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1.
Langenbecks Arch Surg ; 396(8): 1173-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21713593

RESUMO

BACKGROUND: Recurrent laryngeal nerve (RLN) monitoring systems should be reliable and safe. Monitoring via electromyographical systems on an endotracheal tube (ETT) is widely spread. The MagStim™ system consists of an adhesive electrode to be fixed on an endotracheal tube. The Xomed™ endotracheal tube provides integrated electrodes. Reliability and side effects had never been compared. As both systems have very different morphological properties, we hypothesized that there might be differences in reliability and the incidence of side effects. METHODS: In a retrospective quality management analysis of 118 patients (MagStim™ electrode, 57 patients; Xomed™ ETT, 61 patients), we compared laryngeal side effects according to the Chilla score and detection rate of the RLN. RESULTS: Both systems had comparable detection rates of the RLN above 95%. Both electrode systems seemed to have similar reliability. Difficulties to detect the nerve were observed in seven patients (four with MagStim, three with Xomed). In the group with the Xomed™ ETT, significantly less mild laryngeal side effects were observed. CONCLUSION: Both MagStim™ and Xomed™ ETT were reliable in detecting the RLN. The Xomed™ ETT, however, might cause milder laryngeal side effects compared with the MagStim™ electrode.


Assuntos
Eletromiografia/instrumentação , Intubação Intratraqueal/instrumentação , Intubação Intratraqueal/métodos , Monitorização Intraoperatória/instrumentação , Nervo Laríngeo Recorrente/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Coortes , Eletromiografia/métodos , Feminino , Humanos , Complicações Intraoperatórias/prevenção & controle , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Paratireoidectomia/efeitos adversos , Paratireoidectomia/métodos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Tireoidectomia/efeitos adversos , Tireoidectomia/métodos , Resultado do Tratamento , Adulto Jovem
2.
Early Hum Dev ; 136: 39-44, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31302387

RESUMO

BACKGROUND: Small-for-gestational-age (SGA) birth bears an enhanced risk of developing hypertension, obesity, insulin resistance and mental health disorders in later life as a consequence of adaptive processes in utero. Only a small number of studies on pain perception in SGA infants exist. These are indicative of a blunted stress response to pain in SGA newborns. AIM: We initiated a pilot study investigating differences in postoperative pain perception between SGA and appropriate-for-gestational-age (AGA) infants. METHODS: Pain and alertness levels of 10 formerly SGA and 14 AGA infants at the age 0.5-2 years were evaluated by the FLACC scale, Steward and Aldrete Scores following hernia repair, reconstructive surgery of hypospadia and orchidopexy. In addition, the postoperative consumption of non-steroidal anti-inflammatory drugs was compared between SGA and AGA. RESULTS: Postoperative pain and alertness levels were not significantly different in SGA and AGA children. We did not observe significant group differences regarding the consumption of non-steroidal anti-inflammatory drugs. CONCLUSION: While previous studies were suggestive of a suppressed stress response to pain in SGA newborns, these findings did not fully translate into an altered response to pain beyond the newborn age. Further studies in a larger cohort seem necessary to verify this finding.


Assuntos
Herniorrafia/efeitos adversos , Recém-Nascido Pequeno para a Idade Gestacional , Orquidopexia/efeitos adversos , Dor/epidemiologia , Procedimentos de Cirurgia Plástica/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Uretra/cirurgia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Dor/etiologia , Projetos Piloto , Complicações Pós-Operatórias/etiologia
3.
Virchows Arch ; 452(1): 97-101, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17952458

RESUMO

Human brucellosis is a worldwide re-emerging zoonosis. However, its histological appearance has only been occasionally described. We report the case of a young girl who had been suffering from a spontaneous fracture of the eighth thoracic vertebra at the age of 7. At the age of 15, X-ray showed a translucence of the seventh and ninth thoracic vertebra, and additionally, a bi-lateral episcleritis was detected. Three months later, she was admitted to the hospital because of perspiration at night and moderate fever. Computer tomography revealed coarsely spotted infiltrates in the lower fields of both lungs. Serology for rheumatic diseases was negative. Thoracoscopical wedge resection was done for histological clarification of pulmonary changes. Microscopically, a granulomatous inflammation with central necrosis was seen. A Ziehl-Neelsen stain did not demonstrate acid-fast bacteria. In spite of negative serology, real-time polymerase chain reaction detected Brucella melitensis deoxyribonucleic acid in the formalin-fixed tissue samples of the lung. Interrogation of the patient revealed visits in different Arabian countries during childhood as a presumable source of infection. In conclusion, granulomatous inflammation negative for Ziehl-Neelsen and Grocott stains presenting together with other localized lesions should lead to specific investigations on brucellosis.


