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Abstract
Dental anxiety is common and frequently poses a barrier to necessary dental treatment. The increasing availability of conscious sedation in dental practice has made treatment much more accessible for anxious patients. At present, benzodiazepines are the most commonly used drugs in sedation practice and provide a pleasant experience for most, but not all, patients. An understanding of the mechanism of action of benzodiazepines should inform our practice and deepen our understanding of why and how sedation may fail.
CPD/Clinical Relevance: As an increasing number of dentists provide sedation for their patients an update on benzodiazepines is timely.
... The main effects of BZDs are sedation, hypnosis, decreased anxiety, anterograde amnesia, central muscle relaxation, and anticonvulsant activity. In addition to their action on the central nervous system, BZDs have a dose-dependent ventilatory depressant effect and also cause a modest reduction in blood pressure and an increase in heart rate as a consequence of a decrease in systemic vascular resistance [11], [12], [13]. ...
... Midazolam, diazepam, and lorazepam are widely used for sedation and, to some extent, also for induction and maintenance of anesthesia. Flumazenil is used as an antidote to sedation induced by BZDs [13], [14]. ...
Background: Pediatric patients undergoing surgery under anesthesia may experience anxiety and distress during the perioperative period, for which benzodiazepines (BZD) can be employed as premedication in these scenarios. For this reason, it is important to highlight the pharmacological profile, use, and possible side effects in the pediatric perioperative population. Methods: Narrative Review using the Pubmed, Scopus and
Embase databases for articles between 2000 and 2021 in English and Spanish using the keywords “Benzodiazepines”, “Pediatric Anesthesiology”, “Pharmacology”, “Adverse Effects”, and “Cerebral Apoptosis”
Results: The principal side effects seen with BZD use in children mainly revolves around neurological manifestations, which include sedation, respiratory depression and prolonged awakening. There is evidence on the effectiveness of BZD in the pediatric population, which is used in a limited number of situations, such as surgical procedures that trigger acute anxiety.
Conclusion: BZD has been widely studied in the literature, however it is important to highlight the possible complications and level of safety in the pediatric population. It has been evidenced that prolonged treatments not only increase the severity of neurodegeneration in the most vulnerable cerebral regions, but also trigger certain connectomic pathologies through wallerian and transneuronal degeneration.
... It is a rapid onset, short-acting, water soluble, highpotency benzodiazepine with no active metabolites. 10 Slow titration to a recognized end point, through the small incremental administration, while assessing the patient's response, avoids oversedation. It is impossible to predict what dose is needed for any individual patient. ...
This article highlights an alternative sedation technique by providing inhalation sedation with nitrous oxide and oxygen alongside intravenous sedation with midazolam as an additional option for patients within special care dentistry. Two case reports are described, as well as a short overview of the available literature on this technique and the indications, advantages and disadvantages. This technique should be considered alongside other sedation techniques. As with all treatment for which sedation is provided, each case needs to be considered on an individual basis and the most appropriate option selected following discussion with the patient.
CPD/Clinical Relevance: Although single sedation techniques provide a good level of sedation to facilitate dental treatment for the majority of patients, it is desirable to have an awareness of alternative sedation options that may be available for patients.
Introdução: Para o atendimento de pacientes ansiosos durante um tratamento odontológico, o uso de benzodiazepínicos constitui-se como um método de controle farmacológico capaz de possibilitar um atendimento confortável e seguro. Através desse método pode-se obter a sedação mínima da consciência, porém efeitos adversos podem ser associados ao emprego desses fármacos. Objetivo: realizar uma revisão de literatura identificando os possíveis efeitos adversos desencadeados por benzodiazepínicos que são usados como método de controle farmacológico da ansiedade na prática odontológica. Material e método: Os artigos selecionados e analisados foram obtidos através das bases de dados Scielo, PubMed e Periódicos CAPES. Resultados/Discussão: Os efeitos adversos ao uso de benzodiazepínicos para sedação mínima possuem baixa ocorrência, e os mais reconhecidos pela literatura são: amnésia anterógrada, alucinações de caráter sexual, sonolência, além de efeitos paradoxais como excitação, agressividade e irritabilidade. Conclusão: É importante que o cirurgião-dentista esteja capacitado para empregar o uso de benzodiazepínicos de forma sensata e responsável, selecionando o fármaco mais adequado para a devida situação.
