Sufentanil potentiates the inhibitory effect of epinephrine on intestinal motility

OBJECTIVE: The aim of our study was to evaluate the effect of the combination of different catecholamines and sufentanil on peristalsis of the isolated guinea pig small bowel in vitro. DESIGN: In vitro study on excised guinea pig small-bowel segments (8-10 segments per substance tested). SETTING: Laboratory for experimental studies at the University. SUBJECTS: Isolated guinea pig small-bowel segments. INTERVENTIONS: Excised segments of guinea pig small bowel were mounted in a tissue bath (37 degrees C) in Tyrode's solution and bubbled with carbogen (95% O2/5% CO2). The lumina were perfused with Tyrode's solution at 0.5 ml/min. The test drugs (epinephrine, norepinephrine, dobutamine, sufentanil, and a combination of these catecholamines with sufentanil) were added to the tissue bath and peristalsis recorded via changes in the intraluminal pressure. One-way and two-way ANOVA were used for statistical analysis. MEASUREMENTS AND RESULTS: All the tested substances, both individually and in combination, inhibited intestinal peristalsis in a dose-dependent manner. High doses resulted in a complete blockade of peristalsis. Preexposure of the segments to sufentanil at 0.1 nM barely influenced the effects of the catecholamines on peristalsis. However, sufentanil at 0.3 nM enhanced the antiperistaltic activity of epinephrine in a supraadditive manner, whereas the effect on norepinephrine and dobutamine was less pronounced. CONCLUSIONS: Our experimental data suggest that the combination of epinephrine and sufentanil might be the worst choice for the intensive care setting. This is due to its pronounced inhibitory effect on peristalsis in vitro at moderate and higher concentrations.     

Cholinergic neurons mediate intestinal propulsion in the rat

Cholinergic influences on intestinal propulsion were determined in vivo in fasted rats by measuring the movement of a nonabsorbable radioactive marker along the intestine following treatment with cholinergic drugs. The marker was instilled directly into the intestine via a previously implanted cannula. The direct effects of cholinergic drugs on intestinal contractions were determined in vitro using isolated segments of duodenum and jejunum. Neostigmine (0.1 mg/kg) produced a marked increase in intestinal transit that was blocked by atropine pretreatment (1.0 mg/kg) but not hexamethonium pretreatment (20 mg/kg). Atropine pretreatment alone significantly delayed transit while hexamethonium treatment alone did not affect intestinal transit. Neostigmine produced a concentration-dependent (0.3-30 microM) increase in contractions in both duodenal and jejunal segments in vitro. Prior incubation of the tissues with atropine (10(-7) M) blocked the neostigmine-induced contractions while prior incubation with hexamethonium (10(-6) M) did not. Contractions produced by substance P were not affected by atropine or hexamethonium. These data indicate that enhancement of cholinergic neurotransmission by neostigmine treatment increased intestinal propulsion and that this effect was mediated at muscarinic cholinergic receptors. Furthermore, inhibition of ongoing cholinergic transmission by atropine treatment reduced intestinal propulsion. The increase in transit produced by neostigmine may result from a stimulation of intestinal contractions. Cholinergic neurons are important mediators of intestinal propulsion in the rat as in other species.     

Low potential of dobutamine and dopexamine to block intestinal peristalsis as compared with other catecholamines

OBJECTIVE: Catecholamines are frequently used in critically ill patients to restore stable hemodynamics and to improve organ perfusion. One effect of short-term or long-term administration of catecholamines may be inhibition of propulsive motility in the intestine. We therefore analyzed the effect of dopexamine, dobutamine, and dopamine on ileal peristalsis and compared their action with that of epinephrine and norepinephrine, which have long been known to suppress intestinal peristalsis. DESIGN: In vitro study on excised guinea pig ileum segments. SETTING: Laboratory for experimental studies at the University. SUBJECTS: Isolated guinea pig ileum. INTERVENTIONS: Segments of ileum excised from guinea pigs were mounted in a tissue bath in Krebs-Henseleit solution and bubbled with 95% oxygen/5% CO2. Luminal perfusion with the same solution was performed at a rate of 0.35 mL/min. The bath temperature was kept at 36.5 degrees C. Peristalsis was recorded via changes in the intraluminal pressure. The drugs under investigation (dopamine, epinephrine, norepinephrine, dobutamine, and dopexamine) were added to the tissue bath. MEASUREMENTS AND MAIN RESULTS: Low concentrations of each catecholamine, except epinephrine, caused a decrease in the pressure threshold, which reflects a stimulatory effect on peristalsis. Higher catecholamine concentrations caused a concentration-related increase in the threshold, cumulating in a complete block of peristalsis. The rank order of inhibitory potency was epinephrine > norepinephrine > dopamine > dobutamine approximately dopexamine. Dobutamine and dopexamine were about 500-fold less active than epinephrine in suppressing peristalsis. CONCLUSIONS: This study shows that dobutamine and dopexamine have the least potential to block propulsive motility in the intestine, whereas epinephrine demonstrates the most adverse inhibitory effect. Because at low concentrations dobutamine and dopexamine even stimulate peristalsis, these drugs appear to be superior compared with other catecholamines with regard to their direct effects on intestinal motility.     

