Ephedrine accelerates psychomotor recovery from anesthesia in macaque monkeys.

BACKGROUND: Ephedrine is used in treatment of hypotension during anesthesia. We investigated its effects on the psychomotor recovery and its potential adverse reactions on cardiorespiratory functions in rhesus monkeys. METHODS: The monkeys received 50 µg/kg medetomidine, 2.0 mg/kg S-ketamine with 150 IU hyaluronidase i.m. Pulse rate, blood pressure and saturation of haemoglobin were monitored for 20 minutes. Thereafter, 1 mg/kg of ephedrine or a placebo was administered i.m. and behavioural changes, pulse rate, blood pressure and saturation of haemoglobin were monitored every 5 minutes. RESULTS: Ephedrine shortened recovery from anaesthesia from 80.4 ± 25.8 to 14.83 ± 13.70 minutes. Ephedrine also increased oxygen saturation of haemoglobin and systolic blood pressure and caused significant decrease in pulse rate 5 minutes after its administration. CONCLUSIONS: Ephedrine can be successfully used to accelerate psychomotor recovery after the use of common anesthetic protocols combining dissociative anesthetic agent and alpha 2-adrenoceptor agonist in primates.

External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer.

BACKGROUND: Data for selpercatinib [a selective REarranged during Transfection (RET) inhibitor] from a single-arm trial (LIBRETTO-001, NCT03157128) in RET-fusion-positive advanced/metastatic non-small-cell lung cancer (NSCLC) were used in combination with external data sources to estimate comparative efficacy [objective response rate (ORR), progression-free survival, and overall survival (OS)] in first- and second-line treatment settings. METHODS: Patient-level data were obtained from a de-identified real-world database. Patients diagnosed with advanced/metastatic NSCLC with no prior exposure to a RET inhibitor and one or more prior line of therapy were eligible. Additionally, individual patient-level data (IPD) were obtained from the pemetrexed + platinum arm of KEYNOTE-189 (NCT03950674, first line) and the docetaxel arm of REVEL (NCT01168973, post-progression). Patients were matched using entropy balancing, doubly robust method, and propensity score approaches. For patients with unknown/negative RET status, adjustment was made using a model fitted to IPD from a real-world database. RESULTS: In first-line unadjusted analyses of the real-world control, ORR was 87.2% for LIBRETTO-001 versus 66.7% for those with RET-positive NSCLC (P = 0.06). After adjustment for unknown RET status and other patient characteristics, selpercatinib remained significantly superior versus the real-world control for all outcomes (all P < 0.001 except unadjusted RET-fusion-positive cohort). Similarly, outcomes were significantly improved versus clinical trial controls (all P < 0.05). CONCLUSIONS: Findings suggest improvement in outcomes associated with selpercatinib treatment versus the multiple external control cohorts, but should be interpreted with caution. Data were limited by the rarity of RET, lack of mature OS data, and uncertainty from assumptions to create control arms from external data.

Can changes in skin impedance be used to monitor sedation after midazolam and during recovery from anesthesia?

It has been suggested that sympathetic activity, measured as changes in electrical skin impedance (SI), can be used to assess the adequacy of general anesthesia. Our prospective study investigated if measurements of skin impedance can determine levels of sedation induced by midazolam. Twenty-seven patients scheduled for arthroscopy requiring general anesthesia were served as their own control. These were blinded to the order of injections by telling them that they will be randomly administered a placebo (saline) orsedative agent. A DM 3900 multimeter was used for SI measurements. The degree of sedation was measured using the modified Observer's Assessment of Alertness and Sedation (mOAAS) scale. Resting SI values were noted, and all participants were then administered the placebo followed 5 min later by midazolam 2 mg i.v. Five min after that, patients were administered standard general anesthesia with propofol, oxygen, nitrous oxide 60 %, and isoflurane 1 MAC via a laryngeal mask, and sufentanil 5 - 10 µg. SI significantly increased after administration of midazolam and induction of anesthesia. There were no significant differences between pre-administration (baseline) and placebo and end of surgery and end of anesthesia with closed eyes. There were highly significant differences (p<0.001) between pre-administration vs. midazolam, placebo vs. midazolam, pre-administration vs. induction of anesthesia. We found slight correlation between mOAAS and SI. There were no significant changes between the end of surgery and the end of anesthesia with closed eyes, but SI significantly decreased (p<0.01) after eyes opened.

Experience with a naphthylmedetomidine-ketamine-hyaluronidase combination in inducing immobilization in anthropoid apes.

