Is crystalloid co-loading necessary to prevent spinal hypotension during elective cesarean delivery? A randomized double-blind trial.

BACKGROUND: Hypotension is common during spinal anesthesia for cesarean delivery. Preventive strategies include fluid loading and phenylephrine. We hypothesized that if prophylactic phenylephrine infusion is used, omission of fluid loading would be non-inferior to fluid co-loading in maintaining cardiac output. We assumed that if there was a difference, the increase in cardiac output would be greater in the no-loading than in the co-loading group. METHODS: Term pregnant women scheduled for elective cesarean delivery were randomized to receive 1 L crystalloid co-loading or maintenance fluids only. Phenylephrine was titrated to maintain blood pressure. Changes in cardiac output following spinal anesthesia were the primary outcome. The study was powered as a non-inferiority trial, allowing the no-loading arm to have a 50% greater change in cardiac output. Heart rate, dose of phenylephrine, occurrence of nausea and vomiting, Apgar scores and neonatal acid base status were secondary outcomes. RESULTS: Data from 63 women were analyzed. In contrast to our hypothesis, there was 33% less increase in cardiac output with no loading (ratio 0.67, 95% CI 0.15 to 1.36), and 60% greater reduction of cardiac output with no loading (ratio 1.6, 95% CI 1.0 to 2.7). Total dose of phenylephrine was higher in the no-loading group. There may be a less favorable neonatal acid base status without volume loading. CONCLUSION: Omission of crystalloid co-loading leads to a decrease in cardiac output which has a potentially unfavorable impact on neonatal acid base status. We conclude that crystalloid co-loading may be useful in the presence of phenylephrine infusion.

[Peripartum hemorrhage, diagnostics and treatment : Update of the S2k guidelines AWMF 015/063 from August 2022]. / Peripartale Blutungen, Diagnostik und Therapie : Update der S2k-Leitlinie AWMF 015/063 vom August 2022.

The current S2k guidelines on the diagnostics and treatment of peripartum hemorrhage are summarized in this article from the perspective of anesthesiology based on a fictitious case report. The update of the guidelines was written under the auspices of the German Society of Gynecology and Obstetrics with the participation of other professional societies and interest groups from Germany, Austria and Switzerland and published by the AWMF in 2022 under the register number 015/063.

Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists.

Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life-threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri-operative management of the patients.

Platypnea-orthodeoxia syndrome: an unusual cause of breathlessness in late pregnancy.

A pregnant patient with shortness of breath and arterial oxygen desaturation is presented. The primary and tentative initial diagnosis was pulmonary embolism. Her desaturation and dyspnea were aggravated in the upright compared with the supine position. The minimal response to supplemental oxygen suggested right-to-left shunting, which was confirmed by echocardiography. Shunting was minimal in the supine and maximal in the upright position, leading to the diagnosis of platypnea-orthodeoxia syndrome. By two weeks postpartum the patient's symptoms had resolved and shunting was undetectable.

A systematic review of phenylephrine vs. noradrenaline for the management of hypotension associated with neuraxial anaesthesia in women undergoing caesarean section.

Phenylephrine is recommended for the management of hypotension after spinal anaesthesia in women undergoing caesarean section. Noradrenaline, an adrenergic agonist with weak ß-adrenergic activity, has been reported to have a more favourable haemodynamic profile than phenylephrine. However, there are concerns that noradrenaline may be associated with a higher risk of fetal acidosis, defined as an umbilical artery pH < 7.20. We performed a systematic review of trials comparing noradrenaline with phenylephrine, concentrating on primary outcomes of fetal acidosis and maternal hypotension. We identified 13 randomised controlled trials including 2002 patients. Heterogeneity among the studies was high, and there were too few data to calculate a pooled effect estimate. Fetal acidosis was assessed in four studies that had a low risk of bias and a low risk of confounding, that is, studies which used a prophylactic vasopressor and where women received the allocated vasopressor only. There were no significant differences between these studies. No significant differences were observed for hypotension. Two trials found a significantly lower incidence of bradycardia when using noradrenaline. Cardiac output was significantly higher after noradrenaline in two of three studies. For other secondary outcomes including nausea, vomiting and Apgar scores at 1 and 5 min, no studies found significant differences. The evidence so far is too limited to support an advantage of noradrenaline over phenylephrine. Concerns of a deleterious effect of noradrenaline on fetal blood gas status cannot currently be assuaged by the available data from randomised controlled studies.

