Diazepam for treating tetanus.

BACKGROUND: Clinical management of the muscle spasms and rigidity of tetanus poses a difficult therapeutic problem to physicians everywhere, especially in resource poor countries. There are wide variations in therapeutic regimens commonly used in clinical practice due to uncertainties about effectiveness of conventional drugs. Diazepam compared to other drugs (eg phenobarbitone and chlorpromazine) may have advantages because of combined anticonvulsant, muscle relaxant, sedative and anxiolytic effects. OBJECTIVES: To compare diazepam to other drugs in treating the muscle spasms and rigidity of tetanus in children and adults. SEARCH STRATEGY: We searched the Cochrane Neonatal Group trials register (October 2003), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2003), MEDLINE (1966 to October 2003), EMBASE (1980 to October 2003), LILACS (2003), CINAHL (October 2003), Science Citation Index, African Index Medicus, conference abstracts and reference lists of articles. We contacted researchers, experts and organizations working in the field and used personal communication. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials. DATA COLLECTION AND ANALYSIS: We independently identified eligible trials, assessed trial methodological quality and extracted data. MAIN RESULTS: Two studies met the inclusion criteria. Method of generation of allocation sequence, concealment of allocation and blinding were unclear in both studies. A total of 134 children were allocated to three treatment groups comprising diazepam alone, phenobarbitone and chlorpromazine, or phenobarbitone and chlorpromazine and diazepam.Meta-analysis of in-hospital deaths indicates that children treated with diazepam alone had a better chance of survival than those treated with combination of phenobarbitone and chlorpromazine (Relative Risk for death 0.36; 95% confidence interval 0.15 to 0.86; Risk Difference -0.22; 95% CI -0.38 to -0.06).Giving diazepam alone, or supplementing conventional anticonvulsants (phenobarbitone and chlorpromazine) with diazepam, was reported in one study to be associated with a statistically significantly milder clinical course and shorter duration of hospitalization. REVIEWER'S CONCLUSIONS: Although there is evidence that diazepam alone compared with combination of phenobarbitone and chlorpromazine is more effective in treating tetanus, the small size, methodological limitations and lack of data on drug safety from available trials preclude definite conclusions to support change in current clinical practice. The application of the present evidence should be moderated by local needs and circumstances, pending the availability of more evidence. We recommend a large multicenter, randomized controlled trial which compares diazepam alone with combinations of other drugs (excluding diazepam).

Comparison of Tc99m-DTPA and indium-111 DTPA studies of baclofen pump function.

Division of Nuclear Medicine, Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Baclofen toxicity in an 8-year-old with an intrathecal baclofen pump.

Baclofen delivered by intrathecal pumps (ITB) is increasingly being utilized in the pediatric population, however, resources and education to support problems with these devices are limited. Typical management strategies for systemic baclofen overdose include removal of baclofen from the device reservoir or removal of cerebrospinal fluid from the adjacent device catheter. Appropriate care of these patients requires awareness of the clinical patterns of toxicity and mechanics of the ITB pump delivery system. This report describes the clinical presentation, unfamiliar dilemmas, and the management of a pediatric patient with intrathecal baclofen toxicity, noting problems that may arise in the care of these patients.

Dantrolene--a review of its pharmacology, therapeutic use and new developments.

Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant / relaxants dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.