Assuntos
Brucella melitensis/isolamento & purificação , Brucelose/microbiologia , Pneumopatias/microbiologia , Adolescente , Animais , Antibacterianos/uso terapêutico , Brucella melitensis/genética , Brucelose/tratamento farmacológico , Brucelose/patologia , Bovinos , DNA Bacteriano/análise , Diagnóstico Diferencial , Doxiciclina/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Pneumopatias/tratamento farmacológico , Pneumopatias/patologia , Imageamento por Ressonância Magnética , Prednisona/uso terapêutico , Radiografia Torácica , Rifampina/uso terapêutico , Resultado do Tratamento
4.
Crit Care ; 9(3): R200-10, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15987391

RESUMO

INTRODUCTION: This randomised, open-label, multicentre study compared the safety and efficacy of an analgesia-based sedation regime using remifentanil with a conventional hypnotic-based sedation regime in critically ill patients requiring prolonged mechanical ventilation for up to 10 days. METHODS: One hundred and five randomised patients received either a remifentanil-based sedation regime (initial dose 6 to 9 microg kg(-1) h(-1) (0.1 to 0.15 microg kg(-1) min(-1)) titrated to response before the addition of midazolam for further sedation (n = 57), or a midazolam-based sedation regime with fentanyl or morphine added for analgesia (n = 48). Patients were sedated to an optimal Sedation-Agitation Scale (SAS) score of 3 or 4 and a pain intensity (PI) score of 1 or 2. RESULTS: The remifentanil-based sedation regime significantly reduced the duration of mechanical ventilation by more than 2 days (53.5 hours, P = 0.033), and significantly reduced the time from the start of the weaning process to extubation by more than 1 day (26.6 hours, P < 0.001). There was a trend towards shortening the stay in the intensive care unit (ICU) by 1 day. The median time of optimal SAS and PI was the same in both groups. There was a significant difference in the median time to offset of pharmacodynamic effects when discontinuing study medication in patients not extubated at 10 days (remifentanil 0.250 hour, comparator 1.167 hours; P < 0.001). Of the patients treated with remifentanil, 26% did not receive any midazolam during the study. In those patients that did receive midazolam, the use of remifentanil considerably reduced the total dose of midazolam required. Between days 3 and 10 the weighted mean infusion rate of remifentanil remained constant with no evidence of accumulation or of a development of tolerance to remifentanil. There was no difference between the groups in SAS or PI score in the 24 hours after stopping the study medication. Remifentanil was well tolerated. CONCLUSION: Analgesia-based sedation with remifentanil was well tolerated; it reduces the duration of mechanical ventilation and improves the weaning process compared with standard hypnotic-based sedation regimes in ICU patients requiring long-term ventilation for up to 10 days.


Assuntos
Analgésicos Opioides , Sedação Consciente , Fentanila , Midazolam , Piperidinas , Respiração Artificial , Anestésicos Combinados/administração & dosagem , Anestésicos Combinados/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Remifentanil , Fatores de Tempo , Desmame do Respirador
5.
Pain ; 106(1-2): 91-9, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14581115