Generalisability of randomised trials of the programmed intermittent epidural bolus technique for maintenance of labour analgesia: a prospective single centre cohort study.

BACKGROUND: Several randomised controlled trials show that maintenance of labour epidural analgesia with programmed intermittent epidural bolus reduces the maternal motor block compared with maintenance with a continuous infusion. However, these trials were usually restricted to healthy nulliparous parturients. To assess the generalisability of these randomised controlled trials to 'real-world' conditions, we compared maternal motor function (modified Bromage score) over time between healthy nulliparous and parous women using routinely collected quality-control data. METHODS: After ethical approval, all parturients receiving programmed intermittent epidural bolus labour analgesia between June 2013 and October 2014 were included in this prospective cohort study. Bupivacaine 0.1% with fentanyl 2 µg ml-1 was used allowing for patient-controlled bolus every 20 min. The maternal motor function (primary outcome) was regularly assessed from insertion of the epidural catheter until delivery. RESULTS: Of the 839 parturients included, 553 (66%) were nulliparous and 286 (34%) were parous. The parous women had a shorter median duration of epidural analgesia (3 h 59 min vs 5 h 45 min) and a higher incidence of spontaneous delivery (66% vs 37%). The probability of being in a certain Bromage category at birth was similar in nulliparous and parous women in a general additive model adjusting for duration of epidural analgesia, number of rescue top-ups, and number of catheter manipulations (cumulative odds ratio: 1.18; 95% confidence interval: 0.98-1.41). Parous women required a higher time-weighted number and volume of rescue top-ups. CONCLUSIONS: The results of the randomised controlled trials on a reduced motor block with programmed intermittent epidural bolus seem generalisable to parturients typically not included in these trials.

Remifentanil patient-controlled analgesia in labour: six-year audit of outcome data of the RemiPCA SAFE Network (2010-2015).

BACKGROUND: The RemiPCA SAFE Network was established to set standards and monitor maternal and neonatal outcomes when using remifentanil for labour analgesia. The aim of this analysis was to describe the development of the network standard and to report maternal and neonatal outcome data, including severe adverse events. METHODS: Data sets of the RemiPCA SAFE Network database from the initial six consecutive years (2010-2015) were retrospectively analysed. The data were analysed on an annual basis and set in context with changes of the network standard, i.e. adaptations of the network's standard operating procedure. Main outcomes reported are maternal and neonatal data regarding effectiveness and safety, such as satisfaction, need for bag/mask ventilation and/or cardiopulmonary resuscitation. RESULTS: Among 5740 data sets, no need for maternal ventilation or cardiopulmonary resuscitation was registered. Neonatal cardiopulmonary resuscitations, potentially related to remifentanil, occurred in 0.3%. In parallel with adaptations of the network standard, a moderate rate of maternal hypoxia (oxygen saturation <94% in 24.7%) was found, together with a low rate of supplemental oxygen requirement in neonates (5.0%). CONCLUSION: The RemiPCA SAFE Network data show that remifentanil patient-controlled analgesia can be applied safely. There is bias when data from real clinical settings are analysed retrospectively. Notwithstanding, the approach taken by the RemiPCA SAFE Network, with constant, systematic and standardised evaluation of multiple parameters during the course of labour, might identify trends and anomalies and guide the development and application of safety standards, when translating knowledge from scientific trials into clinical practice.

Suppressing protein Z-dependent inhibition of factor Xa improves coagulation in hemophilia A.

