Intravenous ketamine during spinal and general anaesthesia for caesarean section: systematic review and meta-analysis.

BACKGROUND: Intravenous ketamine has been used during general and regional anaesthesia for caesarean section. No systematic review and meta-analysis on the desired effects and adverse effects of ketamine administration during caesarean section have yet been performed. METHODS: After a systematic literature search a meta-analysis was conducted with the random effects model. Weighted mean difference (WMD) or risk ratio and 95% confidence intervals (CIs) were computed. RESULTS: Twelve randomised controlled double-blind trials comprising 953 patients were included: seven studies reported on spinal anaesthesia and five on general anaesthesia. Significant differences in the aforementioned outcome variables were found only in the spinal anaesthesia studies. In the spinal anaesthesia studies the time to the first analgesic request was significantly longer in ketamine-treated women, the WMD was 49.36 min (95% CI 43.31-55.41); visual analogue scale pain scores at rest 2 h after surgery were significantly lower. No differences were observed for maternal nausea, vomiting, pruritus, and psychomimetic effects. Only few data were found for neonatal outcomes. CONCLUSIONS: We conclude that ketamine enhances post-operative analgesia after caesarean section under spinal anaesthesia. There is a paucity of data for several maternal adverse effects as well as for neonatal well-being. Further studies are needed for general anaesthesia.

Prophylactic tranexamic acid in parturients at low risk for post-partum haemorrhage: systematic review and meta-analysis.

Tranexamic acid is effective in reducing blood loss during various types of surgery and after trauma. No compelling evidence has yet been presented for post-partum haemorrhage. A systematic literature search of relevant databases was performed to identify trials that assessed blood loss and transfusion incidence after tranexamic acid administration for post-partum haemorrhage. The random effects model was used for meta-analysis. Risk ratios (RRs) and weighted mean differences (WMDs) were calculated with 95% confidence intervals (CIs). Seven trials with a low risk of bias comparing tranexamic acid vs. placebo with a total of 1760 parturients were included in our systematic review and meta-analysis. Blood loss was significantly lower after tranexamic acid use (WMD -140.29 ml, 95% CI -189.64 to -90.93 ml; P<0.00001). Tranexamic acid reduced the risk for blood transfusions (RR 0.34, 95% CI 0.20-0.60, P=0.0001). The incidence of transfusions in the placebo group varied between 1.4% and 33%. When omitting the two trials with the highest incidence of transfusions, the RR was no longer significant. Additional uterotonics were necessary in the placebo groups; gastrointestinal adverse events were more common after tranexamic acid use. Only four cases of thrombosis were found, two each in the tranexamic acid and control groups. Tranexamic acid effectively reduced post-partum blood loss; the effect on the incidence of blood transfusions requires further studies. Only few trials observed adverse events including thromboembolic complications and seizures.

Meta-analysis of the success of block following combined spinal-epidural vs epidural analgesia during labour.

Observational studies suggest that combined spinal-epidural analgesia (CSE) is associated with more reliable positioning, lower epidural catheter replacement rates, and a lower incidence of unilateral block compared with epidural analgesia. However, evidence from high-quality trials still needs to be assessed systematically. We performed a systematic review that included 10 randomised controlled trials comparing CSE and epidural analgesia in 1722 labouring women in labour. The relative risk of unilateral block was significantly reduced after CSE vs epidural analgesia (0.48, 95% CI 0.24-0.97), but significant between-study heterogeneity was present (I(2) = 69%, p = 0.01). No differences were found for rates of epidural catheter replacement, epidural top-up, and epidural vein cannulation. On the basis of current best evidence, a consistent benefit of CSE over epidural analgesia cannot be demonstrated for the outcomes assessed in our review. A large randomised controlled trial with adequate power is required.

Can the incidence of accidental dural puncture in laboring women be reduced? A systematic review and meta-analysis.