BACKGROUND: The aim of the study was to compare the effect of naphthylmedetomidine to medetomidine on the behavior of orangutans and chimpanzees. METHODS: The immobilization was performed as part of a medical examination in five chimpanzees and three orangutans. Following pre-medication with midazolam (0.70-1.20 mg/kg p.o.), naphthylmedetomidine (50-70 microg/kg), or medetomidine (20-30 microg/kg) was given with ketamine (3 mg/kg) and hyaluronidase (150 M.U.) into musculus deltoideus. RESULTS: We observed the distinct anti-aggressive effect of naphthylmedetomidine. The immobilization with naphthylmedetomidine was shallower and the influence on cardiac frequency less substantial compared to medetomidine. The overall sedative effect of naphthylmedetomidine lasted for less time, and its effect was incompletely antagonized with atipamezole in comparison to medetomidine. CONCLUSIONS: Naphthylmedetomidine could replace medetomidine for inducing immobilization and sedation. A combination of naphthylmedetomidine-ketamine is suitable for relocating animals to other cages or for painless medical examinations.

The effect of medetomidine-ketamine anesthesia on hemodynamic parameters during hemorrhagic shock in minipigs.

Hemorrhagic shock (HS) represents an acute event with high mortality. The optimal combination of anesthetics that would prevent hemodynamic collapse and allow damage control surgery has not yet been determined. We tested the hypothesis that a combination of dissociative anesthetic ketamine with alpha2-agonist medetomidine (MK group, n=10) would provide superior hemodynamic control compared to propofol-remifentanil (PR group, n=10) during HS in minipigs. A modified Wiggers' model of HS with a target mean arterial pressure (MAP) of 40 mm Hg and 2 h duration was used. All minipigs survived. HS led to a ~50 % decrease in cardiac output in both groups (P<0.001 for baseline vs. HS 120 min) with no differences between groups. Total volume of removed blood was larger in the MK group (1321+/-133 ml vs. 1111+/-246 ml in the PR group, respectively; P<0.05). MAP was higher during the initial phases of HS in the MK group than in PR group (P<0.05 at HS 30-90 min). HR was lower in the MK group at the late phases of HS (P<0.05 at HS 60-120 min). In conclusion, medetomidine-ketamine provides a feasible and possibly a more favorable alternative to the propofol-remifentanil combination in our model of HS in minipigs.

Practice management guidelines for the diagnosis and management of injury in the pregnant patient: the EAST Practice Management Guidelines Work Group.

Trauma during pregnancy has presented very unique challenges over the centuries. From the first report of Ambrose Pare of a gunshot wound to the uterus in the 1600s to the present, there have existed controversies and inconsistencies in diagnosis, management, prognostics, and outcome. Anxiety is heightened by the addition of another, smaller patient. Trauma affects 7% of all pregnancies and requires admission in 4 of 1000 pregnancies. The incidence increases with advancing gestational age. Just over half of trauma during pregnancy occurs in the third trimester. Motor vehicle crashes comprise 50% of these traumas, and falls and assaults account for 22% each. These data were considered to be underestimates because many injured pregnant patients are not seen at trauma centers. Trauma during pregnancy is the leading cause of nonobstetric death and has an overall 6% to 7% maternal mortality. Fetal mortality has been quoted as high as 61% in major trauma and 80% if maternal shock is present. The anatomy and physiology of pregnancy make diagnosis and treatment difficult.

[A combination of dexmedetomidine with ketamine and opioids results in significant inhibition of hemodynamic changes associated with laparoscopic cholecystectomy and in prolongation of postoperative analgesia]. / Kombinace dexmedetomidinu s ketaminem a opioidy významne potlacuje hemodynamické zmeny zpusobené laparoskopickou cholecystektomií a prodluzuje trváiní pooperacní analgezie.

