure of "incompleteness" has been unavailable so far. We use a mathematical model to obtain a numerical threshold for this measure which may serve as a future diagnostic marker.

Chronic hypoxia in pregnant mice impairs the placental and fetal vascular response to acute hypercapnia in BOLD-MRI hemodynamic response imaging.

INTRODUCTION: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model). METHODS: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O2;E13.5-17.5) and early-onset hypoxia (12%O2;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO2). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained. RESULTS: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only. CONCLUSIONS: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury.

Obstetric anesthesia services in Israel snapshot (OASIS) study: a 72 hour cross-sectional observational study of workforce supply and demand.

BACKGROUND: We planned an observational study to assess obstetric anesthesia services nationwide. We aimed to assess the effect of the anesthesia workload/workforce ratio on quality and safety outcomes of obstetric anesthesia care. METHODS: Observers prospectively collected data from labor units over 72 h (Wednesday, Thursday and Friday). Independent variables were workload (WL) and workforce (WF). WL was assessed by the Obstetric Anesthesia Activity Index (OAAI), which is the estimated time in a 24-h period spent on epidurals and all cesarean deliveries. Workforce (WF) was assessed by the number of anesthesiologists dedicated to the labor ward per week. Dependent variables were the time until anesthesiologist arrival for epidural (quality measure) and the occurrence of general anesthesia for urgent Cesarean section, CS, (safety measure). This census included vaginal deliveries and unscheduled (but not elective) CS. RESULTS: Data on 575 deliveries are from 12 maternity units only, primarily because a major hospital chain chose not to participate; eight other hospitals lacked institutional review board approval. The epidural response rate was 94.4%; 321 of 340 parturients who requested epidural analgesia (EA) received it. Of the 19 women who requested EA but gave birth without it, 14 (77%) were due to late arrival of the anesthesiologist. Median waiting times for anesthesiologist arrival ranged from 5 to 28 min. The OAAI varied from 4.6 to 25.1 and WF ranged from 0 to 2 per shift. Request rates for EA in hospitals serving predominantly orthodox Jewish communities and in peripheral hospitals were similar to those of the entire sample. More than a fifth (13/62; 21%) of the unscheduled CS received general anesthesia, and of these almost a quarter (3/13; 23%) were attributed to delayed anesthesiologist arrival. CONCLUSIONS: Inadequate WF allocations may impair quality and safety outcomes in obstetric anesthesia services. OAAI is a better predictor of WL than delivery numbers alone, especially concerning WF shortage. To assess the quality and safety of anesthetic services to labor units nationally, observational data on workforce, workload, and clinical outcomes should be collected prospectively in all labor units in Israel.