The daily-practiced post-partum hemorrhage management: an Italian multidisciplinary attended protocol.

Postpartum hemorrhage (PPH) is one of the most frequent causes of mortality and morbidity in the obstetric population globally, causing about a quarter of maternal deaths yearly, and is the leading cause of maternal death worldwide. The management of PPH remains a topic of great debate, even in view of new diagnostic and therapeutic possibilities in recent years, for which, however, the body of evidence available thus far is still scarce, as the standard values are lacking. The protocol hereby presented was developed after a literature review and during several meetings of an Italian multidisciplinary task group of specialists adopting a modified Delphi method, and is the result of the synthesis of therapeutic operational protocols for the treatment of PPH applied by the different specialties within the team. This protocol is intended to represent a practical proposal to support clinicians in the management of a particularly complex event that requires the intervention of a multidisciplinary team and the implementation of dedicated management protocols.

The anaesthetic and recovery profile of two concentrations (0.25% and 0.50%), of intrathecal isobaric levobupivacaine for combined spinal-epidural (CSE) anaesthesia in patients undergoing modified Stark method caesarean delivery: a double blinded randomized trial.

BACKGROUND: In spinal anaesthesia for a Caesarean delivery, it is important to limit anaesthesia only at the surgical area, and to resolve fast motor block. We compared the intraoperative effectiveness, hemodynamic effects, anaesthetic recovery times and patients satisfaction after isobaric levobupivacaine (L) 0.25% versus L0.50% spinal anaesthesia during elective Caesarean deliveries performed with the Stark technique. PATIENTS AND METHODS: In this double-blinded prospective study, seventy women undergoing elective caesarean delivery were randomized to receive either intrathecal 7.5 mg Levobupivacaine 0.25% plus sufentanil 2.5 µg (Group L0.25), or intrathecal 7.5 mg L 0.50% plus sufentanil 2.5 µg (GroupControl). The onset time, duration of anaesthesia, analgesia and sensory and motor block and hemodynamic parameters were measured from the beginning of spinal anaesthesia until four hours after spinal anaesthesia (T240). RESULTS: Onset time, duration of anaesthesia and haemodynamic variations were similar in the two groups. No patients required general anesthesia to complete surgery. Motor block vanished faster in Group L0.25 as compared with GroupControl (p < .01). The cephalad spread of the 0.50% solution was higher than that of the 0.25% solution: no patient in Group L0.25 experienced paresthesia of the upper limbs vs 14% in GroupControl (p < .05). In GroupControl anaesthesia reached the dermatome T1 in 15% of cases. Maternal and surgeon satisfaction was good in every patient. CONCLUSIONS: Levobupivacaine 7.5 milligrams at 0.25% may be used as a suitable alternative to L 0.50% for spinal anaesthesia for caesarean deliveris with the Stark technique with good maternal satisfaction. In Group L0.25 a lower appearance of nausea and hypotension were observed and motor and sensitive block developed and diminished faster while no clinically significant differences in hemodynamic behavior was observed between groups.

Implementation of epidural analgesia for labor: is the standard of effective analgesia reachable in all women? An audit of two years.

BACKGROUND: Social and cultural factors combined with little information may prevent the diffusion of epidural analgesia for pain relief during childbirth. The present study was launched contemporarily to the implementation of analgesia for labor in our Department in order to perform a 2 years audit on its use. The goal is to evaluate the epidural acceptance and penetration into hospital practice by women and care givers and safety and efficacy during childbirth. PATIENTS AND METHODS: This audit cycle measured epidural analgesia performance against 4 standards: (1) Implementation of epidural analgesia for labor to all patients; (2) Acceptance and good satisfaction level reported by patients and caregivers. (3) Effectiveness of labor analgesia; (4) No maternal or fetal side effects. RESULTS: During the audit period epidural analgesia increased from 15.5% of all labors in the first trimester of the study to 51% in the last trimester (p < 0.005). Satisfaction levels reported by patients and care givers were good. A hierarchical clustering analysis identified two clusters based on VAS (Visual Analogue Scale) time course: in 226 patients (cluster 1) VAS decreased from 8.5±1.4 before to 4.1±1.3 after epidural analgesia; in 1002 patients (cluster 2) VAS decreased from 8.12±1.7 before (NS vs cluster 1), to 0.76±0.79 after (p < 0.001 vs before and vs cluster 2 after). No other differences between clusters were observed. CONCLUSIONS: Present audit shows that the process of implementation of labor analgesia was quick, successful and safe, notwithstanding the identification of one cluster of women with suboptimal response to epidural analgesia that need to be further studies, overall pregnant womens'adhesion to labor analgesia was satisfactory.

