International consensus statement on the use of uterotonic agents during caesarean section.

It is routine to give a uterotonic drug following delivery of the neonate during caesarean section. However, there is much heterogeneity in the relevant research, which has largely been performed in low-risk elective cases or women with uncomplicated labour. This is reflected in considerable variation in clinical practice. There are significant differences between dose requirements during elective and intrapartum caesarean section. Standard recommended doses are higher than required, with the potential for acute cardiovascular adverse effects. We recommend a small initial bolus dose of oxytocin, followed by a titrated infusion. The recommended doses of oxytocin may have to be increased in women with risk factors for uterine atony. Carbetocin at equipotent doses to oxytocin has similar actions, while avoiding the requirement for a continuous infusion after the initial dose and reducing the need for additional uterotonics. As with oxytocin, carbetocin dose requirements are higher for intrapartum caesarean sections. A second-line agent should be considered early if oxytocin/carbetocin fails to produce good uterine tone. Women with cardiac disease may be very sensitive to the adverse effects of oxytocin and other uterotonics, and their management needs to be individualised.

A randomised double-blind trial of phenylephrine and metaraminol infusions for prevention of hypotension during spinal and combined spinal-epidural anaesthesia for elective caesarean section.

Prophylactic vasopressor administration is commonly recommended to reduce maternal hypotension during spinal anaesthesia for caesarean section. Metaraminol has undergone limited investigation in obstetric anaesthesia for this purpose, particularly in comparison with phenylephrine. In this multicentre, randomised, double-blind, non-inferiority study, we compared prophylactic phenylephrine or metaraminol infusions, started immediately after spinal anaesthesia, in 185 women who underwent elective caesarean section. Phenylephrine was initially infused at 50 µg.min-1 , and metaraminol at 250 µg.min-1 . The primary outcome was the difference in umbilical arterial pH between groups; secondary outcomes included other neonatal acid-base measures, and maternal haemodynamic changes. The mean (SD) umbilical arterial pH was 7.28 (0.06) in the phenylephrine group vs. 7.31 (0.04) in the metaraminol group (p = 0.0002). The estimated mean (95%CI) pH difference of 0.03 (0.01-0.04) was above the pre-determined lower boundary of clinical non-inferiority, and also met the criterion for superiority. Umbilical artery lactate concentration was 2.8 (1.2) mmol.l-1 in the phenylephrine group vs. 2.3 (0.7) mmol.l-1 in the metaraminol group (p = 0.0018). Apgar scores did not significantly differ between groups. There was a higher incidence of hypotension, defined as systolic arterial pressure < 90% baseline, in the phenylephrine group; there was a higher incidence of hypertension and severe hypertension (systolic arterial pressure > 110% and > 120% baseline, respectively) in the metaraminol group. There was no significant difference between groups in the incidence of nausea, vomiting or maternal bradycardia. We conclude that, when used as an infusion to prevent hypotension after spinal anaesthesia for elective caesarean section, metaraminol is at least non-inferior to phenylephrine with respect to neonatal acid-base outcomes.

Ordinary care in extraordinary times.

The Coronavirus Disease 2019 (COVID-19) has accounted for more than 25 000 cases in Ireland with approximately 28% of the clusters in nursing homes as of June 2020. The older population is the most vulnerable to serious complications from this illness and over 90% of deaths due to COVID-19 to date have been in patients over the age of 65. Continuing to provide routine care within nursing homes in these challenging times is an essential part of ensuring that presentations to hospitals for non-essential reasons are minimized. In this article, we describe a project being undertaken by a rural Psychiatry of Old Age Service in the northwest of Ireland. We aim to provide ordinary care in extraordinary times by using mobile tablets within the nursing homes and long-stay facilities in our region for remote video consultations during the COVID-19 crisis.

Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker rocuronium and perioperative anaphylaxis: implications for drug allergy.