Essentials Protein Z (PZ) catalyzes PZ-dependent proteinase inhibitor (ZPI) inactivation of factor (F)Xa. Gene-deletion of PZ or ZPI improves coagulation in hemophilia (FVIII knockout) mice. A PZ blocking antibody enhances thrombin generation in human hemophilia plasma. Suppression of the PZ/ZPI pathway may ameliorate the phenotype of severe hemophilia. SUMMARY: Background Hemostasis requires a balance between procoagulant and anticoagulant factors. Hemophiliacs bleed because of a procoagulant deficiency. Targeted reduction in the activity of endogenous anticoagulant pathways is currently being investigated as a means of improving hemostasis in hemophilia. Protein Z (PZ) is a cofactor that serves as a catalyst for PZ-dependent protease inhibitor (ZPI) inactivation of activated factor X at phospholipid surfaces. Objectives To evaluate the effects of PZ or ZPI gene deletion in hemophilic mice, and of blocking PZ in human hemophilic plasma. Methods A tail vein rebleeding assay (TVRB) was developed on the basis of the serial disruption of clots forming over a period of 15 min following tail vein laceration in an anesthetized mouse. Wild-type (WT)/FVIII knockout FVIIIKO, PZ knockout PZKO/FVIIIKO and ZPI knockout ZPIKO/FVIIIKO mice were evaluated in this model, and their plasmas were tested in thrombin generation assays. A mAb against PZ was evaluated in human hemophilic plasma thrombin generation assays. Results The numbers of clot disruptions (mean ± standard error of the mean) in the TVRB were: 4.0 ± 0.9 for WT/FVIIIKO mice; 23.8 ± 1.1 for WT/FVIIIKO mice supplemented with 100% FVIII; 15.2 ± 1.1 for PZKO/FVIIIKO mice; and 14.7 ± 1.2 for ZPIKO/FVIIIKO mice. Thrombin generation in PZKO/FVIIIKO and ZPIKO/FVIIIKO mouse plasmas was similar to that in FVIIIKO plasma supplemented with ~ 15% recombinant FVIII. A mAb against PZ added to human hemophilic plasma enhanced thrombin generation to an extent similar to the addition of ~ 15% FVIII. Conclusions Blockade of the PZ/ZPI system may be sufficient to ameliorate the phenotype of severe hemophilia.

Re-evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway inhibitor physiology.

Essentials Mouse models are often used to define roles of tissue factor pathway inhibitor (TFPI) in man. TFPI isoform-specific KOs reveal unexpected differences between mouse and human TFPI physiology. Mouse plasma contains 20 times more TFPI than man, derived from TFPIγ, a form not found in man. TFPIγ null mice, expressing only TFPI isoforms α and ß, may better reflect the human situation. SUMMARY: Background Mouse models can provide insight into the pathophysiology of human thrombosis and hemostasis. Tissue factor pathway inhibitor (TFPI) regulates coagulation through protein S (PS)-enhanced factor (F) Xa inhibition and FXa-dependent inhibition of FVIIa/tissue factor (TF) activity. TFPI is expressed as isoforms α and ß in man, and α, ß and γ in the mouse. Objective Assess the reliability of extending TFPI-related studies in mice to humans. Method Compare mouse and human TFPI physiology using a variety of methods. Results Mouse TFPI and human TFPI are similar in regard to: (i) the mechanisms for FVIIa/TF and FXa inhibition; (ii) TFPIα is a soluble form and TFPIß is glycosyl phosphatidyl inositol (GPI) membrane anchored; (iii) the predominant circulating form of TFPI in plasma is lipoprotein-associated; (iv) low levels of TFPIα circulate in plasma and increase following heparin treatment; and (v) TFPIα is the isoform in platelets. They differ in that: (i) mouse TFPI circulates at a ~20-fold higher concentration; (ii) mouse lines with isolated isoform deletions show this circulating mouse TFPI is derived from TFPIγ; (iii) sequences homologous to the mouse TFPIγ exon are present in many species, including man, but in primates are unfavorable for splicing; and (iv) tandem mass spectrometry (MS/MS) detects sequences for TFPI isoforms α and ß in human plasma and α and γ in mouse plasma. Conclusion To dissect the pathophysiological roles of human TFPIα and TFPIß, studies in TFPIγ null mice, expressing only α and ß, only α or only ß should better reflect the human situation.

APPLICATION OF DROPLET DETECTORS TO ALPHA RADIATION DETECTION.

Superheated droplet detectors (SDDs) are traditionally employed in the detection of neutrons. In this work the focus is on the detection of alpha particles using C2ClF5 as the target liquid. The alpha-droplet interaction is examined via computational studies, and a geometric model developed to describe the expected detector response. Experiments with alpha-emitting uranium- and samarium-doped SDDs at temperatures of 5-12°C confirm that the event rate is related to the size of the droplets, and are in model agreement for temperatures below 8°C; above this temperature, the acoustic sensitivity is reduced by signal attenuation as a result of the increasing bubble population, for which the addition of an attenuation coefficient restores the agreement with experiment. The results suggest the viability of a SDD-based alpha spectrometer using mono-sized droplets.

