Carolyn F. Weiniger

A3 adenosine receptors and mitogen-activated protein kinases in lung injury following in vivo reperfusion

IntroductionAlthough activation of A3 adenosine receptors attenuates reperfusion lung injury and associated apoptosis, the signaling pathway that mediates this protection remains unclear. Adenosine agonists activate mitogen-activated protein kinases, and these kinases have been implicated in ischemia/reperfusion injury; the purpose of this study was therefore to determine whether A3 adenosine receptor stimulation with reperfusion modulates expression of the different mitogen-activated protein kinases. In addition, we compared the effect of the A3 adenosine agonist IB-MECA with the newly synthesized, highly selective A3 adenosine receptor agonist MRS3558 on injury in reperfused lung.MethodStudies were performed in an in vivo spontaneously breathing cat model, in which the left lower lobe of the lung was isolated and subjected to 2 hours of ischemia and 3 hours of reperfusion. The selective A3 adenosine receptor agonists IB-MECA (0.05 mg/kg, 0.1 mg/kg, or 0.3 mg/kg) and MRS3558 (0.05 mg/kg or 0.1 mg/kg) were administered before reperfusion.ResultsBoth A3 adenosine receptor agonists administered before reperfusion markedly (P < 0.01) attenuated indices of injury and apoptosis, including the percentage of injured alveoli, wet/dry weight ratio, myeloperoxidase activity, TUNEL (in situ TdT-mediated dUTP nick end labeling)-positive cells, and caspase 3 activity and expression. The more pronounced effects at low doses were observed with MRS3558. Increases in phosphorylated c-Jun amino-terminal protein kinase (JNK), p38, and extracellular signal-regulated kinase (ERK)1/2 levels were observed by the end of reperfusion compared with controls. Pretreatment with the A3 agonists upregulated phosphorylated ERK1/2 levels but did not modify phosphorylated JNK and p38 levels.ConclusionThe protective effects of A3 adenosine receptor activation are mediated in part through upregulation of phosphorylated ERK. Also, MRS3558 was found to be more potent than IB-MECA in attenuating reperfusion lung injury. The results suggest not only that enhancement of the ERK pathway may shift the balance between cell death and survival toward cell survival, but also that A3 agonists have potential as an effective therapy for ischemia/reperfusion-induced lung injury.

A survey of labour ward clinicians' knowledge of maternal cardiac arrest and resuscitation

BACKGROUND Guidelines for the management of cardiac arrest during pregnancy exist but they are based on little research. The study hypothesis was that experienced medical clinicians who specialise in obstetric care would not follow current International Liaison Committee on Resuscitation/American Heart Association recommendations in this situation. METHODS Following waiver of informed consent by the institutional review board, an anonymous structured scenario questionnaire survey was conducted among relevant hospital clinicians. Demographic details included field of expertise and resuscitation experience. A single case vignette of maternal cardiac arrest was presented, followed by nine questions to examine knowledge of existing recommendations for maternal cardiopulmonary resuscitation. Statistical analyses were performed using SPSS version 12 software (SPSS Inc, Chicago, IL). RESULTS The overall response rate was 67% (30/45 questionnaires). Specialist obstetricians, midwives and anaesthetists from 17 hospitals participated. Forty-three percent (n=13) claimed broad experience, 50% (n=15) claimed some experience and 6.7% (n=2) claimed no experience in adult resuscitation. Participants were divided in their opinions regarding every choice of action: positioning, need to administer cricoid pressure during mask ventilation, timing of intubation, location of external chest compression, location of paddle placement for delivery of shock during ventricular fibrillation, the timing of defibrillation versus fetal delivery, medication doses and the need to rupture the membranes at an early phase of the resuscitation. CONCLUSION Specialist clinicians who treat pregnant women in hospital on a daily basis possess a limited knowledge of the recommendations for treating maternal cardiac arrest.

External cephalic version for breech presentation with or without spinal analgesia in nulliparous women at term: a randomized controlled trial.