Cyclodextrins, oligosaccharides linked in a circular arrangement around a central cavity, are used extensively in the pharmaceutical industry to improve drug delivery. Their usefulness depends on their capacity to form a drug inclusion, or host-guest, complex within the cavity. In an attempt to improve the delivery of the widely used neuromuscular blocking drug (NMBD) rocuronium, a rocuronium inclusion complex was formed with a chemically modified γ-cyclodextrin. The high binding affinity and specificity of the modified carrier (named sugammadex) for rocuronium (and other aminosteroid NMBDs) led to its use in anaesthesia as an innovative and useful agent for rapid reversal of rocuronium-induced neuromuscular block by sequestering the drug as an inclusion complex. This, in turn, led to the suggestion that sugammadex might be useful to remove the NMBD from the circulation of patients experiencing rocuronium-induced anaphylaxis, a suggestion subsequently supported in case reports where traditional treatment had failed. Successful resuscitations suggested that sugammadex might be a valuable new treatment for such intractable cases but, given the inappropriateness of clinical trials, confirmation or refutation will have to await the slow accumulation of results of individual case reports. Important questions related to antibody accessibility of drug allergenic structures on the rocuronium-sugammadex inclusion complex, and the competition between sugammadex and IgE antibodies (both free and cell bound) for rocuronium, also remain and can be investigated in vitro. The sugammadex findings indicate that the use of carrier molecules such as the cyclodextrins to improve drug delivery will sometimes give rise to changed immunologic and allergenic behaviour of some drugs and this will have to be taken into account in preclinical drug safety assessments of drug-carrier complexes. The possibility of encapsulating and removing other allergenic drugs, e.g., penicillins and cephalosporins, in cases of difficult-to-reverse anaphylaxis to these drugs is discussed.

Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein.

Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents. toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains. Such nucleocapside inhibitors were directly virucidal by preventing the initiation of reverse transcription and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors. Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al. also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.

Sugammadex in the management of rocuronium-induced anaphylaxis.

Anaphylaxis during anaesthesia is a rare event that in ∼60-70% of cases is secondary to neuromuscular blocking agents. It has been suggested previously that the recent introduction of sugammadex may provide a novel therapeutic approach to the management of rocuronium-induced anaphylaxis. We describe the case of a 33-yr-old female who suffered a severe anaphylactic reaction to rocuronium, presenting with cardiovascular collapse on induction of anaesthesia. After 19 min of traditional management, she was given a bolus of sugammadex 500 mg. This was associated with an improvement in the adverse haemodynamic state. The underlying reasons for this are unclear, but sugammadex may potentially be a useful adjunct in the management of rocuronium-induced anaphylaxis.

Antepartum and postpartum anemia: a narrative review.

Antepartum anemia impacts over a third of pregnant women globally and is associated with major maternal and perinatal morbidity, including peripartum transfusion, maternal death, maternal infection, preterm birth, and neurodevelopmental disorders among offspring. Postpartum anemia impacts up to 80% of women in low-income and rural populations and up to 50% of women in Europe and the United States, and is associated with postpartum depression, fatigue, impaired cognition, and altered maternal-infant bonding. Iron deficiency is the most common cause of maternal anemia because of insufficient maternal iron stores at the start of pregnancy, increased pregnancy-related iron requirements, and iron losses due to blood loss during parturition. Anemic women should undergo testing for iron deficiency; a serum ferritin cutoff level of 30 µg/L is commonly used to diagnose iron deficiency during pregnancy. The first-line treatment of iron deficiency is oral iron. Intravenous iron is a consideration in the following scenarios: a poor or absent response to oral iron, severe anemia (a hemoglobin concentration <80 g/L), rapid treatment for anemia in the third trimester, women at high risk for major bleeding (such as those with placenta accreta), and women for whom red blood cell transfusion is not an option. Given the high prevalence of antepartum and postpartum anemia, anesthesiologists are advised to partner with other maternal health professionals to develop anemia screening and treatment pathways.