RESUMO

In contrast to an expected preventive analgesic effect, clinical observations suggest that intraoperatively applied opioids can induce postoperative hyperalgesia. We tested the development of post-infusion hyperalgesia in a newly developed experimental model of electrically induced pain and secondary mechanical hyperalgesia. In a double-blind, placebo controlled, cross-over study, 13 subjects received either saline placebo, remifentanil (0.05 or 0.1 microg/kg/min) or naloxone (0.01 mg/kg). Remifentanil dose-dependently reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level (p<0.01 and p<0.05, respectively). Naloxone infusion similarly resulted in increased pain (anti-analgesia) (p<0.001) and mechanical hyperalgesia (p<0.01). Increased pain ratings following withdrawal of remifentanil significantly correlated to anti-analgesia evoked by the mu-opioid antagonist naloxone (p<0.01) and was of similar magnitude, suggesting inhibition of endogenous opioids as an underlying mechanism. In contrast, hyperalgesia after remifentanil was more pronounced than hyperalgesia after naloxone administration and did not correlate to the observed anti-analgesic effects, suggesting the involvement of additional receptors systems other than the endorphin system.


Assuntos
Analgésicos Opioides/efeitos adversos , Naloxona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Dor/induzido quimicamente , Piperidinas/efeitos adversos , Adulto , Estudos Cross-Over , Derme , Estimulação Elétrica , Humanos , Hiperalgesia/induzido quimicamente , Masculino , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas , Remifentanil , Cloreto de Sódio
6.
Pain ; 108(1-2): 148-53, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15109518

RESUMO

Non-steroidal antiinflammatory drugs (NSAIDs) are known to induce analgesia mainly via inhibition of cyclooxygenase (COX). Although the inhibition of COX in the periphery is commonly accepted as the primary mechanism, experimental and clinical data suggest a potential role for spinal COX-inhibition to produce antinociception and reduce hypersensitivity. We used an experimental model of electrically evoked pain and hyperalgesia in human skin to determine the time course of central analgesic and antihyperalgesic effects of intravenous parecoxib and paracetamol (acetaminophen). Fourteen subjects were enrolled in this randomized, double blind, and placebo controlled cross-over study. In three sessions, separated by 2-week wash-out periods, the subjects received intravenous infusions of 40 mg parecoxib, 1000 mg paracetamol, or placebo. The magnitude of pain and areas of pinprick-hyperalgesia and touch evoked allodynia were repeatedly assessed before, and for 150 min after the infusion. While pain ratings were not affected, parecoxib as well as paracetamol significantly reduced the areas of secondary hyperalgesia to pinprick and touch. In conclusion, our results provide clear experimental evidence for the existence of central antihyperalgesia induced by intravenous infusion of two COX inhibitors, parecoxib and paracetamol. Since the electrical current directly stimulated the axons, peripheral effects of the COX inhibitors on nociceptive nerve endings cannot account for the reduction of hyperalgesia. Thus, besides its well-known effects on inflamed peripheral tissues, inhibition of central COX provides an important mechanism of NSAID-mediated antihyperalgesia in humans.


Assuntos
Acetaminofen/administração & dosagem , Analgésicos não Narcóticos/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Hiperalgesia/tratamento farmacológico , Isoxazóis/administração & dosagem , Adulto , Estudos Cross-Over , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Método Duplo-Cego , Estimulação Elétrica , Humanos , Isoenzimas/antagonistas & inibidores , Proteínas de Membrana , Estimulação Física , Prostaglandina-Endoperóxido Sintases
7.
Crit Care ; 8(1): R21-30, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14975051

RESUMO

INTRODUCTION: This open label, multicentre study was conducted to assess the times to offset of the pharmacodynamic effects and the safety of remifentanil in patients with varying degrees of renal impairment requiring intensive care. METHODS: A total of 40 patients, who were aged 18 years or older and had normal/mildly impaired renal function (estimated creatinine clearance >/= 50 ml/min; n = 10) or moderate/severe renal impairment (estimated creatinine clearance <50 ml/min; n = 30), were entered into the study. Remifentanil was infused for up to 72 hours (initial rate 6-9 microgram/kg per hour), with propofol administered if required, to achieve a target Sedation-Agitation Scale score of 2-4, with no or mild pain. RESULTS: There was no evidence of increased offset time with increased duration of exposure to remifentanil in either group. The time to offset of the effects of remifentanil (at 8, 24, 48 and 72 hours during scheduled down-titrations of the infusion) were more variable and were statistically significantly longer in the moderate/severe group than in the normal/mild group at 24 hours and 72 hours. These observed differences were not clinically significant (the difference in mean offset at 72 hours was only 16.5 min). Propofol consumption was lower with the remifentanil based technique than with hypnotic based sedative techniques. There were no statistically significant differences between the renal function groups in the incidence of adverse events, and no deaths were attributable to remifentanil use. CONCLUSION: Remifentanil was well tolerated, and the offset of pharmacodynamic effects was not prolonged either as a result of renal dysfunction or prolonged infusion up to 72 hours.