Protocol for advanced prehospital emergency care of severe head injury

OBJECTIVES: To analyze the frequency of systemic factors leading to secondary brain insults in victims of serious head trauma in a prehospital setting and to evaluate a protocol for the advanced prehospital emergency care by mobile intensive care unit (i.e., the French Samu-Smur system). STUDY DESIGN: Prospective study, over a period of 24 months. PATIENTS AND METHODS: This prospective study involved 60 victims of severe head injuries (with the exception of polytrauma patients). Tracheal intubation was performed on each patient under direct laryngoscopy and after induction of anaesthesia (fentanyl-etomidate-rocuronium). Controlled ventilation and vascular loading (objectives: SpO(2) >or= 97%, PETCO(2) between 30 and 35 mmHg, SAP >or= 90 mmHg) were administered. RESULTS: Hypoxaemia was found to be the most frequent cause of secondary insults (57% of patients with SpO(2) < 97%). In the case involving an accident that occurred 17 km from the hospital (with extremes of 6-65 km), the speed of medical intervention was note-worthy: tracheal intubation was performed 50 min after the accident, and the patient was admitted into a trauma centre 101 min after impact (median). However, faster intervention could be obtained if the transmission of the alert was improved. The conditions under which the tracheal intubation was performed were found to be satisfactory (difficult intubation 1.6%) without deteriorating the haemodynamic status. This is probably related to the use of muscle relaxants / relaxant and the choice of etomidate as the first line hypnotic in the prehospital emergency care.

Cholinesterase unit establishment and issuing of >>Warning Cards<< for carriers of suxamethonium sensitive serum butyrylcholinesterase variants.
Surina B, Nosso D, Siftar Z, Flegar-Mestric Z, Simeon-Rudolf V.
Institute of Clinical Chemistry, Clinical Hospital Merkur, Zagreb, Croatia.
Recognition of butyrylcholinesterase (EC 3.1.1.8) variants in human serum is essential to identify patients who may be susceptible to a prolonged reaction of suxamethonium and mivacurium, short-acting muscle relaxants. Thus they can be given appropriate advice along with their relatives who may be similarly affected. Therefore, Cholinesterase Unit for detection of individuals, carriers of inherited suxamethonium sensitive butyrylcholinesterase variants was established at the Institute for Clinical Chemistry of the Clinical Hospital >>Merkur<<, Zagreb, Croatia. A study was conducted on sera from patients referred to the Unit. Butyrylcholinesterase variants were determined by measuring the enzyme activity and inhibition by specific inhibitors in the sera of 384 patients and of the members of seven families. Cholinesterase Unit issued >>Warning Cards<< to the carriers of inherited serum butyrylcholinesterase variants in order to avoid prolonged apnea that suxamethonium might cause.

Neurosurgical management of abnormal muscle tone in childhood.

No longer are only a limited number of treatments available to help children and their families deal with childhood hypertonia. It is now possible to provide a child with a treatment specific to his or her muscle tone problems and consequently meet the family's functional goals. The prospects can only improve over the next few years, given the level of interest exhibited by pediatric neuro- and orthopedic surgeons supported by pediatricians, pediatric physical and occupational therapists, pediatric neurologists, and pediatric physiatrists.

Can first responders achieve and maintain normocapnia when sequentially ventilating with a bag-valve device and two oxygen-driven resuscitators? A controlled clinical trial in 104 patients.

BACKGROUND AND OBJECTIVE: To evaluate the capability of first responders to achieve and maintain normal ventilation of the lungs of victims employing a bag-valve device and two oxygen-driven resuscitators. METHODS: Prospective, controlled, blinded, single-centre clinical trial using a bag-valve device and one of two FR-300 devices, with 20 cmH2O working pressure, and flows of either 24 or 30 L min(-1). One hundred and four patients were analysed. Induction of anaesthesia followed by ventilation of the lungs with a bag-valve device and an Oxylator in manual and automatic modes performed by a fireman first responder. Each series was repeated for three conditions (anaesthesia; anaesthesia plus muscle relaxation, both with facemask; anaesthesia plus relaxation using an endotracheal tube). RESULTS: Patients age 49 +/- 17 yr; 47% males, 48-132 kg. Normocapnia was achieved and maintained in 66% (bag-valve device), 82% (Oxylator). CONCLUSIONS: The use of an oxygen-driven device improves the ability of first responders to achieve and maintain normocapnia even when distracted. Use of the Oxylators improves performance (P < 0.001) vs. the bag-valve device significantly.

A benefit-risk assessment of baclofen in severe spinal spasticity.