Cardiopulmonary arrest in pregnancy: two case reports of successful outcomes in association with perimortem Caesarean delivery.

Cardiac arrest in pregnancy is a rare event in which the speed of the response and attention to a number of pregnancy-specific interventions is crucial to the outcome. The commencement of a perimortem Caesarean delivery within 4 min of the onset of the arrest has been recommended as a technique to potentially improve survival in both the mother and the fetus but presents significant logistical challenges to the health-care facility. In this report, we describe two cases of cardiac arrest in pregnancy in which a perimortem Caesarean was performed as part of the resuscitation process and was associated with excellent maternal and neonatal outcomes. We discuss some of the issues surrounding the performance of a perimortem Caesarean delivery that were relevant to this case, including experience from the training that is provided in our institution.

Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons.

Recently, we and others reported that the doublecortin gene is responsible for X-linked lissencephaly and subcortical laminar heterotopia. Here, we show that Doublecortin is expressed in the brain throughout the period of corticogenesis in migrating and differentiating neurons. Immunohistochemical studies show its localization in the soma and leading processes of tangentially migrating neurons, and a strong axonal labeling is observed in differentiating neurons. In cultured neurons, Doublecortin expression is highest in the distal parts of developing processes. We demonstrate by sedimentation and microscopy studies that Doublecortin is associated with microtubules (MTs) and postulate that it is a novel MAP. Our data suggest that the cortical dysgeneses associated with the loss of Doublecortin function might result from abnormal cytoskeletal dynamics in neuronal cell development.

Rapid reversal of critical haemodynamic compromise with nitric oxide in a parturient with amniotic fluid embolism.

We describe a case of amniotic fluid embolism presenting as cardiovascular collapse during labour. After initial resuscitation and emergency caesarean section, the patient was transferred to the intensive care unit with profound hypoxaemia, a high inotropic drug requirement and severe coagulopathy. A transoesophageal echocardiogram demonstrated acute right ventricular overload, severe pulmonary artery hypertension and marked diastolic dysfunction of the left ventricle secondary to a dilated right ventricle. The introduction of nitric oxide at 40 ppm produced a dramatic improvement in her cardiorespiratory status. Mother and baby both survived with no apparent long term sequelae.

Immediate postpartum neurological deficits in the lower extremity: a prospective observational study.

BACKGROUND: Neurological deficits noted immediately after childbirth are usually various obstetric neuropathies, but prospective studies are limited. The main study aim was to quantify and describe immediate postpartum neurological deficits of the lower extremity, including the buttocks. METHODS: A prospective observational study of postpartum women delivering in a single maternity hospital during three months of 2016. Among 1147 eligible women, 1019 were screened for symptoms of lower extremity numbness or weakness within eight to 32hours of delivery. Consent to undergo a detailed neurological evaluation was sought from those reporting symptoms. Risk factors were identified using logistic regression. RESULTS: Thirty five women (3.4%) reported symptoms, 27 entered the study and 23 (2.0%) had objective signs of a neurological deficit. The most common injuries were mild lumbosacral plexopathies and cluneal nerve compression. Most deficits were sensory, half of these also having a motor deficit that did not impact functionally. Based on analysis of 22 cases involving a likely intrapartum deficit, no association was found with parity, body weight, duration of labour, mode of delivery or neuraxial block. A past history of a neurological condition or a back injury was associated with odds ratios of 7.98 and 4.82 respectively. There were no neurological deficits that were clinically concerning or that were likely a complication of a neuraxial block. CONCLUSION: Transient neurological complications after labour and delivery are infrequent, mainly sensory involving multiple lumbosacral nerve roots or specific sacral cutaneous nerves, and they typically resolve within a short time.

Single and multiple doses of oral cimetidine do not change liver blood flow in humans.