Objectives
It can be challenging to manage patients who are anxious during dental procedures. There is a lack of evidence regarding the effectiveness and safety of oral sedation in adults. This study evaluated the effectiveness and safety of oral sedation in patients undergoing dental procedures.
Design
Systematic review.
Methods
Randomised clinical trials (RCTs) compared the oral use of benzodiazepines and other medications with a placebo or other oral agents in adult patients. A search of the Cochrane (CENTRAL), MEDLINE (via Ovid), EMBASE (via Ovid) and Cumulative Index to Nursing and Allied Health Literature (via Ovid) databases was conducted, without any restrictions on language or date of publication. The primary outcomes included the adverse effects and anxiety level. The secondary outcomes included sedation, satisfaction with the treatment, heart rate, respiratory rate, blood pressure and oxygen saturation. Reviewers, independently and in pairs, assessed each citation for eligibility, performed the data extraction and assessed the risk of bias. A narrative synthesis of the data was provided.
Results
A number of RCTs (n=327 patients) assessed the use of benzodiazepines (n=9) and herbal medicines (n=3). We found good satisfaction with treatment after the use of midazolam 7.5 mg or clonidine 150 µg and reduced anxiety with alprazolam (0.5 and 0.75 mg). Midazolam 15 mg promoted greater anxiety reduction than Passiflora incarnata L. 260 mg, while Valeriana officinalis 100 mg and Erythrina mulungu 500 mg were more effective than a placebo. More patients reported adverse effects with midazolam 15 mg. Diazepam 15 mg and V. officinalis 100 mg promoted less change in the heart rate and blood pressure than a placebo.
Conclusions
Given the limitations of the findings due to the quality of the included studies and the different comparisons made between interventions, further RCTs are required to confirm the effectiveness and safety of oral sedation in dentistry.
PROSPERO registration number
CRD42017057142.
The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.
Conscious seda(on with midazolam plays an important role in the management of pa(ents requiring oral surgery. Current best prac(ce recommends (tra(on of midazolam according to pa(ent response in order to achieve an op(mum level of seda(on. The aim of this study is to inves(gate whether there are any influencing factors on the dose of midazolam administered to pa(ents undergoing oral surgery procedures with intravenous conscious seda(on. Data collec(on was carried out retrospec(vely for all pa(ents aRending the Oral and entered into MicrosoX Excel for analysis. 52 pa(ents aRended during the study period, with a mean age of 37years (range 17-70years). 67% (35) of pa(ents were female, and 33% (17) male. An equal number of ASA I and II pa(ents was observed in our cohort, with 26 in each ASA category. An average of 8.7pa(ents per month received treatment with conscious seda(on (Fig 1); January was the busiest month (13pa(ents) while December was the quietest (5pa(ents). Six seda(onists were ac(ve during this study period, with the majority (90%) of conscious seda(on being delivered by specialty trainees in oral surgery. Procedures carried out with conscious seda(on included wisdom tooth removal, simple extrac(ons, mul(ple extrac(ons, apicectomy, oro-antral communica(on closure, implant placement, sinus liX surgery, bone graXing, plate removal, archbar removal, biopsy and restora(ve treatment (Fig 2). The most commonly administered dose of midazolam was 7mg, with a median of 6.5mg (range 4-13mg). Five pa(ents (10%) received ≥10mg midazolam (Fig 3). Marked heterogeneity was observed among pa(ents requiring higher levels of midazolam with respect to opera(ve procedure, age, BMI, ASA status and seda(onist involved. The ra(o of males to females in this cohort was 1:4. Midazolam belongs to the benzodiazepine drug group, and has played an important role in medicine for over thirty years. The Intercollegiate Advisory CommiRee for Seda(on in Den(stry recommends intravenous administra(on of midazolam as the gold standard for intravenous conscious seda(on in den(stry 1. The anxioly(c, seda(ve, hypno(c and muscle relaxant effects of midazolam can be explained by its effect on post-synap(c GABA A receptors in the central nervous system; benzodiazepines bind to a specific benzodiazepine-binding site on the post-synap(c membrane, reducing the levels of GABA required to exert an inhibitory effect on the cor(cal and limbic arousal states 2. Midazolam has a rela(vely short elimina(on half-life of 1.5-2.5hours, and is water-soluble, making it a useful