Update on the management of neuromuscular block: focus on sugammadex

Steroidal neuromuscular blocking agents (NMBAs), such as rocuronium, are widely used in clinical anesthesia and emergency medicine to facilitate endotracheal intubation and artificial ventilation and to allow surgical access to body cavities. Reversal of neuromuscular blockade is important for the acceleration of patient recovery and prevention of postoperative residual neuromuscular blockade and reduces the incidence of severe morbidity and mortality associated with anesthesia management. Sugammadex is the first selective relaxant binding agent (SRBA) and has been designed to reverse the steroidal neuromuscular blocking drug rocuronium. Encapsulation of the rocuronium molecule by sugammadex results in a rapid decrease in free rocuronium in the plasma and subsequently at the nicotinic receptor at the motor endplate. After encapsulation, rocuronium is not available to bind to the nicotinic receptor in the neuromuscular junction. This promotes the liberation of acetylcholine receptors, and muscle activity reappears. This new concept of reversal of neuromuscular block induced by rocuronium (or vecuronium) led to impressive results in animal and phase 1 and 2 studies. Sugammadex is currently in phase 3 clinical studies and may be commercially available by 2008.     

Incompatibility of contrast agents with intravascular medications. Work in progress

In vitro and in vivo precipitation of iodinated contrast agents when ioxaglate and papaverine are given together has been reported. To verify these reports and to investigate other medications not previously tested, the authors analyzed mixtures of contrast agents and medications in vitro with a light spectrophotometer and observed them for visible precipitates for up to 120 minutes. Previously reported incompatibilities between ionic or low-osmolality contrast media and medications were verified, and several new incompatibilities were discovered. No incompatibilities were found when the drugs tested were mixed with the new nonionic contrast media.     

Evaluation and audit in a paediatric disability service

Parental and professional responses to questionnaires evaluating a paediatric disability service are reported and the viability of auditing structural, process, and outcome aspects of clinical practice are discussed. Expectations of waiting time to first appointment (met for only 52% of consumers) illustrate structural issues. Process issues are reflected in consumer reactions to outreach work (for example, 94% of parents and 84% of professionals found this supportive). Outcome measures such as consumer satisfaction with the service (76% of consumers reported being 'very satisfied' and 20% 'fairly satisfied') suggest that service aims are being met. Good concurrence of service aims with consumer needs is indicated by parental reasons for referral (for example, 75% for diagnostic help, 73% for a better understanding of the disorder, 88% for practical help), referrers' reasons (for example, 55% for a second diagnostic opinion, 45% due to lack of local expertise), and reports from most other professionals involved with the case that a similar service was not provided locally.     

NMDA receptors trigger neurosecretion of 5-HT within dorsal raphé nucleus of the rat in the absence of action potential firing

Activity and calcium-dependent release of neurotransmitters from the somatodendritic compartment is an important signalling mechanism between neurones throughout the brain. NMDA receptors and vesicles filled with neurotransmitters occur in close proximity in many brain areas. It is unknown whether calcium influx through these receptors can trigger the release of somatodendritic vesicles directly, or whether postsynaptic action potential firing is necessary for release of these vesicles. Here we addressed this question by studying local release of serotonin (5-HT) from dorsal raphé nucleus (DRN) neurones. We performed capacitance measurements to monitor the secretion of vesicles in giant soma patches, in response to short depolarizations and action potential waveforms. Amperometric measurements confirmed that secreted vesicles contained 5-HT. Surprisingly, two-photon imaging of DRN neurones in slices revealed that dendritic calcium concentration changes in response to somatic firing were restricted to proximal dendritic areas. This implied that alternative calcium entry pathways may dominate the induction of vesicle secretion from distal dendrites. In line with this, transient NMDA receptor activation, in the absence of action potential firing, was sufficient to induce capacitance changes. By monitoring GABAergic transmission onto DRN 5-HT neurones in slices, we show that endogenous NMDA receptor activation, in the absence of postsynaptic firing, induced release of 5-HT, which in turn increased the frequency of GABAergic inputs through activation of 5-HT₂ receptors. We propose here that calcium influx through NMDA receptors can directly induce postsynaptic 5-HT release from DRN neurones, which in turn may facilitate GABAergic input onto these cells.     

Dopamine modulates exocytosis independent of Ca(2+) entry in melanotropic cells

Dopamine is a known inhibitor of pituitary melanotropic cells. It reduces Ca(2+) influx by hyperpolarizing the cell membrane and by modulating high- and low-voltage-activated (HVA and LVA) Ca(2+) channels. As a result, dopamine reduces the hormonal output of the cell. However, it is unknown how dopamine affects each of the four different HVA Ca(2+) channel types individually. Moreover, it is unknown whether dopamine interacts with exocytosis independent of Ca(2+) channels. Here we show that dopamine differentially modulates the HVA Ca(2+) channels and that it affects the stimulus-secretion coupling through a direct effect on the exocytotic machinery. Sustained L- and P-type Ba(2+) currents are reduced in amplitude and inactivating N- and Q-type currents acquire different activation and inactivation kinetics in the presence of dopamine. The Q-type current shows slow activation, which is a hallmark for direct G-protein modulation. We used membrane capacitance measurements to monitor exocytosis. Surprisingly, we find that the amount of exocytosis per step depolarization is not diminished by dopamine despite the reduction in Ca(2+) current. To test whether dopamine affects the release machinery downstream of Ca(2+) entry, we stimulated exocytosis by dialyzing cells with buffered high-Ca(2+) solutions. Dopamine increased the amount and the rate of exocytosis. In the first 90 s, the rate of secretion was increased two- to threefold, but it was normalized again at 180 s, suggesting that predominantly vesicles that fuse early in the exocytotic phase are modulated by dopamine. Thus while Ca(2+) channels are inhibited by dopamine, the exocytotic machinery downstream of Ca(2+) influx is sensitized. As a result, release is more effectively stimulated by Ca(2+) influx during dopamine inhibition.     

Bilateral simultaneous tubal sextuplets: pregnancy after in-vitro fertilization--embryo transfer following salpingectomy

The presence of a damaged tube has been suggested in recent studies to have a negative effect on in-vitro fertilization (IVF) outcome. Performing bilateral salpingectomy prior to IVF to maximize pregnancy rates may also result in unnecessary surgery. This case is also an example of the occurrence of interstitial pregnancy after salpingectomy. This unusual type of ectopic pregnancy must be kept in mind when evaluating a patient suspected of a possible early abnormal gestation after assisted reproductive technolologies.      

Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB)

Glycogen storage disease due to phosphorylase kinase deficiency occurs in several variants that differ in mode of inheritance and tissue- specificity. This heterogeneity is suspected to be largely due to mutations affecting different subunits and isoforms of phosphorylase kinase. The gene of the ubiquitously expressed beta subunit, PHKB, was a candidate for involvement in autosomally transmitted phosphorylase kinase deficiency of liver and muscle. To identify such mutations, the complete PHKB coding sequence was amplified by RT-PCR of RNA isolated from blood samples of patients and analyzed by direct sequencing of PCR products. The characterization of mutations was complemented by PCR of genomic DNA. In one female and four male patients, we identified five independent nonsense mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one single-base insertion in codon N421, one splice-site mutation affecting exon 31, and a large deletion involving the loss of exon 8. Although these severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, they are associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of approximately 10%.      

Endometrial fluid collection in women with hydrosalpinx after human chorionic gonadotrophin administration: a report of two cases and implications for management

The impact of hydrosalpinx (HSPX) on in-vitro fertilization (IVF) outcome has recently been the subject of intense debate. Most, but not all, studies have reported decreased implantation and pregnancy rates and increased early pregnancy loss in HSPX patients. This has led to prophylactic salpingectomies prior to IVF in HSPX patients despite the lack of any prospective studies to suggest that any improvement will occur. Women with HSPX constitute a heterogeneous population because some conceive easily with IVF while others do not until after surgical correction. HSPX also increases in size with ovarian stimulation, and can cause implantation failure by fluid reflux into the uterine cavity. Careful assessment of the endometrial lining is mandatory in HSPX to rule out fluid reflux from the HSPX. We present two case reports of patients whose HSPX enlarged with ovarian stimulation, causing fluid reflux into the uterine cavity which was only noted after human chorionic gonadotrophin (HCG) administration.