Liver blood flow was measured in 10 healthy men for 6 hours after single (300 mg) and multiple (300 mg every 6 hours for 5 days) oral doses of cimetidine. Blood flow measurements were determined in the superior mesenteric and hepatic arteries and in the intrahepatic branches of the portal and hepatic veins by use of a duplex Doppler ultrasound technique. Compared with baseline measurements obtained before drug administration, cimetidine treatment did not change blood flow in any of the four blood vessels. Cimetidine serum concentrations and pharmacokinetic parameters were similar to those reported in other studies conducted in healthy adults. The findings of this study indicate that single and multiple 300 mg doses of oral cimetidine do not change liver blood flow.

Zinc ejection as a new rationale for the use of cystamine and related disulfide-containing antiviral agents in the treatment of AIDS.

The highly conserved and mutationally intolerant retroviral zinc finger motif of the HIV-1 nucleocapsid protein (NC) is an attractive target for drug therapy due to its participation in multiple stages of the viral replication cycle. A literature search identified cystamine, thiamine disulfide, and disulfiram as compounds that have been shown to inhibit HIV-1 replication by poorly defined mechanisms and that have electrophilic functional groups that might react with the metal-coordinating sulfur atoms of the retroviral zinc fingers and cause zinc ejection. 1H NMR studies reveal that these compounds readily eject zinc from synthetic peptides with sequences corresponding to the HIV-1 NC zinc fingers, as well as from the intact HIV-1 NC protein. In contrast, the reduced forms of disulfiram and cystamine, diethyl dithiocarbamate and cysteamine, respectively, were found to be ineffective at zinc ejection, although cysteamine formed a transient complex with the zinc fingers. Studies with HIV-1-infected human T-cells and monocyte/macrophage cultures revealed that cystamine and cysteamine possess significant antiviral properties at nontoxic concentrations, which warrant their consideration as therapeutically useful anti-HIV agents.

Safety of GM-CSF in patients with AIDS: a review of the literature.

We performed a literature search for all clinical studies reporting outcomes in patients with the acquired immunodeficiency syndrome (AIDS) receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) for any indication. Safety outcomes included human immunodeficiency virus replication, immune status, and frequency of opportunistic infections and neoplasms. Data were synthesized qualitatively. We identified 22 studies (274 patients): 12 addressed AIDS neutropenia, 8 AIDS cancer therapy, and 2 opportunistic infections. Viral burden was assessed by serum p24Ag in 15 studies. Nine reported no change in levels, three net decreases, and three net increases. All studies showing net increases involved patients receiving GM-CSF without a concurrent antiretroviral. The CD4 counts were unchanged in 5 studies, increased in 3, and not reported in 14. The incidence of neoplasms or new opportunistic infections was low. The literature suggests no increased risk of viral replication or clinical deterioration in patients with AIDS who take GM-CSF concurrently with zidovudine.

A randomised controlled trial of parecoxib, celecoxib and paracetamol as adjuncts to patient-controlled epidural analgesia after caesarean delivery.

The benefit of combining non-opioid analgesics with neuraxial opioids for analgesia after caesarean delivery has not been clearly established. Larger doses of paracetamol or cyclooxygenase-2 inhibitors have not been evaluated. A randomised, double blind, double-dummy, parallel group placebo-controlled clinical trial was conducted among women having elective caesarean delivery under spinal anaesthesia, followed by pethidine patient-controlled epidural analgesia. Patients received placebos (group C); intravenous parecoxib 40 mg then oral celecoxib 400 mg at 12 hours (group PC); intravenous paracetamol 2 g then oral 1 g six-hourly (group PA); or these regimens combined (group PCPA). The primary outcome was 24-hour postoperative patient-controlled epidural pethidine use and the main secondary outcome was postoperative pain. One hundred and thirty-eight women were recruited but 27 subsequently met exclusion criteria, leaving 111 who were randomised, allocated and analysed by intention-to-treat (n=23, 30, 32 and 26 in groups C, PC, PA and PCPA respectively). There were no differences between groups for pethidine consumption, based on either intention-to-treat (median 365, 365, 405 and 360 mg in groups C, PC, PA and PCPA respectively, P=0.84) or per protocol analysis (17 major violations). Dynamic pain scores did not differ between groups but requirement for, and dose of, supplementary oral tramadol was least in group PCPA (incidence 23% versus 48%, 70% and 58% in groups C, PC and PA respectively, P=0.004). The addition of regular paracetamol, cyclooxygenase-2 inhibitors or both to pethidine patient-controlled epidural post-caesarean analgesia did not provide a pethidine dose-sparing effect during the first 24 hours.