Biochemical and molecular characterization of von Willebrand disease type 2N in a pregnant patient who gave birth under analgesia with remifentanil.

von Willebrand 's disease (vWD) is the commonest inherited bleeding disorder. Although in literature there are some cases reported of epidural analgesia for labor pain in pregnancies with Von Willebrand's disease, the technique is not free from risk of neurolocal complications. Authors reported a case of spontaneous labor in a pregnant woman with type II vWD, delivered under local analgesia administered through a continuous intravenous infusion of remifentanil integrated by boli. A 34-year-old woman at the 39th week of her second pregnancy was admitted for an active labor of a single fetus in cephalic presentation. The patient had been diagnosed with type II vWD by a hematologist during her first pregnancy. The patient coagulation panel was as follows: a reduction of VIIIth factor concentration (21 percent); a normal value of vWD functional assay; an increase of vWf:Ag (antigen) and a reduction of XIth factor. During labor she was put on remifentanil in PCA (patient controlled analgesia), administered with slow boli followed by continuous infusions at increasing doses. The woman delivered a female fetus weighing 3,550 g, in vertex presentation, in left anterior occipital position, with an A.P.G.A.R. of 8 at the first minute and 9 at the fifth minute. The total duration of labor was 3 hours and 10 minutes. The patient was satisfied with analgesia in labor. The bleeding during and after delivery was regular. In the authors ' opinion, it is important to know that an alternative to epidural analgesia can be used in order to avoid the risk of neurological complications in labor pain for patients with type II Von Willebrand's disease.

Intrapartum sonography head transverse and asynclitic diagnosis with and without epidural analgesia initiated early during the first stage of labor.

PURPOSE: To investigate if early epidural analgesia can influence fetal head engagement into the pelvis and if it can increase the rate of transverse and asynclitic position during labour. MATERIALS AND METHODS: 195 women with combined spinal-epidural analgesia (CSE) or without neuraxial analgesia were studied. CSE was performed using a mixture of ropivacaine 0.02% with 0.3 microg/ml of sufentanil administered in the spinal space. Maintenance of analgesia was managed with intermittent epidural administration of 10-15 ml of ropivacaine (0.07%-0.10%) mixed with 0.5 microg/ml of sufentanil, based on the stage of labour and the degree of pain. 2D transabdominal ultrasound (US) was used. Serial transabdominal US examinations were performed at 45-90 min intervals to detect transverse and asynclitic positions, using the following signs: squint sign, sunset thalamus and cerebellum signs that best details the fetal head station. After delivery, the complete set of clinical and US data obtained by each examination were recorded and compared in women with and without labour analgesia. Data were examined by independent reviewers. RESULTS: There was no difference in obstetric outcome between women in whom CSE had been used and those who did not request analgesia during labour (p > 0.05). CONCLUSIONS: Epidural analgesia initiated early during labour and using low doses does not increase the rate of dystocic labors. Transverse fetal head positioning with anterior or posterior asynclitism does not seem to be promoted by drug or technique-related mechanisms, but rather should be the consequence of cephalopelvic disproportion.

Development and characterization of immobilized cannabinoid receptor (CB1/CB2) open tubular column for on-line screening.

Cannabinoid receptors, CB1 and CB2, are therapeutic targets in the treatment of anxiety, obesity, movement disorders, glaucoma, and pain. We have developed an on-line screening method for CB1 and CB2 ligands, where cellular membrane fragments of a chronic myelogenous leukemia cell line, KU-812, were immobilized onto the surface of an open tubular (OT) capillary to create a CB1/CB2-OT column. The binding activities of the immobilized CB1/CB2 receptors were established using frontal affinity chromatographic techniques. This is the first report that confirms the presence of functional CB1 and CB2 receptors on KU-812 cells. The data from this study confirm that the CB1/CB2-OT column can be used to determine the binding affinities (K(i) values) for a single compound and to screen individual compounds or a mixture of multiple compounds. The CB1/CB2-OT column was also used to screen a botanical matrix, Zanthoxylum clava-herculis, where preliminary results suggest the presence of a high-affinity phytocannabinoid.

Intrapartum sonography for occiput posterior detection in early low dose combined spinal epidural analgesia by sufentanil and ropivacaine.