OBJECTIVE: To compare the success of external cephalic version using spinal analgesia with no analgesia among nulliparas. METHODS: A prospective randomized controlled trial was performed in a tertiary referral center delivery suite. Nulliparous women at term requesting external cephalic version for breech presentation were randomized to receive spinal analgesia (7.5 mg bupivacaine) or no analgesia before the external cephalic version. An experienced obstetrician performed the external cephalic version. Primary outcome was successful conversion to vertex presentation. RESULTS: Seventy-four women were enrolled, and 70 analyzed (36 spinal, 34 no analgesia). Successful external cephalic version occurred among 24 of 36 (66.7%) women randomized to receive spinal analgesia compared with 11 of 34 (32.4%) without, P=.004 (95% confidence interval [CI] of the difference: 0.0954–0.5513). External cephalic version with spinal analgesia resulted in a lower visual analog pain score, 1.76±2.74 compared with 6.84±3.08 without, P<.001. A secondary analysis logistic regression model demonstrated that the odds of external cephalic version success was 4.0-fold higher when performed with spinal analgesia P=.02 (95% CI, odds ratio [OR] 1.2–12.9). Complete breech presentation before attempting external cephalic version increased the odds of success 8.2-fold, P=.001 (95% CI, OR 2.2–30.3). Placental position, estimated fetal weight, and maternal weight did not contribute to the success rate when spinal analgesia was used. There were no cases of placental abruption or fetal distress. CONCLUSION: Administration of spinal analgesia significantly increases the success rate of external cephalic version among nulliparous women at term, which allows possible normal vaginal delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00119184 LEVEL OF EVIDENCE: I

Pulse oximeter perfusion index as an early indicator of sympathectomy after epidural anesthesia.

Background: The pulse oximeter perfusion index (PI) has been used to indicate sympathectomy‐induced vasodilatation. We hypothesized that pulse oximeter PI provides an earlier and clearer indication of sympathectomy following epidural anesthesia than skin temperature and arterial pressure.

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.

Review of prolonged local anesthetic action.

Importance of the field: Pain following surgery is often treated by local anesthetic agents. Duration of the analgesia can be extended safely following administration of encapsulated large doses of local anesthetic agents. Areas covered in this review: This review considers formulations used for encapsulation of local anesthetic agents for prolonged anesthesia effect. All studies describing encapsulation of a commercial local anesthetic agent for providing prolonged analgesia were considered using the NCBI Medline site. of local anesthetic, prolonged anesthesia, polymers and liposomes were entered in order to retrieve appropriate articles and reviews from 1966 to 2010, with emphasis on the last 10 years. Reference pages were searched manually for other relevant articles. The topics covered include an overview of local anesthetic agents and a review of local anesthetic carrier agents, with emphasis on liposomes and polymer carriers. Articles were limited to the English language. What the reader will gain: The current research areas for prolongation of local anesthetic effect are evaluated, along with their limitations. Each topic has been summarized, and the review has attempted to cover all current laboratory and clinical studies in a simple manner that should also be useful for readers without a pharmacology background. The direction of research is promising and exciting, and this review should be a useful up-to-date reference. Take home message: Many formulations including polymer and liposome carriers have facilitated prolonged local anesthetic action for several days, although few clinical studies have been performed. This field promises a safe way to deliver local anesthetics for effect far beyond that of commercially available agents, with potential cost and health benefits for patients suffering chronic or postoperative pain

Randomized controlled trial of external cephalic version in term multiparae with or without spinal analgesia

BACKGROUND Neuraxial analgesia significantly increases the success rate of external cephalic version (ECV) among nulliparae. The study objective was to compare ECV success among multiparae with and without spinal analgesia. METHODS Prospective randomized controlled trial performed over a pre-defined 6 yr period in a tertiary referral delivery suite. Healthy multiparae at term requesting ECV for breech presentation, without fetal or uterine anomaly, were enrolled after written informed consent. Women were randomized to receive either spinal analgesia (bupivacaine 7.5 mg) or no analgesia before the ECV. The primary outcome was successful conversion from breech to vertex presentation, confirmed by ultrasound. Visual analogue pain score and adverse outcomes (complications of anaesthesia or ECV) were recorded. Statistical analysis was performed according to intention to treat using two-sided tests. RESULTS Among 265 multiparae who underwent ECV, 65 consented to enrol, one subsequently refused ECV; therefore, data from 64 women were analysed. ECV was successful in 27 of 31 patients (87.1%) receiving spinal analgesia vs 19 of 33 (57.5%) with no analgesia (P=0.009; 95% CI of difference: 0.075-0.48). ECV with spinal analgesia reduced visual analogue pain score, mean (sd) 1.7 (2.4) vs 5.5 (2.9) without (P<0.0001). Maternal hypotension was seen after spinal analgesia in 10 of 31 (32%) (P=0.0003) and easily treated without adverse outcome. No complications were noted after the ECV. CONCLUSIONS Administration of spinal analgesia significantly increased the rate of successful ECV among multiparae at term with increased patient comfort. The trial was registered at the National Institute of Health Trials Registry, NCT00119184, www.clinicaltrials.gov.

