Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work?

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.     

Anesthesia‐induced rhabdomyolysis or malignant hyperthermia: is defining the crisis important?

Anesthesia‐induced rhabdomyolysis and malignant hyperthermia occur in response to the same agents and present with similar clinical features. Distinguishing between these diagnoses can be challenging in a clinical crisis yet making the distinction is critical as prompt appropriate management may be life‐saving, whereas delayed recognition and/or inappropriate management will almost certainly result in death. This focused review examines the differences between these conditions and focuses on the emergency management of anesthesia‐induced rhabdomyolysis.     

International publishing in anaesthesia – how do different countries contribute?

BACKGROUND: The evaluation of the international distribution in biomedicine research is a subject that creates expectations. This study assesses the recent evolution of world-wide distribution of research in the anaesthesiology field and discusses some of the possible factors which could give rise to changes in the interpretation of absolute results. METHODS: A search on Medline was run to obtain the source country of the journal articles (with abstract) from 10 important anaesthesia journals in the 1997-2001 period. The data were analysed and standardized to journal impact factor values of each publication and population size. Annual evolution in the number of publications in the countries with the largest scientific production was analysed. Furthermore, the distribution of articles by country of origin was studied for each journal. RESULTS: The 9724 publications came from 65 countries. In absolute numbers, the USA leads research in anaesthesiology (24.4%). The evaluation of the contribution of the more productive countries revealed a progressive increase in the German contribution (from 5.1% to 9.4%) and a decrease in the American contribution (from 28.6% to 21.8%) over the 5 years analysed. In relative terms, Finland, Sweden and Denmark were the most productive countries per million inhabitants (8.8, 7.2 and 6 publications/year, respectively). CONCLUSION: The geographic distribution of the publications on anaesthesiology must not only be analysed in absolute numbers, where the USA is the most productive. The North-European countries show the largest production/number of inhabitants ratio; whereas the largest percentage increase during the period is found in Germany.     

How to treat refractory arthritis in lupus?

Arthritis in systemic lupus erythematosus (SLE) is episodic and self-limited in most patients. However, in some cases, refractory joint problems occur and may be poorly controlled by NSAIDs and other treatments. Damage to joints and to other organs must be considered when making any decision to prescribe such other treatments. In the context of new and potent biodrugs, we have reviewed and analysed here all Medline published data on arthritis treatment in SLE, as well as the French recommendations (Protocol national de diagnostic et de soins [PNDS] and Club Rhumatismes et Inflammation [CRI]). In SLE patients with isolated, intermittent joint symptoms, short courses of NSAIDs should be used as the first-line treatment. If joint symptoms are more severe or recurrent, a combination of low-dose corticosteroids (≤ 10 mg/day) and antimalarial drugs is recommended. Corticosteroid infiltrations may be useful on occasions, in cases of persistent localised arthritis. If joint symptoms persist, treatment indications depend on the other organs affected. In joint forms that are refractory to treatment or corticodependent and requiring an unacceptable dose of prednisone in a patient with confirmed compliance with treatment, methotrexate should be proposed initially, in combination with antimalarial drugs. In cases of treatment failure or intolerance, mycophenolate mofetil or even azathioprine may be considered as an alternative treatment. As a last resort, after having weighed up the individual benefit-risk ratio, leflunomide, belimumab, rituximab or abatacept may be considered, on a case-by-case basis, and anti-TNF antibodies may be considered in exceptional cases.     

Awareness: a problem in paediatric anaesthesia?

Intraoperative awareness has been reported to occur in 0.8-5.0% of paediatric patients undergoing anaesthesia and, therefore, seems to be more common than in adults (incidence 0.1-0.2%). In adult patients, the consequences of intraoperative awareness are well known and can be severe, in children, however, they have not yet been adequately studied. The causes for intraoperative awareness can be divided into three broad categories: First, no or only a light anaesthetic is given on purpose, second, an insufficient dose of an anaesthetic is given inadvertently, third, there is equipment malfunction or the anaesthesiologist makes an error. Unfortunately, especially in young children, painful interventions are still performed without adequate analgesia, e.g. awake intubation or fracture manipulation under midazolam sedation alone. The key issue is, however, that pharmacokinetics and pharmacodynamics change enormously from the 500 g preterm baby to the adolescent patient. Adequate dosing is much more difficult in paediatric patients compared to standard adult surgical patients. Solid knowledge of the pharmacokinetic and pharmacodynamic characteristics of commonly used drugs in different paediatric age groups, as well as aiming for perfection in daily care will help to reduce the incidence of awareness. Methods for monitoring the depth of hypnosis, e.g. the bispectral index, will be used increasingly, at least in children above 1 year of age. In addition to clinical parameters, they will hopefully help to further reduce the incidence of intraoperative awareness.     

What can you do in 12 weeks as a house officer in anaesthesia at a District General Hospital?

Editor—A house officer in anaesthetics and intensive care?It must be a holiday! Do you feel like a medical student again?Are you allowed to do anything? These are some of the commentsI repeatedly heard throughout my 3 month placement from doctorsin other specialities outside anaesthesia and intensive care(ITU). However, contrary to     

Site of local anaesthesia in transrectal ultrasonography‐guided 12‐core prostate biopsy: does it make a difference?

OBJECTIVE: To prospectively compare the efficacy of bi-basal vs bi-apical periprostatic nerve block (PPNB) during 12-core prostate biopsy guided by transrectal ultrasonography (TRUS), and to evaluate the pain experienced on inserting the probe compared to the biopsy procedure, as PPNB with lignocaine local anaesthesia has been used for over a decade for minimizing pain during prostatic biopsy. PATIENTS AND METHODS: In all, 143 men who were to have a TRUS-guided prostate biopsy were systematically randomized to two groups, to receive PPNB at the apex or base. A 10-cm visual analogue score was used to record the pain experienced during probe insertion, the biopsy and just before to leaving the department . RESULTS: The mean pain score on biopsy in the apical group was similar to that of the basal group (apex 1.9, base 1.6, P = 0.36). Probe introduction produced a significantly higher pain score (probe 2.2, biopsy 1.7, P < 0.001) than at the biopsy. CONCLUSIONS: Patients who experienced greater pain with the introduction of the probe also reported more pain with the biopsy procedure. The site of local anaesthetic before prostatic biopsy showed no significant difference in pain scores. Older men tolerated the procedure better. Analgesia after PPNB at near either the apex or base appears equal, regardless of the site of injection. We suggest that topical perianal anaesthetic agents could significantly reduce not only pain perception, but also improve tolerance.