AIM: To evaluate the incidence of occiput posterior position in labour with and without combined spinal epidural analgesia (CSE) by low dose of sufentanyl and ropivacaine. MATERIAL AND METHODS: This study focused on 132 women subdivided in two groups, patients in spontaneous and in labour analgesia, administered by a low dose CSE by sufentanyl and ropivacaine; all women were evaluated by digital examinations and ultrasound till delivery. All data were collected and analyzed by an independent reviewer. RESULTS: In the second stage, 79 were persistent occiput posterior position (POPP) fetuses and 36 were translated from anterior to posterior position (TAPP) fetuses. Specifically, in spontaneous labour on 25 women in anterior position, there were 17 TAPP and in CSE analgesia on 28 women in anterior, there were 19 in TAPP, without significant differences. The number of asynclitisms was higher in the POPP group (84%) respect to the TAPP group (75%), so as the rate of caesarean section (67% versus 52.7%). CONCLUSIONS: The labour with low dose of ropivacaine and sufentanyl does not increase the occiput posterior position during fetal descent, leading to a POPP. Finally, since in the occiput anterior presentation labour analgesia significantly lengthens time to delivery, in the occiput posterior position this is significantly increased, with a prolonged second stage of labour and reduced time of descent of fetal head in obstetric pelvis.

Low-dose sequential combined spinal-epidural anaesthesia in elective Stark caesarean section: a preliminary cohort study.

AIM: To compare combined spinal-epidural anaesthesia (CSE) VS spinal anaesthesia (SA) in caesarean section (CS) performed by Stark method. MATERIAL AND METHODS: 200 women were prospectively studied before undergoing to a Stark CS in two groups: 95 patients were assigned to a local anaesthesia by SA (first group) and 105 women to CSE anaesthesia (second group). After a pre-load of 500 ml of plasma expander in both groups, SA was performed at the L1-L2 interspace with an injection of 5 ml of levobupivacaine 0.15%, with a 5 mcg of Sufentanil. The CSE was performed by a spinal-epidural injection at the L1-L2 interspace, primarily by 4 ml of levobupivacaine 0.125% and 5 mcg of Sufentanil, then by 3-7 mL of xilocaine carbonate 0.5% plus 1 mcg/ml of Sufentanil. Successively a CS by Stark method was performed in both groups. The recorded anaesthesiologic side effects in two groups were: motor block, intraoperative discomfort, vomiting, bradycardia and hypotension. Statistical evaluation was by Z-Test referred to the comparison of 2 portions with great, independent samples. RESULTS: In the group with CSE anaesthesia, the prevalence of side effects was less than in the group treated with SA, where the prevalence of the motor block and intraoperative discomfort were greater and statistically significant (p<0.001); so as the vomiting and bradycardia were all in a major percentage in SA group, but only significant for hypotension (p<0.001). CONCLUSIONS: These preliminary data show that the association between CS and CSE anaesthesia in elective CS by Stark method allow to have less intra and post-operative side effects; further studies need to provide specific details on the anaesthetic and surgical techniques, to tailor and optimize both in each patient to select for surgery.

Long-term epidural analgesia treatment in pre-eclamptic women: a preliminary trial.

Pre-eclampsia (PE) is a clinical pregnancy-related condition, characterised by an elevated blood pressure and proteinuria. The author treated selected cases of PE with long-term epidural analgesia (LTEA), that reduced labour pain and operated directly on the PE aetiopathogenesis, not on the symptoms. A total of 15 women with PE were hospitalised at 35-37 weeks of pregnancy, checked for blood pressure, liver and renal function, platelet count and had an epidural catheter inserted for a continuous administration of an analgesic mixture of Naropin, Sufentanil and Clonidine. The average weeks at delivery were 37 weeks and 1 day; 10 women had a spontaneous delivery and five a caesarean section: the mean birth weight was 2,906 g and the Apgar scores at 1 min and 5 min exceeded 7 in all cases. All the parameters improved after hospital admission and at discharge. All the patients were discharged in good condition and no patients needed supplementary antihypertensive treatment. The LTEA utilisation for 1 week is well tolerated and improves uteroplacental perfusion, but further studies and a larger number of patients are required to evaluate this pharmacological procedure and determine its place in the management of PE.

In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands.