Outcomes of prospectively-collected consecutive cases of antenatal-suspected placenta accreta

BACKGROUND Accurate diagnosis of placenta accreta is tentative before surgery. This study developed a predictive score for antenatal diagnosis of placenta accreta through mathematical modeling using clinical signs. METHODS Antenatal cases of suspected placenta accreta were collected prospectively in a single-site tertiary delivery center. Women with clinical signs of placenta accreta (placenta previa, number of previous cesarean deliveries and/or ultrasound suspicion of placenta accreta) were included. The diagnosis of accreta was confirmed surgically. The primary endpoint was the proportion of surgically-diagnosed placenta accreta among all suspected cases. Logistic regression modeling was performed to assess preoperative risk factors for placenta accreta. The risk score was tested on a receiver operator characteristic curve to identify subjects with placenta accreta and the optimum cut-point was chosen. RESULTS Over nine years, 92 suspected accreta cases were identified from 46623 deliveries (0.2%). The diagnosis was confirmed at surgery in 52/92 cases (56%) and there were no maternal deaths. Blood transfusion requirements were greater in patients with placenta accreta versus patients without placenta accreta (median 7 [range 0-25, interquartile range 3-10] versus 0 [0-6, 0-2] units of blood, P <0.0001). Area under the curve of the receiver operator characteristic curve was 0.846, with contribution from three variables (placenta previa, number of previous cesarean deliveries and ultrasound suspicion), each with a P value <0.05. From the ROC curve a cut-point with 100% sensitivity and specificity 25% (95% CI 12.69%-41.20%) was achieved, compared with 86.6% sensitivity (95% CI 74.21%-94.41%) and 60.0% specificity (95% CI 43.33%-75.14%) using ultrasound alone. CONCLUSIONS Combining diagnostic features associated with placenta accreta through mathematical modeling has better positive predictive value than ultrasound alone.

National and International Guidelines for Patient Blood Management in Obstetrics: A Qualitative Review.

In developed countries, rates of postpartum hemorrhage (PPH) requiring transfusion have been increasing. As a result, anesthesiologists are being increasingly called upon to assist with the management of patients with severe PPH. First responders, including anesthesiologists, may adopt Patient Blood Management (PBM) recommendations of national societies or other agencies. However, it is unclear whether national and international obstetric societies’ PPH guidelines account for contemporary PBM practices. We performed a qualitative review of PBM recommendations published by the following national obstetric societies and international groups: the American College of Obstetricians and Gynecologists; The Royal College of Obstetricians and Gynecologists, United Kingdom; The Royal Australian and New Zealand College of Obstetricians and Gynecologists; The Society of Obstetricians and Gynecologists of Canada; an interdisciplinary group of experts from Austria, Germany, and Switzerland, an international multidisciplinary consensus group, and the French College of Gynaecologists and Obstetricians. We also reviewed a PPH bundle, published by The National Partnership for Maternal Safety. On the basis of our review, we identified important differences in national and international societies’ recommendations for transfusion and PBM. In the light of PBM advances in the nonobstetric setting, obstetric societies should determine the applicability of these recommendations in the obstetric setting. Partnerships among medical, obstetric, and anesthetic societies may also help standardize transfusion and PBM guidelines in obstetrics.

Outcomes of subsequent pregnancies after conservative treatment for placenta accreta

To estimate the association between conservative treatment for placenta accreta and subsequent pregnancy outcomes.