Pharmacokinetics of long-term sufentanil infusion for sedation in ICU patients

Objective To determine the pharmacokinetics of long-term infusion of sufentanil in ICU patients.Design and setting Open-label study in a surgical intensive care unit.Patients Ten consecutive patients without renal or hepatic failure requiring mechanical ventilation for at least 6 days.Interventions Patients received sufentanil (initial bolus 0.5 µg/kg and continuous infusion rate of 0.5 µg/kg per hour) and midazolam (initial bolus 0.08 mg/kg and continuous infusion 0.05 mg/kg per hour). Sedation was adjusted according to the Ramsay scale (score >3). Blood samples were taken during and up to 72 h after the infusion, and plasma concentrations were measured using a sensitive radioimmunoassay method.Measurements and results Plasma concentration-time profiles of sufentanil and pharmacokinetic parameters such as initial postinfusion half-life (t_1/2), elimination half-life (t_1/2), total clearance (Cl), volume of distribution (Vd), and time required to obtain a 50% decrease in plasma concentration (tcp_0/2). The mean duration of sedation was 12±7 days. The initial half-life t_1/2 was 1.33±1.15 h. The observed prolonged elimination half-life (t_1/2=25.5±9.4 h) was related to the large volume of distribution (Vd=22.6±9.4 l/kg). The mean total clearance was 13.4±7.0 ml/kg per minute. The mean time required to obtain a 50% decrease in plasma concentration was short (tcp_0/2=4.7±3.7 h).Conclusions The pharmacokinetic analysis of sufentanil for ICU sedation revealed increased volume of distribution and elimination half-life. Nevertheless the rapid distribution and elimination processes suggest that the rapid reversibility of sedation with sufentanil is maintained after long duration of infusion. Further studies should be carried out to evaluate the clinical relevance of these results.     

In vitro susceptibility of clinical isolates of Brucella melitensis to fucidic acid

Brucella species are facultative intracellular bacteria, and therefore a limited number of antibiotics are effective against these organisms. The side effects of drug combination schemes, and the incidences of relapses and therapeutic failures, have led to investigations of new drugs to treat brucellosis. The purpose of this study was to test the in vitro susceptibility of 50 Brucella melitensis isolates to fucidic acid, which has not previously been used for the treatment of brucellosis. The minimum inhibitory concentrations (MICs) of fucidic acid to 50 B. melitensis isolates that were obtained from blood and bone marrow cultures of patients with brucellosis were studied by the broth microdilution method. The MIC₅₀ and MIC₉₀ values for the 50 B. melitensis strains susceptibility to fucidic acid were determined to be 0.5 and 2µg/ml, respectively, and the MIC range was 0.125–2.0µg/ml. Further experiments are needed to reassess the activity of fucidic acid against intracellular Brucella spp.     

Neurally mediated nonadrenergic relaxation in cat airways occurs independent of cholinergic mechanisms