BACKGROUND: Accidental dural puncture (ADP) after epidural analgesia (EDA) for labor pain may cause severe postdural puncture headache (PDPH) and may prolong hospital stay. We aimed to identify techniques that reduce the incidence of ADP. METHODS: A systematic literature search was performed. Data on the occurrence of ADP and PDPH were extracted and subjected to meta-analysis. The random effects model was applied. Risk ratios (RR) and 95% confidence intervals (CI) were calculated. RESULTS: We identified 54 articles, 13 non-randomized controlled trials and 41 randomized controlled trials (RCTs), reporting on a total of 98,869 patients. In non-RCTs, the use of liquid for the identification of the epidural space was associated with a reduced risk of ADP compared to the use of air (RR 0.55, 95% CI 0.39 to 0.79, P=0.001). In our analysis of RCTs this comparison did not produce a significant difference. No effect was found for combined spinal-epidural analgesia, maternal position, type of the catheter, needle size, bevel direction, operator experience, or use of ultrasound. CONCLUSION: A reduction of the risk of ADP was found for liquid use for the loss of resistance, but only in lower quality studies. Based on current evidence, we cannot make a recommendation regarding any of the techniques under study. Therefore, clinicians should focus on measures to prevent or treat PDPH once ADP has occurred.

Maternal and foetal effects of remifentanil for general anaesthesia in parturients undergoing caesarean section: a systematic review and meta-analysis.

BACKGROUND: Remifentanil has been suggested for the induction of general anaesthesia for caesarean section. We aimed to define remifentanil effects on maternal stress response as well as neonatal effects. METHODS: Relevant articles were retrieved by a systematic literature search. Randomized, controlled trials comparing remifentanil use before delivery with placebo were selected. Maternal outcome parameters were blood pressure and heart rate; neonatal effects included the need for mask ventilation and intubation, base excess, pH values, Apgar < 7 at 1 and 5 min. The random effects model was used for meta-analysis; risk ratio or weighted mean difference (WMD) and 95% confidence interval (95% CI) were calculated. RESULTS: Five articles including 186 patients were identified. Highest and lowest systolic blood pressure were significantly lower in the remifentanil group (WMD: -29.98, -50.90 to -9.07 mmHg, 95% CI; P = 0.005; and WMD: -12.46, -18.21 to -6.71 mmHg, 95% CI; P < 0.0001), the lowest heart rate was significantly lower after remifentanil treatment (WMD: -8.22, -11.67 to -4.78, 95% CI; P < 0.00001). Base excess was significantly higher in infants of remifentanil-treated mothers (WMD: 1.15, -0.27 to 2.03, 95% CI; P = 0.01); pH was also higher in the remifentanil group, but significance was missed (P = 0.07). No differences were observed for Apgar values or the need of airway assist. CONCLUSION: Remifentanil was found to attenuate the maternal circulatory response to intubation and surgery. Higher base excess and pH suggest a beneficial effect on the neonatal acid-base status. A trial with adequate power is warranted that addresses neonatal side-effects of remifentanil.

Insertion of an intrathecal catheter following accidental dural puncture: a meta-analysis.

BACKGROUND: Inserting an intrathecal catheter after accidental dural puncture in parturients to prevent postdural puncture headache is becoming increasingly popular. We aimed to identify relevant published articles investigating this intervention and subject data to a meta-analysis. METHODS: A systematic literature search was performed, paralleled by a hand search of abstract publications. Studies that reported the dichotomous outcome parameters postdural puncture headache or need for an epidural blood patch were considered eligible. Risk ratios with 95% confidence intervals were calculated. RESULTS: We identified nine reports investigating placement of intrathecal catheters after accidental dural puncture. The risk ratio for an epidural blood patch after intrathecal catheter insertion was 0.64 (95% CI 0.49-0.84, P=0.001). The risk ratio for postdural puncture headache was 0.82 (95% CI 0.67-1.01, P=0.06). DISCUSSION: Inserting an intrathecal catheter significantly reduced the risk for an epidural blood patch; the incidence of postdural puncture headache was reduced but not significantly. Accidental dural puncture is a rare complication and therefore trials on intervention need to include a large number of patients which is time-consuming and costly. Intrathecal catheterisation is a promising approach for the prevention of postdural puncture headache and should be evaluated further. This intervention has additional benefits including a reduced risk of repeat dural puncture, rapid onset of action and use for anaesthesia.

Vasopressors for the management of hypotension after spinal anesthesia for elective caesarean section. Systematic review and cumulative meta-analysis.