choice of drug for use in seda(on techniques. It has long been recognised that op(mum levels of seda(on are achieved by careful pa(ent selec(on, drug (tra(on according to pa(ent response, and ongoing monitoring of vital signs (airway patency, responsiveness, respiratory rate/depth), oxygen satura(on using pulse oximetry and blood pressure 3. What has become apparent is that conscious seda(on with midazolam is not a 'one size fits all' treatment, and there is no pre-defined target dose of midazolam that will suit each pa(ent. Complica(ons that may arise during intravenous midazolam seda(on include: • Respiratory depression • Paradoxical reac(on • Disinhibi(on, hallucina(ons, sexual fantasies • Over-seda(on Other complica(ons may include hiccoughs, under-seda(on, cardiovascular depression and allergy to benzodiazepines 4. One single-unit study demonstrated a complica(on rate of 3% in pa(ents undergoing conscious seda(on with midazolam, with a mean drug dose of 7.6mg in their cohort of pa(ents. Two cases of paradoxical reac(on in female pa(ents receiving (trated midazolam doses of 5mg and 7mg, have also been reported 5. In these cases, treatment was abandoned and flumazenil administered. Interes(ngly in our cohort, the mean dose of administered midazolam was 6.6mg over the study period. No adverse events or complica(ons were recorded. Of those five pa(ents receiving a dose of midazolam ≥10mg, 80% (4) were females. This finding, together with findings of previous reports 5 may well suggest that females are at greater risk of experiencing complica(ons as a result of requiring higher drug doses. However, further research is needed to support this extrapola(on. The majority of pa(ents can be treated comfortably in a clinical sepng with a (trated dose to effect of midazolam. This study shows that it is possible to undertake a wide variety of surgical procedures using intravenous seda(on with midazolam, in many cases sparing pa(ents the added risks of a general anaesthe(c. The findings of this study suggest females are more likely to require higher levels of midazolam to achieve a sa(sfactory level of seda(on. We plan to expand the study sample size for further inves(ga(on.
The ability of differing subunit combinations of -aminobutyric acid type A (GABA) receptors produced from murine α1, β2, and 2L subunits to form functional cell surface receptors was analyzed in both A293 cells and Xenopus oocytes using a combination of molecular, electrophysiological, biochemical, and morphological approaches. The results revealed
that GABA receptor assembly occurred within the endoplasmic reticulum and involved the interaction with the chaperone molecules immunoglobulin
heavy chain binding protein and calnexin. Despite all three subunits possessing the ability to oligomerize with each other,
only α1β2 and α1β22L subunit combinations could produce functional surface expression in a process that was not dependent on N-linked glycosylation. Single subunits and the α12L and β22L combinations were retained within the endoplasmic reticulum. These results suggest that receptor assembly occurs by defined
pathways, which may serve to limit the diversity of GABA receptors that exist on the surface of neurons.
The importance of understanding barriers to dental attendance of adults in the UK was acknowledged in the first Adult Dental Health Survey in 1968 and has been investigated in all subsequent ADH surveys. In 1968, approximately 40% of dentate adults said they attended for a regular check-up; by 2009 this was 61%. Attendance patterns were associated with greater frequency of toothbrushing, use of additional dental hygiene products, lower plaque and calculus levels. Just under three-fifths of adults said they had tried to make an NHS dental appointment in the previous five years. The vast majority (92%) successfully received and attended an appointment, while a further 1% received an appointment but did not attend. The remaining 7% of adults were unable to make an appointment with an NHS dentist. The majority of adults were positive about their last visit to the dentist, with 80% of adults giving no negative feedback about their last dentist visit. Cost and anxiety were important barriers to care. Twenty-six percent of adults said the type of treatment they had opted for in the past had been affected by the cost and 19% said they had delayed dental treatment for the same reason. The 2009 survey data demonstrated a relationship between dental anxiety and dental attendance. Adults with extreme dental anxiety were more likely to attend only when they had trouble with their teeth (22%) than for a regular check-up.