Activation of the nonadrenergic noncholinergic (NANC) inhibitory system in cat airways causes coincident release of acetylcholine from vagal nerve terminals. The present study was undertaken to determine if neurally released acetylcholine is involved in initiating or modulating activity in the lung NANC inhibitory system. Electrical field stimulation experiments were performed on isolated segments of cat trachea and bronchi and additional studies were conducted in intact anesthetized, mechanically ventilated cats. In isolated airways, frequency-dependent NANC relaxations of bethanechol contracted tissues were identical to NANC responses of airways contracted with 5-hydroxytryptamine. This result suggested that muscarinic receptor activation did not influence NANC inhibitory system function. In additional studies where agents that inhibited or potentiated the actions of acetylcholine were used, similar results were obtained. Pretreatment of tissues with hexamethonium or atropine did not alter NANC frequency response curves. Contractile responses evoked by field stimulation were potentiated by neostigmine and abolished by hemicholinium treatment; NANC relaxation responses were not significantly affected by either agent. In intact cats, neostigmine pretreatment did not alter the magnitude or duration of vagally mediated NANC bronchodilation. Acetylcholine administered as an aerosol to cats treated with atropine did not mimic the NANC response. These findings suggest that NANC inhibitory system function in cat airways is neither dependent upon nor modulated by neurally released acetylcholine.     

Precipitation of sugammadex with nicardipine and labetalol: A laboratory research

There is a paucity of clinical data about whether sugammadex forms precipitates with other medications. This laboratory experimental study was performed to determine the drugs that produce precipitates with sugammadex. Samples of 1 ml of sugammadex were prepared in transparent cylinders, to which 1 ml of test drugs (rocuronium, neostigmine, glycopyrrolate, atropine, nitroglycerin, dobutamine, dopamine, epinephrine, vasopressin, norepinephrine, phenylephrine, ephedrine, esmolol, nicardipine, and labetalol) was added. The precipitation reaction was observed visually and via light microscope. The pH of each drugs before and after mixing with sugammadex was measured. White crystals were formed when sugammadex was mixed with nicardipine or labetalol. Sugammadex formed precipitate when mixed with nicardipine or labetalol. Sufficient fluid flushing is required between injections of each drug to prevent these reactions.     

Sympathoadrenal contribution to nicotinic and muscarinic modulation of bradykinin-induced plasma extravasation in the knee joint of the rat.

Previous results from this laboratory demonstrated that plasma extravasation produced by intra-articular infusion of bradykinin in the rat is mediated by an action on the sympathetic terminals in the knee joint and that adrenal medullary epinephrine regulates the plasma extravasation provoked by bradykinin. Because the release of epinephrine is under cholinergic control, we have now evaluated the effect of nicotinic and muscarinic cholinergic agonists on bradykinin-induced plasma extravasation in the knee joint of the rat. We report that s.c. administration of nicotine and carbachol attenuated plasma extravasation induced by bradykinin; this attenuation was significantly antagonized by systemic injection of hexamethonium and atropine, respectively. The nicotine and carbachol effects were also significantly attenuated after removal of the adrenal medulla. These results indicate that both nicotine and carbachol can inhibit bradykinin-induced plasma extravasation and that this inhibition is mediated, at least in part, through activation of nicotinic and muscarinic receptors in the adrenal medulla. Finally, local perfusion of the knee joint with hexamethonium did not affect the inhibition of bradykinin-induced plasma extravasation produced by systemic nicotine. Intra-articular perfusion of atropine potentiated the inhibition of bradykinin-induced plasma extravasation by systemic carbachol, indicating that muscarinic receptors in the synovium also contribute to plasma extravasation. The inhibitory action of nicotine on plasma extravasation may contribute, in part, to the reported increased severity of arthritis in individuals who smoke.     

In vitro activities of new ketolide, telithromycin, and eight other macrolide antibiotics against Streptococcus pneumoniae having mefA and ermB genes that mediate macrolide resistance

The comparative in vitro activity of a new ketolide, telithromycin (TEL), and eight other macrolide-lincosamide antibiotics (MLS) against 215 strains, of Streptococcus pneumoniae including penicillin-resistant isolates (PRSP), was determined by the agar dilution method. These strains were isolated from patients with pneumonia, otitis media, and purulent meningitis between 1995 and 1997. Two genes, mefA and ermB, that encode MLS resistance in the strains were identified by polymerase chain reaction (PCR). Of the strains, 30.2% (n = 65) had the mefA gene, 37.7% (n = 81) had the ermB gene, and 1.4% (n = 3) had both resistant genes. The minimum inhibitory concentration (MIC_90s) of TEL and 16-membered ring MLS for strains having the mefA gene were 0.063–0.25µg/ml, which were the same level as those for MLS-susceptible strains. On the other hand, the strains with the mefA gene showed low-level resistance to 14- and 15-membered ring MLS, with MIC_90s ranging from 1 to 4µg/ml. Only the MIC₉₀ of TEL at 0.5µg/ml, for strains having the ermB gene was superior to that of the 14-, 15-, and 16-membered ring MLS (MIC₉₀, 64µg/ml). TEL also showed excellent activity against PRSP having abnormal pbp1a, pbp2x, and pbp2b genes. Most strains having the mefA and ermB genes were serotyped to 3, 6, 14, 19, and 23. These results suggest that TEL may be a useful chemotherapeutic agent for respiratory tract infections caused by S. pneumoniae.     