BACKGROUND: Phenylephrine use has been recommended over ephedrine for the management of hypotension after spinal anesthesia for elective caesarean section. The evidence for this is rather limited because in previous trials, pH was significantly lower after ephedrine, but absolute values were still within normal range. We pooled the available data to define maternal and neonatal effects of the two vasopressors. METHODS: Literature was identified by a systematic search. Hypotension, hypertension, and bradycardia of the mothers, fetal acidosis defined as a pH < 7.20, and the continuous variables base excess (BE) and arterial pCO(2) of the neonates were recorded. Meta-analysis using the random effects model was performed, and the weighted mean difference (WMD) or risk ratio (RR), and 95% confidence interval (95% CI) were calculated. RESULTS: The criteria for eligibility were fulfilled by 20 trials including 1069 patients. The RR of true fetal acidosis was 5.29 (95%CI 1.62-17.25, ) for ephedrine vs. phenylephrine (P = 0.006). BE values after ephedrine use were significantly lower than after phenylephrine (WMD -1.17; 95% CI -2.01 - -0.33). Umbilical artery pCO(2) did not differ. Mothers treated with ephedrine had a lower risk for bradycardia (RR 0.17; 95%CI 0.07-0.43; P = 0.004). No differences between vasopressors were observed for hypotension and hypertension. CONCLUSIONS: Our analysis could clearly demonstrate a decreased risk of fetal acidosis associated with phenylephrine use. In addition with our findings for BE, this suggests a favorable effect of phenylephrine on fetal outcome parameters. The mechanism of pH depression is not related to pCO(2) .

Definitions of hypotension after spinal anaesthesia for caesarean section: literature search and application to parturients.

BACKGROUND: Spinal anaesthesia for caesarean section may cause hypotension, jeopardizing the foetus and its mother. We aimed to identify the spectrum of definitions of hypotension used in the scientific literature. In a second part, we applied these definitions to a prospective cohort in order to evaluate the effect of different definitions on the incidence of hypotension. METHODS: A systematic literature search in PubMed was performed from 1999 to 2009 with the search terms 'hypotension' and 'caesarean section'. Consecutive parturients undergoing caesarean section under spinal anaesthesia were included in a prospective study. RESULTS: Sixty-three eligible publications (7120 patients) were retrieved, revealing 15 different definitions of hypotension. A decrease below 80% baseline and the combined definition of a blood pressure below 100 mmHg or a decrease below 80% baseline were the two most frequent definitions, found in 25.4% and 20.6% of the papers, respectively. When applying the spectrum of definitions to a prospective cohort, the incidences of hypotension varied between 7.4% and 74.1%. The incidence increased from 26.7% to 38.5% when using a value below 75% of baseline instead of below 70% of baseline. CONCLUSION: There is not one accepted definition of hypotension in the scientific literature. The incidence of hypotension varies depending on the chosen definition. Even minor changes of the definition cause major differences in the frequency of hypotension. This makes it difficult to compare studies on interventions to treat/prevent hypotension and probably hampers progress in this area of research.

Use of human preconditioned phagocytes for extracorporeal immune support: introduction of a concept.

Neutrophils are critical effector cells in humoral and innate immunity and play a vital role in phagocytosis and bacterial killing. If they and/or their specific functions are lacking, then immunoparalysis may occur, and severe diseases like systemic inflammatory response syndrome (SIRS) or sepsis can take a fatal course. In this paper, we discuss the possibility of using preconditioned cells in an extracorporeal biohybrid immune support system. A human promyelocytic cell line was stimulated for different times with all-trans retinoic acid. The resulting cells displayed major signs and functions of mature neutrophilic granulocytes including oxygen radical production, phagocytosis of living and dead Escherichia coli, Staphylococcus aureus, Candida albicans, intracellular killing, and interleukin production. The cells can be expanded to yield a sufficient cell mass, and subsequent prestimulation results in an expression of specific neutrophil functions. Extracorporeal bioreactor experiments seem to be feasible to test the benefit in immunoparalysis-associated diseases like SIRS or sepsis.

Tandem mass spectrometry studies of green tea catechins. Identification of three minor components in the polyphenolic extract of green tea.