THE AIM OF THE STUDY: Recently, alpha2 sympathoadrenergic drugs are used in premedication to improve the perioperative course. The aim of our study was to compare a premedication with a new alpha2 sympathoadrenergic drug and standard premedication. METHODS: After ethic committee approval and written patient consent, in a randomised, double-blinded study, combination of dexmedetomidine 1.0 microg x kg(-1) + ketamine 0.5 mg x kg(-1) + fentanyl 1.0 microg x kg(-1) + atropine 0.5 mg (group FNT), dexmedetomidine 1.0 microg x kg(-1) + ketamine 0.5 mg x kg(-1) + alfentanil 5.0 microg x kg(-1) + atropine 0.5 mg (group ALFNT), or pethidine 1.0 mg x kg(-1) + atropine 0.5 mg (group Dolsin) was administered to a deltoid muscle 15 min. before anaesthesia (GA) in patients elicited for laparoscopic cholecystectomy (LCHE). GA was performed in a standard way, ECG, NIBP, respiration rate, SpO2, onset of effect, Observers Assessment of Alertness Sedation Score (OAASS) before GA, circulatory reaction to intubation and capnoperitoneum, fentanyl consumption during GA, time to the first request for post-operative analgesia and postoperative nausea and vomiting were measured. The data were processed by Kruskal-Wallis and Fisher tests. P-value < 0.05 was considered significant. RESULTS: There were 16 patients in FNT and Dolsin and 15 patients in ALFNT with no differences in demography except for younger age in ALFNT. The main differences were in hypertension during capnoperitoneum: 0/16 FNT and 1/15 ALFNT vs. 11/16 Dolsin, both p < 0.001, per-operative fentanyl consumption: FNT 31.5 microg vs. Dolsin 165.0 microg, p < 0.001 and ALFNT 50.0 microg, p < 0.05 (ALFNT vs. Dolsin, p < 0.01) and request to the first analgesic post surgery: FNT 1.3 h. vs. Dolsin 0.45 h., p < 0.05 vs. ALFNT 0.8 h., p < 0.01. There were no differences in side effects except for bradycardia in ALFNT (p < 0.05). CONCLUSIONS: Dexmedetomidine-ketamine-fentanyl-atropine combination is superior to pethidine-atropine combination in suppressing of adverse hemodynamic effects of capnoperitoneum, decreased need for analgesia during GA and prolonged postoperative analgesia.

Motor abilities of children diagnosed with fragile X syndrome with and without autism.

BACKGROUND: Previous studies suggested that children diagnosed with fragile X syndrome (FXS) often meet criteria for autism or PDD. This study describes the fine motor abilities of children diagnosed with FXS with and without autism spectrum disorder, and compares the motor scores of those groups controlling for cognitive level. METHOD: Forty-eight children, ages 12-76 months (SD = 16) diagnosed with FXS were assessed with the Mullen Scales of Early Learning, and the Autism Diagnostic Observation Schedule. Their parents were interviewed with the Autism Diagnostic Interview-Revised. We used a one-way analysis of variance to determine if the fine motor scale of the Mullen would show group differences based on autism classifications for the sample. In addition, we used Pearson correlation coefficient to examine the relationship between the cognitive level, the autism severity and the motor abilities. Lastly, we conducted a one-way analysis of covariance to determine the difference between the motor abilities of the Autism Spectrum Disorder groups controlling for cognitive level. RESULTS: We found that 60% of the children with FXS met criteria for autism or Pervasive Developmental Disorder - Not otherwise specified (PDD-NOS). Children with FXS with autism and PDD-NOS had lower fine motor scores than those without. However, there was no significant association between degree of motor impairment and communication and social impairments after controlling for cognitive level, indicating that cognitive level contributes to impaired motor abilities of children diagnosed with FXS and autism, more than the severity of autism symptoms. CONCLUSION: children with FXS and autism are at risk for impaired motor abilities. Implications for development and intervention are discussed.

Non-traditional administration of remifentanil in an experimental setting.

Remifentanil is ultrashort-acting opioid with a unique pharmacokinetic profile. It is used exclusively intravenously. While considering its rapid onset of action and other pharmacokinetic properties, we decided to assess its effects following administration via non-traditional routes. Rabbits (n=10 per each group) were randomized into six groups: remifentanil 1 microg/kg and 3 microg/kg IM, 5.0 and 10.0 microg/kg conjunctivally, and 10 microg/kg and 25.0 microg/kg intranasally. Sedating effects were assessed via a loss of the righting reflex. Secondary, mean arterial blood pressure, arterial oxygen saturation of hemoglobin, and pulse rate was monitored in all rabbits. Non-traditional routes of administration were shown to provide a rapid onset of action as well as fast recovery. Importantly, the administration of remifentanil did not result in any deterioration of cardiovascular functions.

Klebsiella pneumoniae and Klebsiella oxytoca meningitis in infants. Epidemiological and clinical features.

BACKGROUND: The incidence of meningitis caused by Klebsiella pneumoniae (Kp) and Klebsiella oxytoca (Ko) in high-income countries is unknown, and no series have been published to date. METHODS: We conducted a nationwide multicenter observational study in France between 2006 and 2016. All children from the French national registry for paediatric bacterial meningitis under the age of 1 year and hospitalized for Kp or Ko meningitis were included. Virulence factors of four Klebsiella spp. strains were explored by whole genome sequencing. RESULTS: Of 1859 cases of meningitis in children under the age of 1 year, 13 cases (0.7%) of Klebsiella spp. meningitis (nine for Kp meningitis and four for Ko meningitis) were registered in the French national registry. Three of the patients died and 50% of the survivors had developmental delays. CONCLUSIONS: Prematurity, low birth weight, and congenital anomalies of the urinary tract appear to be risk factors for Klebsiella spp. meningitis as well as virulence factors of the strain.