We have developed a method to determine the stoichiometry of subunits within an oligomeric cell surface receptor using fluorescently tagged antibodies to the individual subunits and measuring energy transfer between them. Anti-c-Myc monoclonal antibody (mAb 9-E10) derivatized with a fluorophore (europium cryptate, EuK) was used to individually label c-Myc-tagged alpha1-, beta2-, or gamma2-subunits of the hetero-oligomeric gamma-aminobutyric acid (GABAA) receptor in intact cells. The maximal fluorescent signal derived from the alpha1(c-Myc)beta2gamma2 and the alpha1beta2(c-Myc)gamma2 receptors was twice that obtained with alpha1beta2gamma2(c-Myc), suggesting that there are 2x alpha-, 2x beta-, and 1x gamma-subunits in a receptor monomer. This observation was extended using fluorescence energy transfer. Receptors were half-maximally saturated with EuK-anti-c-Myc mAb, and the remaining alpha1(c-Myc) subunits were labeled with excess anti-c-Myc mAb derivatized with the fluorescence energy acceptor, XL665. On exposure to laser light, energy transfer from EuK to XL665 occurred with alpha1(c-Myc)beta2gamma2 and alpha1beta2(c-Myc)gamma2, but no significant energy transfer was observed with alpha1beta2gamma2(c-Myc) receptors, indicating the absence of a second gamma-subunit in a receptor monomer. We confirm that the GABAA receptor subtype, alpha1beta2gamma2, is composed of two copies each of the alpha- and beta-subunits and one copy of the gamma-subunit (i.e. (alpha1)2(beta2)2(gamma2)1) and conclude that this method would have general applicability to other multisubunit cell surface proteins.
The main actions of benzodiazepines (hypnotic, anxiolytic, anticonvulsant, myorelaxant and amnesic) confer a therapeutic value in a wide range of conditions. Rational use requires consideration of the large differences in potency and elimination rates between different benzodiazepines, as well as the requirements of individual patients.
As hypnotics, benzodiazepines are mainly indicated for transient or short term insomnia, for which prescriptions should if possible be limited to a few days, occasional or intermittent use, or courses not exceeding 2 weeks. Temazepam, loprazolam and lormetazepam, which have a medium duration of action are suitable. Diazepam is also effective in single or intermittent dosage. Potent, short-acting benzodiazepines such as triazolam appear to carry greater risks of adverse effects.
As anxiolytics, benzodiazepines should generally be used in conjunction with other measures (psychological treatments, antidepressants, other drugs) although such measures have a slower onset of action. Indications for benzodiazepines include acute stress reactions, episodic anxiety, fluctuations in generalised anxiety, and as initial treatment for severe panic and agoraphobia. Diazepam is usually the drug of choice, given in single doses, very short (1 to 7 days) or short (2 to 4 weeks) courses, and only rarely for longer term treatment. Alprazolam has been widely used, particularly in the US, but is not recommended in the UK, especially for long term use.
Benzodiazepines also have uses in epilepsy (diazepam, clonazepam, clobazam), anaesthesia (midazolam), some motor disorders and occasionally in acute psychoses.
The major clinical advantages of benzodiazepines are high efficacy, rapid onset of action and low toxicity. Adverse effects include psychomotor impairment, especially in the elderly, and occasionally paradoxical excitement. With long term use, tolerance, dependence and withdrawal effects can become major disadvantages. Unwanted effects can largely be prevented by keeping dosages minimal and courses short (ideally 4 weeks maximum), and by careful patient selection. Long term prescription is occasionally required for certain patients.
GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine alpha 1-subunit gene, that alpha 1-type GABA(A) receptors, which are mainly expressed in cortical areas and thalamus(1), are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter gamma-aminobutyric acid is preserved. alpha 1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA(A) receptors found in the limbic system (alpha 2, alpha 5), in monoaminergic neurons (alpha 3) and in motoneurons (alpha 2, alpha 5)(1). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.
Les réactions paradoxales d’agressivité sous benzodiazépines ont fait l’objet d’une littérature scientifique spécifique depuis 1960. Si peu d’études contrôlées ont pu être réalisées, de nombreux cas cliniques ont été recensés et discutés dans la littérature. Désinhibition, anxiété, comportements auto ou hétéroagressifs et actes médicolégaux ont été observés chez des patients présentant différents facteurs de vulnérabilité, sans qu’une modélisation des processus incriminés ait pu être élaborée. Cependant, le rôle de la personnalité limite et de la personnalité anxieuse, l’influence du contrôle gabaergique sur le système sérotoninergique ainsi que l’impact de l’alcool semblent être autant d’hypothèses expliquant une partie de ces phénomènes paradoxaux.
Conscious sedation for young patients continues to be challenging. Few studies have shown positive results using intravenous midazolam when sedating young patients. This case series reports an investigation of conscious sedation using intravenous midazolam for young patients receiving dental treatment.
