Fentanyl clearance and volume of distribution are increased in patients with major burns

This study examined the pharmacokinetics of fentanyl in burned patients during the hyperdynamic phase. Twenty adults, aged 37 +/- 2 years (mean +/- SE), with 49 +/- 3% total body surface area burn, were studied at 17 +/- 2 days after the injury and compared to demographically matched controls. After a 200-microg IV bolus of fentanyl, blood samples (n = 20) were collected for 4.5 hours. Concentration-time curves were fitted to a 2-compartment model. Burned patients had a higher cardiac index. Median fentanyl clearance (CL, 21.0 vs 29.4 mL/kg/min), central compartment volume (V(1), 0.37 vs 0.61 L/kg), and total volume of distribution (V(area), 3.6 vs 5.8 L/kg) were higher in burned patients. Cardiac index was unrelated to CL. The increased V(1) and V(area) are likely due to large intravenous fluid replacement and tissue edema. Higher CL and larger V(1) and V(area) leading to a lower fentanyl plasma concentration may partially explain the increased opiate requirement previously observed after burn injury.     

Mechanism of suppression of insulin signalling with lignocaine

Lignocaine suppresses insulin-stimulated glucose transport into the cells and insulin-stimulated glycogenesis at doses equivalent to that used in the treatment of muscle pain disorder. We evaluated the direct effect of lignocaine on insulin receptor (IR) kinase activity. After lignocaine (40 mM, approximately equivalent to 1%) or an equal volume (100 microl) saline had been injected into the tibialis anterior muscle of rat, insulin (50 mM g-1 body weight) was administered into the portal vein in vivo. Immunoprecipitation and immunoblotting were used to detect insulin-mediated tyrosine phosphorylation of both IR-beta and insulin receptor substrate (IRS)-1, and insulin-stimulated binding of IRS-1 to p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) in the extracted muscle. In the in vitro study, purified IR from rat liver and/or recombinant IRS-1 protein with adenosine triphosphate were incubated with lignocaine (4 or 40 mM). Lignocaine reduced insulin-stimulated tyrosine phosphorylation of IR-beta to 12.6+/-5.7% (P<0.001), and IRS-1 to 32.1+/-18.8% (P<0.01), and also reduced insulin-stimulated binding of IRS-1 to p85 to 27.4+/-12.7% (P<0.001) relative to control (100%) in muscle in vivo. The in vitro study revealed that lignocaine directly inhibited both basal and insulin-stimulated tyrosine phosphorylation of IR. These results indicate that clinically used doses of lignocaine inhibit insulin signalling in skeletal muscle. The inhibitory effect of lignocaine on tyrosine kinase activity of the IR underlies the suppression of insulin signalling with lignocaine.     

Changes in booking body mass index over a decade: retrospective analysis from a Glasgow Maternity Hospital

Whether booking body mass index (BMI) in the UK is increasing is unknown but is of clinical interest since overweight or obese pregnant women face far greater risks of pregnancy complications including pre-eclampsia and gestational diabetes. We examined booking BMI in 1990 and 2002/2004, of women with singleton pregnancies. Our analyses indicate an increase of 1 U in mean BMI over this period despite lower parity in recent years. When the model was adjusted for maternal age, parity, smoking status and deprivation category the mean BMI was 1.37 U higher in 2002/2004 than in 1990. More striking was the significant increase in the proportion of women who were obese (BMI > or = 30 kg/m2) at booking--more than twofold higher in unadjusted analysis (18.9% vs 9.4%) rising to greater than threefold higher in multivariate analysis. These findings suggest that obesity-related pregnancy complications are likely to increase with implications for both mother and child.     

Nitric oxide is not a mediator of inflammation-induced resistance to atracurium

Resistance to atracurium as a result of increased drug binding to alpha1-acid glycoprotein is associated with increased inducible nitric oxide synthase activity and increased nitric oxide levels in plasma. We investigated if the inhibition of inducible nitric oxide synthase and suppression of nitric oxide can reverse the resistance to atracurium. As a model of alpha1-acid glycoprotein and nitric oxide increase, 84 male Sprague-Dawley rats received an IV injection of either 60 mg/kg Corynebacterium parvum (CP) or saline (control). The 2 groups (CP/Control) were further divided into subgroups, receiving the selective inducible nitric oxide synthase inhibitor, N-Iminolysine, via drinking water at different concentrations. On day 4 post-CP injection, the pharmacodynamics of atracurium were determined. Plasma concentrations of nitric oxide, atracurium, and alpha1-acid glycoprotein were measured and acetylcholine receptor numbers were quantified. In the CP groups, N-Iminolysine suppressed nitric oxide levels in a dose-dependent manner. Resistance to atracurium persisted. alpha1-acid glycoprotein serum levels remained increased in all CP groups with no differences in acetylcholine receptor expression. Our results suggest that the mechanism leading to increased expression of alpha1-acid glycoprotein and consecutive increased protein binding of atracurium is not mediated by inducible nitric oxide synthase induction and nitric oxide expression.     

Follicular dendritic cell sarcoma arising from the hypopharynx

Follicular dendritic cell (FDC) tumours have been described recently as malignant tumours arising from accessory cells of the lymph nodes. They are rare tumours with fewer than 70 cases occurring worldwide. They usually present in cervical or abdominal lymph nodes, with very few occurring extranodally. We present the first case of an FDC tumour to occur in the hypopharynx with simultaneous cervical node metastases. The pathology is discussed and the literature reviewed.     

Systemic inflammation leads to resistance to atracurium without increasing membrane expression of acetylcholine receptors

BACKGROUND: Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha1 -acid glycoprotein in a rat model of systemic inflammation. METHODS: To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of atracurium was determined, followed by an atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using 125I-alpha-bungarotoxin. alpha1 -Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay. RESULTS: The effective dose of atracurium was increased on days 4, 6, and 8. Total atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 micro g/ml) compared with control rats (4.23 +/- 0.82 micro g/ml). The alpha1 -acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6.52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups. CONCLUSION: Resistance to atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha1 -acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.     

The dose response effect of long-acting nondepolarizing neuromuscular blocking agents in children

Cumulative dose-response curves were constructed for pancuronium, metocurine, d-tubocurarine and gallamine in 56 children anaesthetized with thiopentone, N₂O/O₂ and narcotic. The dose response curves of the four relaxants did not deviate significantly from parallelism. The effective dose causing 95 per cent depression of the twitch at 0.1 Hz was: pancuronium 0.08 mg·-kg!, metocurine 0.34 mg·kg^-1, d-tubocurarine 0.6 mg·kg^-1, and gallamine 3.4 mg·kg^-1. Thus, pancuronium is 40 times more potent than gallamine, while metocurine and d-tubocurarine are seven and four times more potent than gallamine. The recovery of twitch height from 5-25 per cent of control for pancuronium (15.6 ± 1.7 min) was significantly faster (p < 0.01) than metocurine (27.3 ± 1.9 min), d-tubocurarine (32.2 ± 4.8 min), or gallamine (30 ± 3.3 min). Compared to studies in adults, the present data indicate that children have a tendency (statistically not significant) to require more relaxant and recover more quickly than adults.