Liquid chromatography/electrospray ionization mass and tandem mass spectrometry (MS/MS) techniques were used to identify two minor components and one new compound in the polyphenolic extract of green tea (Camellia sinensis). Identification and structure assignments were based on previously reported sub-structural features in the MS/MS product, precursor and neutral loss scans of reference samples. The structures of two minor components, related to the known green tea components epicatechin gallate (ECG, 5) and epigallocatechin gallate (EGCG, 6), are formed by methylation at the 3"-O-position of the gallic acid moiety. The new compound contained a gallic acid ester group, but had only one phenolic group in either the A- or B-ring, relative to the structure of 5. High-resolution mass measurements supported the empirical formula assigned to the new compounds. An important fragmentation for defining the position of methylation of the ester function involves ionization of the phenolic group at the 4"-position of the gallic acid, followed by elimination of the ester function as a neutral with concomitant formation of the m/z 169 ion. If the 4"-position is blocked by methylation, the formation of m/z 169 incorporating the gallic acid group would be blocked. Thus, the presence of an ion representing the ester group indicates a free 4"-phenol and the absence of this ion would signify the 4"-position as a site of methylation. The operation of this mechanism should be general and useful in assigning the site of methylation of any polyphenolic ester group in natural products. A similar conclusion can be drawn concerning alkylation or esterification of the 4'-position of the catechins, i. e. blocking the 4'-phenol would prevent formation of the m/z 125 ion common to all of the catechin compounds thus far examined. Therefore, mass spectral data are of considerable importance in deducing the sites of alkylation or esterification in the structures of the components of green tea.

Glucolipsin A and B, two new glucokinase activators produced by Streptomyces purpurogeniscleroticus and Nocardia vaccinii.

During the screening of the natural products for their ability to increase the activity of glucokinase by relieving inhibition by long chain fatty acyl CoA esters (FAC), two novel compounds, glucolipsin A (1) and B (2) were isolated from the butanol extracts of Streptomyces purpurogeniscleroticus WC71634 and Nocardia vaccinii WC65712, respectively. The structures of these two compounds were established by spectroscopic methods and chemical degradation. Glucolipsin A (1) and B (2) relieved the inhibition of glucokinase by FAC with RC50 values of 5.4 and 4.6 microM.

Monitoring in vitro experiments using microdialysis sampling on-line with mass spectrometry.

A method has been developed for the real-time analysis of components in in vitro reactions by the on-line combination of microdialysis sampling (MD) with tandem mass spectrometry (MS/MS) and single stage mass spectrometry (MS). Apparatus and parameters associated with the integration have been studied. Analytical figures of merit for the drug gepirone have been determined. The qualitative 'limit of identification' was found to be 100 ng/ml and 200 ng/ml for methods using thermospray and electrospray MS interfaces, respectively. Using this approach, monitoring of in vitro experiments involving drug metabolites, enzymatic reactions, and ligand-protein binding interactions were performed.

Analysis of amino acid enantiomers derived from antitumor antibiotics using chiral capillary electrophoresis.

The chiral separation of enantiomeric forms of derivatized amino acids have been achieved based on a metalchelate chiral capillary electrophoretic method and a cyclodextrin mediated host-guest interaction approach in micellar electrokinetic chromatography (MEKC) mode with laser-induced fluorescence detection. This approach has been applied to the determination of enantiomeric forms of amino acids derived from novel depsipeptide antitumor antibiotics, BMY-45012 and its analogs. Amino acids were analyzed by complete hydrolysis and the hydrolysate was derivatized with either dansyl chloride for UV absorbance detection or fluorescein isothiocyanate for laser based fluorescence detection. The presence of several amino acids, serine and beta-hydroxyl-N-methy-valine in the proposed structure have been confirmed as D-serine and L-beta-hydroxyl-N-methy-valine enantiomeric forms by both chiral capillary electrophoresis (chiral CE) and MEKC approaches. A non-chiral amino acid, sarcosine, was also confirmed. These methodologies provide a quick and sensitive approach for the determination of amino acids racemization of pharmaceutical natural products and have proven to be useful for structural elucidation refinement.

Isolation and structure determination of sulfonoquinovosyl dipalmitoyl glyceride, a P-selectin receptor inhibitor from the alga Dictyochloris fragrans.

Bioassay-guided fractionation of the marine alga Dictyochloris fragrans led to the isolation and identification of sulfonoquinovosyl dipalmitoyl glyceride (1). The structure of 1 was determined by a combination of spectroscopic methods. On the basis of P-selectin inhibition assays (i.e., P-selectin-IgG ELISA, cell binding assay of receptor globulin, and platelet:HL60 adhesion, it was demonstrated that 1 selectively blocks the P-selectin-ligand interaction in vitro and could be considered a lead compound for synthetic modification in order to design more potent inhibitors of cell adhesion processes that play important roles in development of inflammatory-mediated disease states.