Baclofen is used for treatment of the spasticity of spinal origin that is a common sequela of spinal cord injury and multiple sclerosis; spasticity occurs in about 50% of patients affected by these disorders. In open-label studies of oral baclofen, the drug improved spasticity in 70-87% of patients; additionally, improvement in spasms was reported in 75-96% of patients. In double-blind, crossover, placebo-controlled trials, baclofen was reported to be effective, producing statistically significant improvements in spasticity. Tizanidine ( Zanaflex ) is the antispasticity drug that has been most widely compared with oral baclofen; studies have generally found the two drugs to have equivalent efficacy. However, Tizanidine ( Zanaflex ) has better tolerability, in particular weakness was reported to be occur less frequently with Tizanidine ( Zanaflex ) than with baclofen. The main adverse effects of oral baclofen include: sedation or somnolence, excessive weakness, vertigo and psychological disturbances. The incidence of adverse effects is reported to range from 10% to 75%. The majority of adverse effects are not severe; most are dose related, transient and/or reversible. The main risks of oral baclofen administration are related to withdrawal: seizures, psychic symptoms and hyperthermia can occur. These symptoms improve after the reintroduction of baclofen, usually without sequelae. When not related to withdrawal; these symptoms mainly present in patients with brain damage and in the elderly. The limited data on baclofen toxicity in patients with renal disease suggest that administration of the drug in these persons may carry an unnecessarily high risk. Intrathecal baclofen is indicated for use in patients with spasticity of spinal origin unresponsive to treatment with maximum doses of oral baclofen, Tizanidine ( Zanaflex ) and/or dantrolene. The benefits of continuous intrathecal baclofen infusion have been demonstrated: >80% and >65% of patients have improvement in tone and spasms, respectively. The main risks of intrathecal baclofen infusion are symptoms related to overdose or withdrawal; the latter is more important because of the associated severe effects on clinical status and the possibility of death, but it is responsive to rapid treatment. Overdose primarily arises from drug test doses or human error during refill and programming of the pump, and withdrawal most commonly occurs as a result of a problem with the delivery system. Since the adverse consequences do not exceed the benefits of oral and intrathecal baclofen for patients with spinal spasticity, the benefit/risk assessment is favourable.

Involvement of transient receptor potential-like channels in responses to mGluR-I activation in midbrain dopamine neurons.

We investigated the involvement of store-operated channels (SOCs) and transient receptor potential (TRP) channels in the response to activation of the group I metabotropic glutamate receptor subtype 1 (mGluR1) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG, puff application) in dopamine neurons in rat brain slices. The mGluR1-induced conductance reversed polarity close to 0 mV and at more positive potentials when extracellular potassium concentrations were increased, indicating the involvement of a cationic channel. DHPG currents but not intracellular calcium responses were reduced by low extracellular sodium concentrations but were not affected by sodium channel blockers, tetrodotoxin and saxitoxin or by inhibition of the h-current with cesium. Abolition of calcium responses with intracellular BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; 10 mm) did not affect current responses, indicating they were not calcium activated. Extracellular application of non-selective SOCs and TRP channel blockers 2-aminoethoxydiphenylborane (2-APB), SKF96365, ruthenium red and flufenamic acid (but not gadolinium) reduced DHPG current and calcium responses. Intracellular application of ruthenium red and 2-APB did not affect DHPG currents, indicating that IP3 and ryanodine receptors did not mediate their actions. Single-cell PCR revealed the presence of TRPC1 and 5 mRNA in most dopamine neurons and subtypes 3, 4 and 6 in some. Store depletion evoked calcium entry indicative of SOCs, providing the first functional observation of such channels in native central neurons. Store depletion with either cyclopiazonic acid or ryanodine abolished calcium but not current responses to DHPG. The electrophysiological and pharmacological properties of the mGluR1-induced inward current are consistent with the involvement of TRP channels whereas calcium responses are dependent on the function of SOCs in voltage clamp recordings.