To determine acceptance, safety and efficacy of intravenous midazolam for conscious sedation in children and adolescent patients undergoing dental treatment.Patients and methods Patients from seven to 16 years of age, ASA I, II and III, opted to have extractions, minor oral surgery and/or conservative treatment with IV midazolam and local anaesthesia. A pulse oximeter was used to monitor vital signs and the Houpt scale to assess overall behaviour.
A total of 552 patients, 234 boys and 318 girls with mean ages of 13.3 years and 13.5 years respectively, were included. Three hundred and sixty-five patients (66%) claimed to be anxious or very anxious before treatment. The average dose given was 5.7 mg and dosage ranged from 2 to 10 mg. Four hundred and fifty-seven patients (83%) scored 'very good' and 'excellent' for overall behaviour. Side-effects included crying, drowsiness and amnesia.
Intravenous midazolam is accepted by patients and is a safe and effective method of sedation for use in children and adolescents, producing some level of tearfulness.
The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of this drug, which was filled with chance events, and numerous chemical and clinical errors of approach. Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium®. The benzodiazepines became the most widely prescribed drugs worldwide, provided truly effective treatment for "minor forms" (neuroses) of mental disorders for the first time, increased the quality of scientific methodology in clinical research, and enabled the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in 1977 of their high-affinity receptor complex.
This article reviews some of the important aspects of benzodiazepine-induced disinhibitory reactions. Although reactions of this type are relatively rare, they may sometimes manifest themselves in aggressive behavior accompanied by suicidal or homicidal tendencies. It appears that these reactions occur more commonly in younger patients, although the elderly (above 65 years) may also be at risk. Many mechanisms have been postulated, but none truly explain how these reactions arise. The concept that central cholinergic mechanisms may play a role, however, remains attractive and stems primarily from physostigmine's ability to successfully reverse this type of reaction. The potential role of the benzodiazepine antagonists, eg, flumazenil, in reversing disinhibitory reactions is also discussed. Apart from patients who previously exhibited poor impulse control, there are no reliable indicators for recognizing potential candidates for this type of reaction. To minimize the occurrence of disinhibitory reactions, some guidelines, which include the avoidance of certain drug combinations, the use of low doses of benzodiazepines, slow incremental intravenous administration, and good rapport with patients, are presented.
In the transmitter-gated ion channel class of receptors, the members of which are all believed to be heterooligomers, the number and arrangement of the subunits are only known with any certainty for the nicotinic acetylcholine receptor from Torpedo electric fish. That receptor has been shown to possess a pentameric rosette structure, with five homologous subunits (alpha 2, beta gamma delta) arranged to enclose the central ion channel. The data were obtained by electron image analysis of two-dimensional receptor arrays, which form as a consequence of that receptor's exceptionally high abundance in the Torpedo membranes and are therefore not attainable for other receptors. We have applied another direct approach to determine the quaternary structure of native ionotropic GABA receptors. We have purified those receptors from porcine brain cortex and analysed the rotational symmetry of isolated receptors visualized by electron microscopy. The results show the receptor to have a pentameric structure with a central water-filled pore, which can now be said to be characteristic of the entire superfamily.
Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist available for clinical use. It is a specific competitive antagonist at benzodiazepine receptors, which are associated with receptors for gamma-aminobutyric acid, the most important inhibitory neurotransmitter in the central nervous system. Administered orally, it has a low bioavailability and the preferred route is intravenous. Its usual clinical role is to reverse the effects of benzodiazepine sedation; however, administered before, or with, other benzodiazepines, it modifies their effects, the extent of such modification depending on the dose, duration of effect and relative receptor affinity of the agonist. Flumazenil also reverses adverse physiological effects of benzodiazepines. Its indications include reversal of benzodiazepine-induced sedation, termination of benzodiazepine-induced anaesthesia, return of spontaneous respiration and consciousness in intensive care patients and the treatment of paradoxical reactions to benzodiazepines. Other potential indications include its use in hepatic encephalopathy, alcohol intoxication and coma; however, these claims still require substantiation. Following sedation reversed with flumazenil, minimal residual effects of the agonist can sometimes be detected using psychomotor tests and are due to the relatively short half-life of flumazenil, but are of no clinical consequence. There is concern that flumazenil could precipitate an acute withdrawal syndrome following long-term benzodiazepine administration; however, the available evidence suggests otherwise and that it could be useful in the treatment of benzodiazepine tolerance. The existence of flumazenil is important, with implications for future research and the development of minimally invasive therapy and day-case surgery. With increasing pressures on non-anaesthetically trained practitioners to perform sedation, flumazenil has important implications for safety.