Efficacy and safety of carbetocin given as an intravenous bolus compared with short infusion for Caesarean section - double-blind, double-dummy, randomized controlled non-inferiority trial.

BACKGROUND: Carbetocin is a synthetic oxytocin-analogue, which should be administered as bolus according to manufacturer's recommendations. A higher speed of oxytocin administration leads to increased cardiovascular side-effects. It is unclear whether carbetocin administration as short infusion has the same efficacy on uterine tone compared with bolus administration and whether haemodynamic parameters differ. METHODS: In this randomized, double-blind, non-inferiority trial, women undergoing planned or unplanned Caesarean section (CS) under regional anaesthesia received a bolus and a short infusion, only one of which contained carbetocin 100 mcg (double dummy). Obstetricians quantified uterine tone two, three, five and 10 min after cord-clamping by manual palpation using a linear analogue scale from 0 to 100. We evaluated whether the lower limit of the 95% CI of the difference in maximum uterine tone within the first five min after cord-clamping did not include the pre-specified non-inferiority limit of -10. RESULTS: Between December 2014 and November 2015, 69 patients were randomized to receive carbetocin as bolus and 71 to receive it as short infusion. Maximal uterine tone was 89 in the bolus and 88 in the short infusion group (mean difference -1.3, 95% CI -5.7 to 3.1). Bp, calculated blood loss, use of additional uterotonics, and side-effects were comparable. CONCLUSIONS: Administration of carbetocin as short infusion does not compromise uterine tone and has similar cardiovascular side-effects as a slow i.v. bolus. In accordance with current recommendations for oxytocin, carbetocin can safely be administered as short -infusion during planned or unplanned CS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02221531 and www.kofam.ch SNCTP000001197.

Independent Component Analysis of Resting-State Functional Magnetic Resonance Imaging in Pedophiles.

INTRODUCTION: Neuroimaging and other studies have changed the common view that pedophilia is a result of childhood sexual abuse and instead is a neurologic phenomenon with prenatal origins. Previous research has identified differences in the structural connectivity of the brain in pedophilia. AIM: To identify analogous differences in functional connectivity. METHODS: Functional magnetic resonance images were recorded from three groups of participants while they were at rest: pedophilic men with a history of sexual offenses against children (n = 37) and two control groups: non-pedophilic men who committed non-sexual offenses (n = 28) and non-pedophilic men with no criminal history (n = 39). MAIN OUTCOME MEASURE: Functional magnetic resonance imaging data were subjected to independent component analysis to identify known functional networks of the brain, and groups were compared to identify differences in connectivity with those networks (or "components"). RESULTS: The pedophilic group demonstrated wide-ranging increases in functional connectivity with the default mode network compared with controls and regional differences (increases and decreases) with the frontoparietal network. Of these brain regions (total = 23), 20 have been identified by meta-analytic studies to respond to sexually relevant stimuli. Conversely, of the brain areas known to be those that respond to sexual stimuli, nearly all emerged in the present data as significantly different in pedophiles. CONCLUSION: This study confirms the presence of significant differences in the functional connectivity of the brain in pedophilia consistent with previously reported differences in structural connectivity. The connectivity differences detected here and elsewhere are opposite in direction from those associated with anti-sociality, arguing against anti-sociality and for pedophilia as the source of the neuroanatomic differences detected.

Heparin-induced thrombocytopenia in pregnancy: an interdisciplinary challenge-a case report and literature review.

Heparin-induced thrombocytopenia is a serious adverse event of anticoagulation with a high risk of thromboembolic complications. As a consequence, anticoagulants other than heparins must be administered. These may be unavailable, contraindicated during pregnancy, off-label, impractical due to short half-lives and, most importantly, may be unfamiliar to many anesthesiologists. Impaired coagulation bears the risk of adverse events following neuraxial procedures and of peripartum hemorrhage. We describe the case of heparin-induced thrombocytopenia in a 29-year-old pregnant woman at 27weeks of gestation with severe valvular heart disease.

European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility.

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings.