Neonatal resuscitation in the delivery room. What role does the anesthetist play?]

Neonatal resuscitation in the delivery room of small obstetric units is problematic because of the lack of on-site personnel with adequate training and experience. In large university hospitals this task is usually fulfilled by neonatologists who are present 24 h/day. However, in medium-sized and small obstetric units neonatal resuscitation is performed by a variety of professionals: paediatricians, obstetricians, anaesthetists, midwives, nurses, and nurse anaesthetists. The degree of responsibility and involvement of the anaesthesia specialist in the resuscitation of the newborn in Switzerland is unknown, and therefore an investigation was conducted. METHOD. After a telephone inquiry at all the hospitals in Switzerland, a total of 175 obstetric units were identified. A questionnaire with items regarding organisation, responsibilities, and the extent of involvement of the anaesthesia department of the particular hospital was sent to each of the appropriate anaesthetists. RESULTS. Of the 175 questionnaires, 163 (93%) were returned; 14 could not be analysed (5 were sent to hospitals where there was in fact no obstetric unit and 9 were sent to anaesthetists who shared responsibilities for one unit). In 1988, 76,505 babies were born in Switzerland; two-thirds of these were delivered in hospitals with an annual birth rate of less than 600 births per year. Of the 149 questionnaires that were eligible for further analysis, 118 (79%) documented participation of the anaesthetic team in the resuscitation of the newborn. However, only 22% of these departments had an official contract with the hospital administration. Ninety-nine per cent of all responders agreed that every anaesthetist should have the knowledge--both theoretical and practical--to resuscitate a newborn infant. However, reservations were expressed on how to acquire and how to maintain this competence. The initial evaluation of the newborn was done by an anaesthetist in 3% (2250/76,505) of all deliveries in Switzerland in 1988; 1.2% (882/76,505) of these babies needed bag-and-mask ventilation and in 0.4% (308/76,505) endotracheal intubation was performed by the anaesthetist. Proceeding on the assumption that 5% of all newborns need some sort of resuscitation immediately after birth, it is estimated that in 1988 approximately one-third of resuscitations were performed by anaesthetists. It is therefore concluded that anaesthetists play an important role in the resuscitation of newborns in Switzerland.     

Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees

Malignant hyperthermia (MH) is a potentially fatal autosomaldominant disorder of skeletal muscle and is triggered in susceptiblepeople by all commonly used inhalational anaesthetics and depolarizingmuscle relaxants. To date, six mutations in the skeletal muscleryanodine receptor gene (RYR1) have been identified in malignanthyperthermia susceptible (MHS) and central core disease (CCD)cases. Using SSCP analysis, we have screened the RYR1 gene inaffected individuals for novel MHS mutations and have identifieda G to A transition mutation which results in the replacementof a conserved Gly at position 2433 with an Arg. The Gly2433Argmutation was present in four of 104 unrelated MHS individualsinvestigated and was not detected in a normal population sample.This mutation is adjacent to the previously identified Arg2434Hismutation reported in a CCD/MH family and indicates that theremay be a second region in the RYR1 gene where MHS/CCD mutationscluster.     

Effect of halothane equilibration kinetics on in vitro muscle contractures for malignant hyperthermia screening

In vitro muscle contracture tests for malignant hyperthermia screening are routinely performed using standardized protocols. In the present study on-line monitoring of halothane concentrations in the gas phase was demonstrated to be an improved test standard. The kinetics of halothane concentration and their effect on in vitro muscle contracture tests were evaluated in two test baths, I and II, which contained 3 and 18 ml Krebs-Ringer solution, respectively. The equilibration kinetics for halothane was significantly faster in bath I (t1/2 = 8.2 s) compared with bath II (t1/2 = 25.6 s). Twenty-one pairs of muscle bundles from 21 potentially malignant hyperthermia susceptible patients were investigated, each test bath receiving one bundle from each pair. The variance of muscle contractures was significantly increased in test bath I compared with test bath II. However, there was no influence on malignant hyperthermia diagnosis, suggesting that, within the ranges of t1/2 = 8.2 s-25.6 s, the test bath volumes need not be standardized.     

Biochemical and behavioural properties of clozapine

The selection and early development of clozapine was based upon its gross behavioural, arousal-inhibiting, sleep-promoting, and caudate spindle-prolonging properties. Compared to classical neuroleptics, clozapine causes only a short-lasting elevation of plasma prolactin levels, elevates both striatal homovanillic acid and dopamine content, is devoid of marked apomorphine-inhibitory or cataleptogenic activity and fails to induce supersensitivity of striatal dopaminergic systems after chronic administration. Clozapine's intrinsic anticholinergic activity, while stronger than that of other neuroleptic agents, does not appear to underlie either its failure to induce tardive dyskinesias or its superior antipsychotic activity. Furthermore, the overlap between clozapine and several classical neuroleptics with regard to alpha-adrenergic-, serotonin- and histamine-blocking activity makes it unlikely that one or more of these properties is the key to its atypical characteristics. More recent findings show that clozapine and classical neuroleptics differ with regard to their indirect effects on nigral GABA-ergic mechanisms implicated in the induction of tardive dyskinesias and, possibly in keeping with this, that clozapine and similar agents exhibit preferential blockade of D-1 dopamine receptors in the whole animal. Such an action of clozapine in man could well explain both its low EPS liability and, in some subjects, its superior antipsychotic activity.     

Similar susceptibility to halothane, caffeine and ryanodine in vitro reflects pharmacogenetic variability of malignant hyperthermia

BACKGROUND AND OBJECTIVE: To analyse the use of standardized application of ryanodine for in vitro muscle contracture testing to define cut-off values separating malignant hyperthermia susceptible from malignant hyperthermia negative subjects. Furthermore, we compared the results of in vitro muscle-contracture tests following the halothane, caffeine and ryanodine challenges. METHODS: In 113 subjects, halothane, caffeine and ryanodine muscle-contracture tests were performed according to the protocol of the European Malignant Hyperthermia Group. RESULTS: Malignant hyperthermia susceptible subjects (n = 77) had significantly shorter onset times in the ryanodine in vitro muscle-contracture test (1 micromol ryanodine) compared with malignant hyperthermia negative subjects (n = 36), median 4.8 vs. 20.1 min, respectively, without any influence of age or gender. The best cut-off value was 10 min (sensitivity 0.78 and specificity 0.94, respectively). Shorter cut-off values had greater specificity, but lower sensitivity. Groups could not be separated without an overlap. In susceptible subjects, we found a correlation between onset time and threshold concentrations for halothane and caffeine (p = 0.47 and 0.52, respectively). In addition, muscle bundles with high susceptibility to halothane and caffeine also showed high susceptibility to ryanodine. CONCLUSIONS: The ryanodine in vitro muscle-contracture test confirmed the malignant hyperthermia status that was determined using the halothane and caffeine in vitro muscle-contracture tests. Due to an overlap between the two groups, discrimination ability was not always perfect and short cut-off values with higher specificity had reduced sensitivity and vice versa. The correlation of contractures following the halothane, caffeine and ryanodine challenges points towards a similar individual pharmacogenetic effect rather than a specific, different pharmacological action between the three agents.     

Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia

Malignant hyperthermia (MH) is a potentially fatal pharmacogeneticdisease triggered by several anaesthetic agents. The in vitromuscle contracture test (IVCT) is the standard test to establishan individual’s risk of susceptibility to MH. Clinicalpractitioners and geneticists of the European MH Group haveagreed on the present guidelines for the detection of MH susceptibilityusing molecular genetic techniques and/or IVCT to predict therisk of MH. Br J Anaesth 2001; 86: 283–7 Footnotes ^* for the European Malignant Hyperthermia Group     

Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501

The compounds CGP7930 [2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] and its close analog CGP13501 were identified as positive modulators of gamma-aminobutyric acid(B) (GABA(B)) receptor function. They potentiate GABA-stimulated guanosine 5'-O-(3-[(35)S]thiotriphosphate) (GTP gamma[(35)S]) binding to membranes from a GABA(B(1b/2)) expressing Chinese hamster ovary (CHO) cell line at low micromolar concentrations and are ineffective in the absence of GABA. The structurally related compounds propofol and malonoben are inactive. Similar effects of CGP7930 are seen in a GTP gamma[(35)S] binding assay using a native GABA(B) receptor preparation (rat brain membranes). Receptor selectivity is demonstrated because no modulation of glutamate-induced GTP gamma[(35)S] binding is seen in a CHO cell line expressing the metabotropic glutamate receptor subtype 2. Dose-response curves with GABA in the presence of different fixed concentrations of CGP7930 reveal an increase of both the potency and maximal efficacy of GABA at the GABA(B(1b/2)) heteromer. Radioligand binding studies show that CGP7930 increases the affinity of agonists but acts at a site different from the agonist binding site. Agonist affinity is not modulated by CGP7930 at homomeric GABA(B(1b)) receptors. In addition to GTP gamma[(35)S] binding, we show that CGP7930 also has modulatory effects in cellular assays such as GABA(B) receptor-mediated activation of inwardly rectifying potassium channels in Xenopus laevis oocytes and Ca(2+) signaling in human embryonic kidney 293 cells. Furthermore, we show that CGP7930 enhances the inhibitory effect of L-baclofen on the oscillatory activity of cultured cortical neurons. This first demonstration of positive allosteric modulation at GABA(B) receptors may represent a novel means of therapeutic interference with the GABA-ergic system.