Fusaricide, a new cytotoxic N-hydroxypyridone from Fusarium sp.

A new cytotoxic N-hydroxypyridone, fusaricide (1), was isolated from a Fusarium sp. Its structure was solved by X-ray diffraction and spectroscopic analyses.

Harziphilone and fleephilone, two new HIV REV/RRE binding inhibitors produced by Trichoderma harzianum.

During the screening of the natural products for their ability to inhibit the binding of REV (regulation of virion expression) protein to [33P] labeled RRE (REV responsive element) RNA, two novel fungal metabolites, harziphilone and fleephilone, were isolated from the butanol-methanol (1:1) extract of the fermentation broth of Trichoderma harzianum by bioassay guided fractionation. The structures of these two new compounds were established by spectroscopic methods. Harziphilone and fleephilone showed inhibitory activity against the binding of REV-protein to RRE RNA with IC50 values of 2.0 microM and 7.6 microM, respectively. However both compounds did not protect CEM-SS cells from acute HIV infection at concentration levels up to 200 micrograms/ml using an XTT dye reduction assay. In addition, harziphilone demonstrated cytotoxicity at 38 microM against the murine tumor cell line M-109.

Pyrrolosporin A, a new antitumor antibiotic from Micromonospora sp. C39217-R109-7. II. Isolation, physico-chemical properties, spectroscopic study and X-ray analysis.

Pyrrolosporin A (1) is a new macrolide antitumor antibiotic possessing an unusual spiro-alpha-acyltetronic acid moiety. The antibiotic was isolated from the fermentation broth of Micromonospora sp. by vacuum liquid chromatography, crystallization and reversed phase HPLC (C18). The structure was determined by a combination of NMR, MS, IR, UV, X-ray analysis and degradation studies.

Profiling impurities and degradants of butorphanol tartrate using liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry substructural techniques.

A rapid and systemic strategy based on liquid chromatography/mass spectrometry (LC/MS) profiling and liquid chromatography/tandem mass spectrometry (LC/MS/MS) substructural techniques was utilized to elucidate the degradation products of butorphanol, the active ingredient in stadol NS. This strategy integrates, in a single instrumental approach, analytical HPLC, UV detection, full-scan electrospray mass spectrometry, and tandem mass spectrometry to rapidly and accurately elucidate structures of impurities and degradants. In these studies, several low-level degradation products were observed in long-term storage stability samples of bulk butorphanol. The resulting analytical profile includes information on five degradants including molecular structures, chromatographic behavior, molecular weight, UV data, and MS/MS substructural information. The degradation products formed during long-term storage of butorphanol tartrate included oxidative products proposed as 9-hydroxy-and 9-keto-butorphanol, norbutorphanol, a ring-contraction degradant, and delta 1, 10 a-butorphanol. These methodologies are applicable at any stage of the drug product cycle from discovery through to development. This library of butorphanol degradants provides a foundation for future development work regarding product monitoring, as well as a useful diagnostic tool for new degradation products.

Predictive strategy for the rapid structure elucidation of drug degradants.

Structural information on drug degradants and impurities can serve to accelerate the drug discovery and development cycle. Traditional structure elucidation methodologies for obtaining this information are often slow and resource-consuming; therefore, LC/MS profiling and LC/MS/MS substructural analysis methodologies have been developed to rapidly and accurately elucidate structures of impurities and degradants. This work is a further development of methodologies used for the elucidation of degradation products of paclitaxel [K.J. Volk et al., Proc. 9th AAPS Ann. Meeting, 1994, p.29]. In this study cefadroxil was used as a model compound for the evaluation of a predictive strategy for the production and elucidation of impurities and degradants induced by acid, base, and heat, using LC/MS and LC/MS/MS profiling methodology, resulting in an LC/MS degradant database which includes information on molecular structures, chromatographic behavior, molecular weight, UV data, and MS/MS substructural information. Furthermore, libraries such as this can provide a predictive foundation for pre-clinical development work involving drug stability, synthesis, and monitoring.

Ascosteroside, a new antifungal agent from Ascotricha amphitricha. II. Isolation and structure elucidation.

The novel antifungal agent ascosteroside (1) was isolated from cultured broth of Ascotricha amphitricha (ATCC 74237). The structure based on spectroscopic data was determined to be an alpha-linked glycoside of a lanostane-type triterpenoid.