Studies of the prevalence of dental anxiety in general population samples have produced estimates which range from a low of 2.6% to a high of 20.4%. It is not clear whether these reflect real differences among populations or whether they are the result of the use of different measures and different cut-off points. We undertook a large scale mail survey of dental anxiety in a random sample of the adult population living in Metropolitan Toronto designed to assess the performance of and agreement between three measures. These were Corah's DAS, the single item used by Milgrom and colleagues in Seattle and the ten-point fear scale used by Gatchel. These measures and their published cut-off points produced prevalence estimates of 10.9%, 23.4% and 8.2% respectively. While there was a significant association between scores on pairs of measures the agreement between them was far from perfect. Kappa values ranged from 0.37 to 0.56, indicating only fair to moderate agreement beyond chance. There was evidence to indicate that the dentally anxious subjects identified by each measure differed according to certain behavioural and other characteristics. The results of the study suggest the need to revisit the issue of measurement in studies of dental anxiety.
Several drugs are apparently effective in treating pathologic anger and aggression. Because many of the studies on aggressive populations allowed the use of concomitant medications, it is unclear whether the efficacy of each drug in a particular population is dependent on the presence of other medications, such as antipsychotic agents. Finally, one needs to be circumspect in inferring efficacy of a particular drug in aggressive patients with neuropsychiatric conditions other than the ones in which some efficacy has been established. Lithium appears to be an effective treatment of aggression among nonepileptic prison inmates, mentally retarded and handicapped patients, and among conduct-disordered children with explosive behavior. Certainly, lithium would be the treatment of choice in bipolar patients with excessive irritability and anger outbursts, and it has been shown to be effective in this population. Anticonvulsant medications are the treatment of choice for patients with outbursts of rage and abnormal EEG findings. The efficacy of these drugs in patients without a seizure disorder, however, remains to be established, with the exception perhaps of valproate and carbamazepine. In fact, dyphenylhydantoin did not appear to be effective in treating aggressive behavior in children with temper tantrums and was found to be effective in only a prison population. There is some evidence for the efficacy of carbamazepine and valproate in treating pathologic aggression in patients with dementia, organic brain syndrome, psychosis, and personality disorders. As Yudofsky et al point out in their review of the literature, although traditional antipsychotic drugs have been used widely to treat aggression, there is little evidence for their effectiveness in treating aggression beyond their sedative effect in agitated patients or their antiaggressive effect among patients whose aggression is related to active psychosis. Antipsychotic agents appear to be effective in treating psychotic aggressive patients, conduct-disordered children, and mentally retarded patients, with only modest effects in the management of pathologic aggression in patients with dementia. Furthermore, at least in one study, these drugs were found to be associated with increased aggressiveness in mentally retarded subjects. On the other hand, atypical antipsychotic agents (i.e., clozapine, risperidone, and olanzapine) may be more effective than traditional antipsychotic drugs in aggressive and violent populations, as they have shown efficacy in patients with dementia, brain injury, mental retardation, and personality disorders. Similarly, benzodiazepines can reduce agitation and irritability in elderly and demented populations, but they also can induce behavioral disinhibition. Therefore, one should be careful in using this class of drugs in patients with pathologic aggression. Beta-blockers appear to be effective in many different neuropsychiatric conditions. These drugs seem effective in reducing violent and assaultive behavior in patients with dementia, brain injury, schizophrenia, mental retardation, and organic brain syndrome. As pointed out by Campbell et al in their review of the literature, however, systematic research is lacking, and little is known about the efficacy and safety of beta-blockers in children and adolescents with pathologic aggression. Although widely used in the management of pathologic aggression, the use of this class of drugs has been limited partially by marked hypotension and bradycardia, which are side effects common at the higher doses. The usefulness of the antihypertensive drug clonidine in the treatment of pathologic aggression has not been assessed adequately, and only marginal benefits were observed with this drug in irritable autistic and conduct disorder children. Psychostimulants seem to be effective in reducing aggressiveness in brain-injured patients as well as in violent adolescents with oppositional or conduct disorders, particu
Paradoxical hyperactivity (PH) is a known complication of sedation in children, especially with barbiturates such as pentobarbital. The accompanying inconsolable irritability and agitation, similar to behaviors reported in children with attention deficit hyperactivity disorder (ADHD), is uncomfortable for the child and anxiety-provoking for parents and health-care workers. Our objective was to describe our experience with oral (PO) and intravenous (IV) caffeine as a treatment for sedation-induced PH.