Effect of Anticholinergic Drugs on the Efficacy of Activated Charcoal

Background: Although it is a commonly held belief that the ingestion of drugs with an anticholinergic action would prolong the duration of time after drug ingestion for effective gastrointestinal decontamination, data are lacking to support this belief. The purpose of this study is to determine whether activated charcoal is more effective in the presence of concurrent anticholinergic activity. Methods: A three‐limbed randomized crossover study in 10 healthy volunteers was completed to determine the ability of a 50 g dose of activated charcoal to reduce the bioavailability of a simulated overdose of acetaminophen (12 × 325 mg tablets) in the presence and absence of a concurrently present anticholinergic drug, atropine (0.01 mg/kg I. M. administered 15 min prior to the acetaminophen ingestion). Results: After the acetaminophen ingestion, median C_max occurred at 1 h for all three exposures but was lower in the atropine‐treated study arm (31 ± 19 mg/L) than in the control or charcoal alone intervention arms (49 ± 13 and 51 ± 16 mg/L, respectively) (P < 0.05). Compared to the control area under the serum concentration vs. time curve, a single dose of activated charcoal 1 h after drug ingestion reduced acetaminophen bioavailability by 20% (95% CI 4–36%) and by 47% (95% CI 35–59%) in the presence of atropine (P < 0.05 atropine plus charcoal vs. charcoal alone). Conclusions: Our data support the belief that activated charcoal is more effective in the presence of anticholinergic activity. Additional study is required to determine whether in patients with anticholinergic drug overdose, activated charcoal is effective at times beyond the recommendation for overdoses of drugs without this pharmacodynamic effect.     

In vitro activity of daptomycin against clinical isolates ofGram-positive bacteria

We determined the activity of daptomycin, a recently FDA-approved antimicrobial agent, against clinical isolates of Gram-positive bacteria, including viridans group streptococci (16 Streptococcus mitis species group, 12 S. mutans species group, 9 S. anginosus species group, 8 S. sanguinis species group, 5 S. salivarius species group) from patients with infective endocarditis, 32 methicillin-resistant Staphylococcus aureus, 32 high-level penicillin-resistant Streptococcus pneumoniae, 38 vancomycin-resistant enterococci (including 1 linezolid-resistant isolate), and thefollowing unusual Gram-positive bacteria: 3 Listeria monocytogenes, 4 Erysipelothrix rhusiopathiae, 9 Corynebacterium species, 10 Abiotrophia/Granulicatella species, 2 Rothia (Stomatococcus) mucilaginosus, and 4 Gemella morbillorum. Daptomycin minimum inhibitory concentration (MIC)₉₀ values for the viridans group streptococci, methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, and Enterococcus species were 0.5, 0.5, ≤0.125, and 4 µg/ml, respectively. The daptomycin MIC range for the unusual Gram-postitive bacteria was ≤0.125–2 µg/ml. We conclude that daptomycin has in vitro activity against viridans group streptococci associated with endocarditis as well as against several types of unusual Gram-positive bacteria that can cause endocarditis.Presented in part at the 13^th European Congress of Clinical Microbiology and Infectious Diseases, Glasgow, 2003 and at the 44^th ICAAC, Washington, DC, 2004     