Weight change during chemotherapy as a potential prognostic factor for stage III epithelial ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: Platinum/Paclitaxel-based chemotherapy is a current treatment for advanced epithelial ovarian cancer. We sought to explore the association between weight change during treatment and survival, as well as the association between pre-chemotherapy body mass index (BMI) and survival. METHODS: A retrospective data review was conducted of 792 advanced ovarian cancer patients who participated in a phase III randomized trial of cisplatin/paclitaxel versus carboplatin/paclitaxel. Pre-chemotherapy BMI was calculated following surgery. Weight change was defined as the ratio of body weight at completion of protocol therapy to pre-chemotherapy body weight. Progression-free survival (PFS) and overall survival (OS), classified by BMI or relative weight change, were estimated by Kaplan-Meier, and associations were assessed using a Cox model controlled for known prognostic variables (age, race, performance status, histology, tumor grade, tumor residual and treatment group). RESULTS: There was no association between pre-chemotherapy BMI and survival. There was a significant relationship between median OS and weight change as follows: >5% decrease=48.0 months; 0-5% decrease=49.3 months; 0-5% increase=61.1 months; and >5% increase=68.2 months. Adjusted for covariates, the relative risk of death increased by 7% for each 5% decrease in body weight (HR=0.93, 95% CI=0.88-0.99; p=0.013). CONCLUSIONS: Change of body weight during primary chemotherapy was a strong prognostic factor for overall survival. Loss of body weight during primary therapy is an indicator for poor OS; weight gain is an indicator for improved survival. This study supports the development of strategies to minimize weight loss that can be assessed in a prospective, randomized study to improve patient outcomes.

Electronic residency application service scores: do they correlate with the rank order list for the match?

OBJECTIVE: To investigate the relationship between ERAS-based preinterview scores, residency program postinterview scores and candidate rank order for the match. STUDY DESIGN: Two hundred sixty-three candidates' preinterview and postinterview scores and rank order were evaluated. The rank order was stratified as 1-4, 5-8, 9-12, > 13 and unranked. Spearman's p statistical analysis was used. RESULTS: There was a moderate relationship, r2 = 0.543, between preinterview and postinterview scores for all applicants. There was a significant inverse correlation between preinterview score and rank order, r2 = -0.763, and for the postinterview and rank order, r2 = -0.768. However, there were no significant relationships between factors significant for the top 4 ranked candidates. CONCLUSION: Preinterview and postinterview scores significantly correlated with each other and with the rank order list except for top-ranked candidates. Other factors may influence the rank order list.

Episiotomy rates in private vs. resident service deliveries: a comparison.

OBJECTIVE: To compare the use of episiotomy by private practitioners vs. resident staff and to determine if number of years in practice influences episiotomy use. STUDY DESIGN: A retrospective chart review of vaginal deliveries at 35 weeks or greater between January 2001 and June 2001. The number of years in practice by each private physician was documented. Independent sample t tests and chi2 tests were used to analyze data. RESULTS: In 995 deliveries, episiotomies were performed in 6% of low-risk resident deliveries vs. 26% of low-risk private deliveries (p<0.001). Physicians in practice > or = 15 years performed episiotomies in 32% of low-risk births. Physicians in practice <15 years performed episiotomies in 22% of low-risk births (p = 0.027). CONCLUSION: Deliveries performed by private practitioners are associated with a higher rate of episiotomy than those by resident staff. The number of episiotomies appears to increase by number of years in practice.

Sedative effects of intranasal oxytocin in rabbits and rhesus monkeys.

Oxytocin is a hormone therapeutically used mainly for its peripheral effects during pregnancy in the uterus and breasts. However, additional central effects, i.e. anxiolytic effect, decreased level of social stress and increased empathy have been also observed. Hence, the aim of our study was to evaluate if nasal oxytocin can be used as anxiolytic substance in rhesus monkeys (n=20) and rabbits (n=20). Simultaneously, mean arterial blood pressure, arterial oxygen saturation of hemoglobin and pulse rate were monitored in all the evaluated animals. While rabbits lost righting reflex, monkeys developed a dose-dependent loss of aggressiveness and/or anxiety as evaluated by behavioral methods (aggressive behavior was classified as non-sedated - sedated - strongly sedated).