Parecoxib and paracetamol for pain relief following minor day-stay gynaecological surgery.

Paracetamol and non-steroidal anti-inflammatory drugs are often administered for postoperative analgesia. Dilatation and curettage, with or without hysteroscopy, is a common day-stay procedure that is associated with pain that is partly mediated by prostaglandins. This study aimed to investigate the analgesic efficacy of adjunctive paracetamol and parecoxib in this setting. A randomised, blinded, placebo-controlled, single-centre trial was conducted among 240 women undergoing dilatation and curettage. Patients were randomised intraoperatively into one of four groups, to receive either intravenous paracetamol 2 g, intravenous parecoxib 40 mg, both in combination, or placebos, post-induction and with intravenous fentanyl. The primary endpoints were pain score one hour postoperatively and the Overall Benefit of Analgesia Score. There were no statistically significant differences in primary outcomes across groups. The area under the curve for pain scores to two hours postoperatively was significantly lower in the group receiving paracetamol (P=0.018) and the need for rescue analgesia with tramadol was less in the combination group (P=0.02). There were no significant differences in patient satisfaction or recovery. We conclude that paracetamol or parecoxib does not produce a clinically important reduction in pain in this setting. Women having uterine curettage and receiving intravenous fentanyl do not appear to benefit from administration of these non-opioid analgesics.

Amniotic fluid embolism: a leading cause of maternal death yet still a medical conundrum.

Amniotic fluid embolism is a rare and potentially catastrophic condition that is unique to pregnancy. The presentation may range from relatively subtle clinical events to sudden maternal cardiac arrest. Despite an increased awareness of the condition, it remains a leading cause of maternal mortality. The underlying mechanisms of amniotic fluid embolism are poorly understood, but current theories support an immune-based mechanism which is triggered by potentially small amounts of amniotic fluid gaining access to the maternal circulation. This can result in a wide spectrum of clinical findings, with cardiovascular and haematological disturbances being prominent. The management of a suspected episode of amniotic fluid embolism is generally considered to be supportive, although in centres with specific expertise, echocardiography may assist in guiding management. Whilst outcomes after an episode of amniotic fluid embolism are still concerning, mortality would appear to have decreased in recent times, likely secondary to an improved awareness of the condition, advances in acute care and the inclusion of less severe episodes in case registries.

Hyperfibrinolysis diagnosed by rotational thromboelastometry in a case of suspected amniotic fluid embolism.

Rotational thromboelastometry is a viscoelastomeric, point-of-care method for testing haemostasis in whole blood which can be visualised rapidly, in real time, in the operating theatre. Advantages over traditional coagulation tests relate to the rapid feedback of results and the ability to visualise hyperfibrinolysis. We present a case of suspected amniotic fluid embolism that presented with sudden respiratory arrest associated with haemodynamic compromise during a non-elective caesarean delivery. Soon after the collapse, coagulopathy developed. Rotational thromboelastometry showed hyperfibrinolysis and hypofibrinogenaemia, which allowed targeted coagulation factor replacement therapy and the use of tranexamic acid. Hyperfibrinolysis may be a contributor to the coagulopathy associated with amniotic fluid embolism but has been infrequently reported, perhaps due to limited diagnosis with traditional coagulation tests. Treatment of the coagulopathy associated with a suspected amniotic fluid embolism with antifibrinolytic agents may deserve greater consideration.