Streptococcus sanguinis‐induced cytokine release from platelets

Summary. Background: There is increasing evidence that both chronic and acute infections play a role in the development and progression of atherothrombotic disorders. One potential mechanism is the direct activation of platelets by bacteria. A wide range of bacterial species activate platelets through heterogeneous mechanisms. The oral micro‐organism S. sanguinis stimulates platelet aggregation in vitro in a strain‐dependent manner, although there are no reports of associated cytokine production. Objective: The aim of the present study was to determine whether platelet activation by S. sanguinis involved the release of pro‐inflammatory and immune modulating factors, and whether activation was enhanced by epinephrine. Methods and results: Four strains of S. sanguinis and one of S. gordonii stimulated the release of RANTES, PF4, sCD40L and PDGF‐AB, whereas only one S. sanguinis strain caused the release of sCD62p. Epinephrine enhanced S. sanguinis‐induced platelet aggregation and phosphorylation of phospholipase Cγ2 and Erk, but inhibited RANTES, PF4, sCD40L and PDGF‐AB release. Wortmannin inhibited S. sanguinis‐induced aggregation and release; however, only aggregation was partially reversed by epinephrine. Conclusions: The present study demonstrates that platelets respond to S. sanguinis with both prothrombotic and pro‐inflammatory/immune‐modulating responses. Epinephrine, potentially released in response to infection and/or stress, can significantly enhance the prothrombotic response, thereby providing a putative link between bacteraemia and acute coronary events during stress. In contrast, epinephrine inhibited the pro‐inflammatory/immune‐modulating response by an undetermined mechanism.     

Between observer variation is not eliminated by standardised analysis of dobutamine-atropine stress echocardiography

Aims: The conventional analysis of dobutamine–atropine stress echocardiography (DASE) is poorly defined and subject to considerable variation. The aim of this study was to investigate the reproducibility of strictly standardised qualitative analysis in DASE. Methods and results: Strict criteria for standardised DASE interpretation were defined through logistic regression analysis on categorical parameters obtained from 20 patients with coronary artery disease (CAD) and 20 healthy controls subjected to DASE. Three expert echocardiographers analysed DASE recordings from 100 consecutive patients referred for coronary angiography. Specificity for CAD and for predicting significant stenosis of a major coronary artery was 94% (95% CI: 83–100%) and 79% (95% CI: 63–96%), whereas sensitivity was 49% in both cases (95% CI: 38–60% and 37–61%). Within and between observer reproducibility was moderate to fair ( = 0.56 and 0.38; 95% CI: 0.40–0.72 and 0.24–0.52). In patients without prior myocardial infarction and in echogenic patients within observer reproducibility was good ( = 0.72 and 0.74; 95% CI: 0.52–0.92 and 0.56–0.92). Conclusions: Observer variation was not eliminated in standardised qualitative DASE interpretation based on criteria that predicted the presence of CAD with a high specificity and reproducibility was good only in certain subgroups of patients.     

Relationship of thyroid function to post-traumatic S-100b serum levels in survivors of severe head injury: preliminary results

Objective To assess thyroid function abnormalities in survivors of severe head trauma and to examine their relationship with indices of brain injury severity.Design Prospective study.Setting General intensive care unit (ICU) in a university hospital.Patients and participants Twenty-two (21 men) head-injured patients, with a median age of 25.5 years at the time of injury, were investigated. Severity of brain trauma was assessed by Glasgow Coma Scale (GCS) score, Marshall Computerized Tomographic Classification, intracranial pressure levels and serum S-100b concentrations measured over a 6-day period.Interventions Thyroid function testing was performed 1 year after ICU discharge and included the measurement of free thyroxine, triiodothyronine and thyrotropin.Measurements and results On admission to the ICU, GCS ranged from 3 to 8. Peak S-100b was 1.49 µg/l (range: 0.37–5.26 µg/l). Median triiodothyronine and thyrotropin were 123 ng/dl and 1.60 IU/ml, respectively. Free thyroxine was 1.08±0.22 ng/dl (range: 0.7–1.5 ng/dl). Overall, 7 of the 22 patients (32%) had thyroid dysfunction. Four patients had central hypothyroidism and three patients had subclinical hypothyroidism. Peak S-100b correlated negatively with free thyroxine (r=–0.47, p=0.02). There were no correlations between other brain injury severity indices and thyroid hormone levels.Conclusions A significant subset of brain injury patients presents with changes in thyroid function 1 year after ICU discharge; these depend upon biochemical serum markers of head trauma severity.     