BACKGROUND AND PURPOSE: We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 cannabinoid receptors. We assessed here their functional activity. EXPERIMENTAL APPROACH: The effect of the two compounds on forskolin-induced cAMP formation in intact cells or GTP-gamma-S binding to cell membranes, and their action on nociception in vivo was determined. KEY RESULTS: CB-25 enhanced forskolin-induced cAMP formation in N18TG2 cells (EC50 approximately 20 nM, max. stimulation = 48%), behaving as an inverse CB1 agonist, but it stimulated GTP-gamma-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50 =100 nM, max. stimulation = 48%). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB1-CHO cells (EC50 = 1600 nM, max. inhibition = 68% of CP-55,940 effect). CB-52 inhibited forskolin-induced cAMP formation by N18TG2 cells (IC50 = 450 nM, max. inhibition = 40%) and hCB1-CHO cells (EC50 = 2600 nM, max. inhibition = 62% of CP-55,940 effect), and stimulated GTP-gamma-S binding to mouse brain membranes (EC50 = 11 nM, max. stimulation approximately 16%). Both CB-25 and CB-52 showed no activity in all assays of CB2-coupled functional activity and antagonized CP55940-induced stimulation of GTP-gamma-S binding to hCB2-CHO cell membranes. In vivo, both compounds, administered i.p., produced dose-dependent nociception in the plantar test carried out in healthy rats, and antagonised the anti-nociceptive effect of i.p. WIN55,212-2. In the formalin test in mice, however, the compounds counteracted both phases of formalin-induced nociception. CONCLUSIONS AND IMPLICATIONS: CB-25 and CB-52 behave in vitro mostly as CB1 partial agonists and CB2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors.

Nuclear magnetic resonance for studying recognition processes between anandamide and cannabinoid receptors.

The understanding of the molecular basis of cannabinoid activity has greatly improved since the discovery of CB1 and CB2 receptors. In this paper, the ligand binding processes between the endogenous cannabimimetic ligand, anandamide (AEA), and the cannabinoid receptors from different parts of rat brain were studied by nuclear magnetic resonance spectroscopy. The NMR approach is based on the comparison of selective (R1(SE)) and non-selective (R1(NS)) proton spin-lattice relaxation rates of the ligand in the presence and absence of macromolecular receptors, as well as R1(NS) and R1(SE) temperature dependency analysis. From these studies, the ligand-receptor binding strength was evaluated on the basis of the calculation of the "affinity index". The derivation of the "affinity index" from chemical equilibrium kinetics for all systems allowed the comparison of the ability of anandamide to interact with cannabinoid receptors present in different brain sectors.

An approach to the stereo-controlled synthesis of polycyclic derivatives of l-4-thiazolidinecarboxylic acid active against HIV-1 integrase.

Herein, we describe a new strategy for the preparation of thiazolothiazepine-based inhibitors of human immunodeficiency virus type-1 integrase (IN). The present method allows facile preparation of the title compounds in a single enantiomeric form starting from l-4-thiazolidinecarboxylic acid. This method could be easily extended to the synthesis of several analogs derived from optically active cyclic aminoacids. We also present a putative model showing the interaction between l- and d-isomers of compound 1 in the IN active site. A sensibly lower IC(50) value was found for (-)-1 over racemic-1 in an anti-IN assay.

Comparison of sequential combined spinal-epidural anesthesia and spinal anesthesia for cesarean section.

AIM: The aim of our study was to prove that by using sequential combined spinal-epidural (CSE) anesthesia it is possible to overcome the limits connected to the use of spinal anesthesia (SA) alone for elective cesarean section. METHODS: We examined 100 women submitted to cesarean section; SA was administered to 50 patients and sequential CSE technique to the other 50. In every woman before execution of the anesthesia we infused 500 mL of a plasma expander and a previous administration of 5 mg of ephedrine. The CSE was executed at the L1-L2 intervertebral space, administering in spinal anesthesia 5 mg of levobupivacaine with 5 _g of sufentanil, and in peridural anesthesia 10-12 mL of levobupivacaine 0.25% according to the patient's height. The peridural catheter for postoperative analgesia was then positioned. In the group of women submitted only to SA, 7.5-8 mg of levobupivacaine was injected, according to the patient's height, in the L1-L2 intervertebral space, with 5 _g of sufentanil. We considered the following adverse effects: hypotension; bradycardia; vomiting; intraoperative discomfort and motor block. RESULTS: The results obtained showed that, with a P < or = 0.05, the incidence of motor block (P < 0.001), discomfort (P < 0.001) and hypotension (P = 0.021) in the SA group is greater than in the CSE group. The difference in the incidence of vomiting (P = 0.147) and bradycardia (P = 0.067) between the 2 groups is not statistically significant. CONCLUSIONS: In our opinion sequential CSE can be considered an important step forward in the regional anesthesia used for elective cesarean section.