From January 2000 to April 2003, 19,894 children were sedated in our institution for radiology procedures. Of these, 360 children were diagnosed with PH. A total of 229 children exhibiting symptoms of PH after sedative administration were treated with PO caffeine ( n=88; 43 boys, 45 girls; mean age 4.5 years, mean weight 18.7 kg) or IV caffeine ( n=131; 73 boys, 58 girls; mean age 4.8 years, mean weight 20.1 kg) or both ( n=10; 8 boys, 2 girls; mean age 5.0 years, mean weight 19.9 kg). A positive effect was defined as a decrease in agitation, crying, or hyperactivity within 40 min of caffeine administration. A control group ( n=45) was obtained from those 141 children who experienced post-sedation PH but were not treated with caffeine, and matched for age and sex with samples of children treated with IV caffeine ( n=45) and PO caffeine ( n=45).
Children treated intravenously received the equivalent of 20 mg/kg caffeine citrate (to a maximum of 200 mg). Of those treated with IV caffeine, 82/131 (63%) showed a positive effect, and returned to baseline behavioral status after an average of 33 min (SD=23 min). The untreated control group required a significantly longer time to recover ( P<0.01) than those treated with IV caffeine. Children treated orally received approximately 1.0-2.5 mg/kg caffeine in Mountain Dew (Pepsi-Cola Company), and 36/88 (41%) showed a positive effect and returned to baseline behavioral status after an average of 42 min (SD=27 min). Of the 10 children treated with both PO and IV caffeine, 6 showed a positive effect. There was no significant difference in recovery time between the untreated control group and either the matched orally treated group or the group treated with both IV and PO caffeine. No complications occurred after caffeine administration.
IV caffeine appears to be an effective treatment for PH in children with sedation-induced PH. Further controlled prospective study is needed to determine the optimum dose and route of administration and to compare efficacy with other potential drug classes.
Benzodiazepines frequently are administered to patients to induce sedation. Paradoxical reactions to benzodiazepines, characterized by increased talkativeness, emotional release, excitement, and excessive movement, are relatively uncommon and occur in less than 1% of patients. The exact mechanism of paradoxical reactions remains unclear. Most cases are idiosyncratic; however, some evidence suggests that these reactions may occur secondary to a genetic link, history of alcohol abuse, or psychological disturbances. This review evaluates the numerous cases of paradoxical reactions to benzodiazepines in adult and pediatric patients that have been reported in the biomedical literature. It also explores the advantages and disadvantages of the various available treatment options.
Paradoxical reactions to benzodiazepines include restlessness, violent behavior, physical assault, act of self-injury and need for restraints. These may occur at variable times after administration. This study was designed to determine the incidence of paradoxical reactions following intravenous midazolam premedication in pediatric patients and to compare the efficacy of extra doses of midazolam with low-dose intravenous ketamine to rapidly tranquillize them.
A total of 706 ASA I, II children scheduled for elective surgery were given intravenous midazolam premedication. Children who developed a paradoxical reaction were randomly divided into three equal groups to receive: (i) extra midazolam, (ii) ketamine, or (iii) placebo as the test drug for treatment of paradoxical reaction. Ease of rapid tranquillization and need for a rescue tranquillizer (i.e. ketamine; irrespective of patient group) were compared among the three groups.
Twenty-four (3.4%) children developed paradoxical reaction after midazolam premedication. Those who received ketamine as the test drug responded rapidly to ketamine. But the responses of the other two groups to their test drug were poor and the majority of them required ketamine as rescue tranquillizer (six in midazolam, seven in placebo, but no patient in the ketamine group; P < 0.05).
The results of this study demonstrate that ketamine is an effective drug for the treatment of paradoxical reaction following intravenous midazolam premedication. The exact mechanisms of these reactions and how it is aborted by ketamine are not clear.
Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter gamma-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABA(A) receptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to "wire together" so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.