Macrolide-resistant genes of <Emphasis Type="Italic">Streptococcus pyogenes</Emphasis> isolated from the upper respiratory tract by polymerase chain reaction

The growing number of macrolide-resistant strains of Streptococcus pyogenes is an increasing problem worldwide. This study evaluated 300 clinical isolates obtained from the upper respiratory tract. Minimal inhibitory concentrations (MICs) of erythromycin (EM), azithromycin (AZM), and clindamycin (CLDM), serotypes, and macrolide resistance genes of mefA, ermB, and ermTR were determined. The genetic relationship of EM-resistant and susceptible strains were also analyzed by pulsed-field gel electrophoresis (PFGE). Twenty-nine (9.7%) EM-resistant S. pyogenes were identified. Of the 29 strains showing resistance to EM, 22 isolates (7.3%, MIC 3.13–12.5µg/ml) expressed the mefA gene. The predominant serotypes among the mefA-positive isolates were T12, emm9 or T25, emm75-1. The two isolates (0.1%) that possessed the ermB gene were highly resistant to EM (MIC 100µg/ml). The remaining five strains (1.6%) possessed the ermTR gene (MIC 3.13–100µg/ml). Restriction fragment polymorphism analyzed by pulsed-field gel electrophoresis (PFGE) by SmaI and ApaI digestions showed several clones among the mefA-positive S. pyogenes. Our findings suggest that the mefA gene is the predominant mechanism for macrolide resistance and that this gene is horizontally transmitted among M phenotype strains of S. pyogenes. Consequently, macrolides would not be the first drug of choice for treatment of tonsillitis and other S. pyogenes-related diseases. Physicians and researchers need to take into consideration the macrolide resistance of some strains of S. pyogenes.     

Impaired gastric emptying in mechanically ventilated,critically ill patients

Objective To measure gastric emptying in critically ill patients using an acetaminophen absorption model and determine which variables are associated with impaired gastric emptying.Design A prospective, cohort study.Setting A medical/surgical ICU at a tertiary care hospital: Hamilton General Hospital, Hamilton, Ontario.Patients and participants We recruited 72 mechanically ventilated patients expected to remain in the ICU for more than 48h. Our results were compared to those in healthy volunteers.Intervention Within 48 h of admission to the ICU, 1.6 g acetaminophen suspension were administered via a nasogastric tube into the stomach. Blood samples were drawn at=0, 30, 60, 90, and 120 min for measurement of plasma acetaminophen levels determined by the enzymatic degradation method.Measurements and results Maximal concentration of acetaminophen was 94.1 (75.3) mol/l compared to 208.4 (33.1) mol/l in a control population (p<0.0001). The time to reach the maximal concentration was 105 min (60–180) compared to 30 min (15–90) in controls (p<0.0001). The area under the time-acetaminophen concentration curvet=120 was 9301 (7343) mol/min per 1 compared to 11644 (1336) mol/min per 1 in the controls (p=0.28). The variables associated with delayed gastric emptying were age, sex and use of opioids for analgesia and sedation.Conclusions Gastric emptying is delayed in critically ill patients. The important consequences of this phenomenon include intolerance to enteral nutrition and gastric colonization. Strategies to minimize the use of narcotics may improve gastric emptying. Studies to examine the effect of gastrointestinal prokinetic agents on gastric emptying are needed.     

Different susceptibilities of <Emphasis Type="Italic">Staphylococcus</Emphasis> and Gram-negative rods to epigallocatechin gallate

We examined the antibacterial effects of epigallocatechin gallate (EGCg, the main constituent of tea catechins) against various strains of Staphylococcus and Gram-negative rods. Compared to the minimum inhibitory concentrations (MICs) of EGCg against S. aureus, S. epidermidis, S. hominis, and S. haemolyticus (50–100µg/ml), higher MICs (800µg/ml) were observed against Gram-negative rods, including Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens. And difference was observed between the binding abilities of EGCg with viable S. aureus and with E. coli. The bactericidal activity of EGCg for S. aureus was blocked dose-dependently by purified peptidoglycan but not by lipopolysaccharide or dextran. It was also found that peptone and protein, but not amino acids, in the culture medium greatly affected the antibacterial activity of EGCg. These results indicate that the structure of the bacterial cell wall and the different affinities of EGCg with the various cell wall components are responsible for the different susceptibilities of Staphylococcus and Gram-negative rods to EGCg.     

Nature of the vagal inhibitory innervation to the lower esophageal sphincter.