Phalloidin reduces the release of inorganic phosphate during actin polymerization.

Phalloidin, an actin-filament stabilizing peptide from Amanita phalloides, did not inhibit ATP hydrolysis during actin polymerization but strongly retarded the release of the hydrolysis product Pi. Thus, the lifetime of the intermediate F-actin-ADP-Pi is significantly increased by phalloidin. The results suggest a close correlation between filament stability and F-actin-ADP-Pi intermediates.

Characteristics of uterine activity in gestations less than 20 weeks.

Ambulatory tocodynamometry has been used for some time to record uterine activity during pregnancy. Most studies, however, have been performed in the third trimester (more than 24 weeks). The current study was initiated to assess uterine activity at earlier gestational ages. One hundred thirty-seven patients were studied between 14-19 weeks' gestation (inclusive). Seven patients who were being monitored were noted to have preterm labor, and six of these seven were found to have increased uterine activity before the diagnosis of preterm labor. There was no difficulty encountered in the vast majority of cases in recording objective, accurate uterine activity information even at these early gestational ages. There was an increase in the uterine activity (during the 18th and 19th weeks) in patients destined to develop preterm labor later in gestation as compared with the contraction pattern of those who labored at term. This study demonstrates that accurate uterine activity information can be gained at these early gestational ages and that when increased contraction frequency is present, it is related to preterm labor.

Significance of opaque discolored amniotic fluid at second-trimester amniocentesis.

From June 1978 to December 1983, 100 patients with viable pregnancies involving opaque, discolored, second-trimester amniotic fluid were identified. During this period 7018 genetic amniocenteses were performed for an incidence of discolored fluid of 1.4%. Compared with case matched control subjects there were no statistically significant differences in the incidence of elevated amniotic fluid alpha-fetoprotein, preterm labor, fetal distress during labor, intrauterine growth retardation, or stillbirth. The rate of spontaneous abortion (7 versus 0%; P less than .05) was increased in the discolored fluid group. The patients with discolored fluid also had an increased incidence of prior vaginal bleeding (P less than .001).

Group B streptococcal sepsis and death in utero following funipuncture.

The technique of umbilical cord puncture for diagnosis and therapy, which has been shown to be feasible and relatively safe for both mother and fetus, is being used increasingly. The fetal loss rate with this technique has been estimated to be approximately 1%. A case is presented of fetal death from group B beta-streptococcal sepsis after funipuncture, the first report of this complication.

Correlation of uterine activity using the Term Guard monitor versus standard external tocodynamometry compared with the intrauterine pressure catheter.

Uterine activity monitoring to detect preterm contractions and thus to manage patients in active labor is valuable to the clinician. Uterine activity measured by external devices using the guard ring principle or by standard tocodynamometers has been shown to be accurate concerning the frequency of uterine activity as compared with intrauterine pressure catheter-derived data in the third trimester. In this study, 26 women from 19-34 weeks in documented preterm labor had their uterine activity measured by a standard in-hospital monitor and a Term Guard tocodynamometer simultaneously. The standard monitor reflected 16-91% of the frequency of contractions noted by the Term Guard device, with a reduction in the correlation at gestational ages under 30 weeks. In another 20 patients between 17-36 weeks' gestation, these two methods of external tocodynamometry were compared with a transcervical catheter which measured actual intrauterine pressure and frequency of contractions. There was a good correlation between the Term Guard device and transcervically measured contractions (94.6%). At gestational ages of 28 weeks or less, there was poor performance from standard devices (less than 38% correlation with the intrauterine pressure catheter). These data have important implications for clinicians who monitor preterm patients on an ambulatory basis for early detection of preterm labor and also have clinical impact for the management of patients at early gestational ages in active labor.

Plasma and amniotic fluid concentrations of fibronectin during normal pregnancy.

To ascertain the influence of pregnancy on plasma concentrations of fibronectin, we quantified plasma concentrations of fibronectin in 22 normal, pregnant women during the first, second, and third trimesters; at the time of delivery; and at six weeks and eight months postpartum, using a rapid, immunoturbidimetric procedure. Mean plasma concentrations of fibronectin rose significantly throughout pregnancy, and were significantly greater than umbilical cord plasma concentrations. Maternal plasma concentrations of fibronectin at six weeks postpartum were similar to those observed at the time of delivery, but returned to concentrations observed in nonpregnant women by eight months postpartum. No significant differences between concentrations of fibronectin in amniotic fluid obtained during the second and third trimesters of pregnancy were observed. Six-week postpartum values appeared to depend upon the type of infant feeding as values rose in bottle feeding but fell in breast-feeding mothers.