A randomised controlled trial on the efficacy of hydroelectrophoresis in acute recurrences in chronic low back pain patients.

AIM: Physical therapy efficacy in the treatment of low back pain (LBP) has been widely debated and is far from achieving high levels of evidence. Hydroelectrophoresis (Hydrofor) is a novel method of driving drugs through the dermal tissue, which has been proposed for muscle pain treatment. Aim of this randomised placebo-controlled study was to ascertain the efficacy of Hydrofor treatment on acute relapsing episodes of pain in chronic LBP subjects. METHODS: Eighteen under-50 adults (M/F: 7/11; age 35+/-8 years) suffering from chronic LBP were enrolled within 3 to 4 days of back pain relapse. After a complete clinical and functional assessment patients were randomly divided into 2 equal groups. Group A received 3 Hydrofor applications of a mixture containing both NSAIDs and muscle relaxants, whereas Group B received 3 Hydrofor applications of a drug-free solution. Afterwards, both groups performed the same rehabilitation treatment consisting of 7 group sessions of standard physiotherapy, including stretching, range of motion and extension exercises. The Oswestry disability index (ODI), the Million instrument scale and a visual analogue scale (VAS) were chosen as outcome measures and applied at baseline, after Hydrofor/placebo applications, after completion of rehabilitation sessions and, at last, 2 months later. The two-way Friedman test was used to analyse within-group (time effect) and between-group (time x group effect) differences. RESULTS: All subjects declared a significant pain reduction since the first Hydrofor application. Pain evolution overlapped in the 2 groups until the 3rd session, after which Group A significantly diverged from Group B, as they affirmed a greater symptom reduction than controls (time x group effect: VAS: F = 7.4, p <0.01). Such difference disappeared after the physiotherapy sessions as well as 2 months later (time x group effect: VAS: F = 2.1, p =0.08). Pain-related disability showed a greater reduction in Group A than B immediately after Hydrofor application (time x group effect: ODI: F=3.9 p <0.05; Million: F=4.1 p<0.05), but the mean scores almost overlapped at the 2 month follow-up (time x group effect: ODI: F=2.3 p =0.08; Million: F=1.3 p=0.26). CONCLUSIONS: Hydrofor treatment relieves relapsing LBP and could be recommended to active adults as a safe technique shortening the time needed to achieve functional restoration.

Thiazolothiazepine inhibitors of HIV-1 integrase.

A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN. By contrast, compounds with a naphthalene ring system showed enhanced potency, suggesting that a hydrophobic pocket in the IN active site might accommodate an aromatic system rather than a halogen. The position of sulfur in the thiazole ring appears important for potency against IN, as its replacement with an oxygen or carbon abolished activity. Further extension of the thiazole ring diminished potency. Compounds 1, 19, and 20 showed antiviral activity and inhibited IN within similar concentrations. These compounds inhibited IN when Mn(2+) or Mg(2+) was used as cofactor. None of these compounds showed detectable activities against HIV-1 reverse transcriptase, protease, virus attachment, or nucleocapsid protein zinc fingers. Therefore, thiazolothiazepines are potentially important lead compounds for development as inhibitors of IN and HIV replication.

Amino acid requirements and peptidase activities of Streptococcus salivarius subsp. thermophilus.

The aim of this work was to investigate the relationship between amino acid requirements and peptidase enzyme systems in three Streptococcus salivarius subsp. thermophilus strains. A synthetic medium without nitrogen components and a milk (RD milk) without its non-protein nitrogen fraction were prepared with different mixtures of amino acids. The strains showed different amino acid requirements. Some amino acids proved to be essential, some were required, while others did not affect growth. In the synthetic medium, only leucine and glutamic acid were essential for growth. In RD milk, the amino acid requirements were found to be lower, with only the absence of glutamic acid causing complete inhibition of growth. Relationships between aminopeptidase activities of the strains and their amino acid requirements were observed. Strains with higher amino acid requirements were also found to express a wider range of peptidases.

Chromatin condensation in isolated rat hepatocyte nuclei induced by ribonuclease treatment.

Ribonuclease treatment of isolated rat hepatocyte nuclei induced a 75% solubilization in hnRNA, a reduction of the quantity of perichromatin fibrils, and a marked condensation of chromatin.