The purpose of the present study was to investigate the nature of the vagal inhibitory innervation to the lower esophageal sphincter in the anesthetized opossum. Sphincter relaxation with electrical stimulation of the vagus was not antagonized by atropine, propranolol, phentolamine, or by catechloamine depletion with reserpine. A combination of atropine and propranolol was also ineffective, suggesting that the vagal inhibitory influences may be mediated by the noncholinergic, nonadrenergic neurons. To determine whether a synaptic link with nicotinic transmission was present, we investigated the effect of hexamethonium on vagal-stimulated lower esophageal sphincter relaxation. Hexamethonium in doses that completely antagonized the sphincter relaxation in response to a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), did not block the sphincter relaxation in response to vagal stimulation at 10 pulses per second, and optimal frequency of stimulation. A combination of hexamethonium and catecholamine depletion was also ineffective, but hexamethonium plus atropine markedly antagonized sphincter relaxation (P less than 0.001). Moreover, 4-(m-chlorophenyl carbamoyloxy)-2-butyltrimethylammonium chloride (McN-A-343), a muscarinic ganglionic stimulant, also caused relaxation of the lower esophageal sphincter. We suggest from these results that: (a) pthe vagal inhibitory pathway to the sphincter consists of preganglionic fibers which synapse with postganglionic neurons: (b) the synaptic transmission is predominantly cholinergic and utilizes nicotinic as well as muscarinic receptors on the postganglionic neuron, and; (c) postganglionic neurons exert their influence on the sphincter by an unidentified inhibitory transmitter that is neither adrenergic nor cholinergic.     

Efficacy and safety of different doses of granisetron for the prophylaxis of cisplatin-induced emesis

The purpose of this study was to evaluate the efficacy and safety of four different doses of granisetron when administered as a single intravenous (i.v.) dose for prophylaxis of cisplatin-induced emesis in a multicenter, randomized, parallel-group, double-blind investigation. A total of 353 chemotherapy-naive patients were enrolled, stratified according to cisplatin dose (moderate dose: 50–80 mg/m²,n = 169; high dose: 81–120 mg/m²,n = 184) and randomized to one of four granisetron doses: 5, 10, 20, or 40 µ/kg. Control of emesis was evaluated by the percentages of patients attainingcomplete response (no vomiting or retching, and no rescue medication) andmajor response (2 episodes of vomiting or retching, and no rescue medication). Patients were assessed on an inpatient basis for 18–24 h. Safety analyses consisted of adverse events and laboratory parameter changes. Complete response rates over 24 h after chemotherapy were 23%, 48%, 48%, and 44% for granisetron doses of 5, 10, 20, and 40 µg/kg, respectively, in the combined patient population (P=0.011 for linear trend); 29%, 56%, 58%, and 41%, respectively, in the moderate-dose cisplatin stratum (P=0.278 for linear trend); and 18%, 41%, 40%, and 47%, respectively, in the high-dose cisplatin stratum (P = 0.011 for linear trend). Transient headache was the most frequently reported adverse event (19%). There was no evidence of association between increased dose and headache. A single 10-, 20- or 40-µg/kg dose of granisetron is comparably effective in controlling nausea and vomiting associated with moderateor high-dose cisplatin chemotherapy. Granisetron was safe and well tolerated at all doses.     

Sedation management during therapeutic hypothermia for neonatal encephalopathy: Atropine premedication for endotracheal intubation causes a prolonged increase in heart rate

Aim

Heart rate (HR) plays an important role in the assessment of stress during therapeutic hypothermia (TH) for neonatal encephalopathy; we aimed to quantify the effect on HR of endotracheal (ET) intubation and drugs given to facilitate it. If atropine premedication independently increased HR, the main indicator of effective sedation, we hypothesised that increased sedation would have been given.

Methods

Thirty-two, term, neonates recruited into a randomised pilot study comparing TH and TH combined with 50% Xenon inhalation were studied. Indications for ET intubation included: resuscitation at delivery, clinical need and elective re-intubation with a cuffed ET tube if randomised to Xenon. Standard intubation drugs comprised one or more of intravenous morphine, atropine, and suxamethonium. Local cooling guidelines were followed including morphine infusion for sedation.

Results

At postnatal hours five to eight atropine increased HR in a linear regression model (p < 0.01). All other independent variables were excluded. Where more than one dose of atropine was given total morphine sedation given up to 8 h into the treatment period was significantly higher (p < 0.01).

Conclusion

We have shown that atropine premedication for ET intubation significantly increased HR, the main indicator of effective sedation and total morphine dose for sedation during early TH was increased where more than one dose of atropine was given. Bradycardia was not reported in any neonate, even without atropine premedication. We suggest that the use of atropine as part of standard premedication for ET intubation of term neonates undergoing TH should be reconsidered.