Assuntos
Analgésicos Opioides/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Unidades de Terapia Intensiva , Piperidinas/uso terapêutico , Agitação Psicomotora/tratamento farmacológico , Insuficiência Renal/complicações , Adolescente , Adulto , Idoso , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Sedação Consciente , Quimioterapia Combinada , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacologia , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Propofol/administração & dosagem , Propofol/uso terapêutico , Agitação Psicomotora/complicações , Remifentanil , Insuficiência Renal/patologia , Segurança , Índice de Gravidade de Doença , Fatores de Tempo
8.
Anesthesiology ; 106(1): 100-6, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17197851

RESUMO

BACKGROUND: Milrinone used for acute cardiac insufficiency could be of interest during cardiopulmonary resuscitation because of its positive inotropic effects. In this study, the combination of milrinone-vasopressin was compared with epinephrine and vasopressin, as well as with the combination of epinephrine-vasopressin, in reference to hemodynamics. METHODS: Thirty-two pigs underwent ligation of the circumflex coronary artery and induction of ventricular fibrillation lasting for 4 min. Cardiopulmonary resuscitation was performed after randomization to one of four groups: epinephrine (30-microg/kg bolus), vasopressin (0.4-U/kg bolus), epinephrine-vasopressin (15-microg/kg epinephrine bolus, 0.2-U/kg vasopressin bolus), or milrinone-vasopressin (0.4-U/kg vasopressin bolus, 50-microg/kg milrinone bolus over 5 min and a continuous infusion of 0.4 microg.kg.min). The hemodynamic variables were measured before cardiopulmonary resuscitation as well as 4, 8, 15, and 30 min after return of spontaneous circulation. RESULTS: All animals were resuscitated successfully. The animals of the milrinone-vasopressin group displayed significantly (P<0.05) higher cardiac index values (30 min after return of spontaneous circulation: epinephrine, 65.8+/-13.2; vasopressin, 70.7+/-18.3; epinephrine-vasopressin, 69.1+/-36.2; milrinone-vasopressin, 120.7+/-34.8 ml.min.kg) without a decrease in mean arterial pressure or coronary perfusion pressure. CONCLUSIONS: The combination of vasopressin-milrinone as compared with epinephrine during cardiopulmonary resuscitation leads to an improved cardiac index without relevant decrease of mean arterial pressure or coronary perfusion pressure.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Reanimação Cardiopulmonar , Circulação Coronária/efeitos dos fármacos , Milrinona/administração & dosagem , Infarto do Miocárdio/terapia , Inibidores de Fosfodiesterase/administração & dosagem , Vasopressinas/administração & dosagem , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Suínos
9.
Paediatr Anaesth ; 16(3): 333-7, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16490102

RESUMO

Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of the urea cycle. Several specific factors require care during anesthesia in patients with this condition to avoid metabolic decompensation with acute hyperammonemia and encephalopathy. We report monozygous twins with severe neonatal-onset OTCD undergoing general anesthesia twice each, with midazolam, s-ketamine, fentanyl and isoflurane in combination with surgical field infiltration with ropivacaine. Alternative pathway medication and high-caloric diet with 10% glucose solutions were continuously administered during the perioperative course. Both children were extubated within 10 min of the final suture, and their neurological state remained unchanged. Perioperatively, blood ammonia levels remained within the normal range.


Assuntos
Anestesia Geral/métodos , Doenças em Gêmeos , Cuidados Intraoperatórios , Doença da Deficiência de Ornitina Carbomoiltransferase , Anestésicos Combinados , Cateterismo Venoso Central , Cateteres de Demora , Pré-Escolar , Feminino , Fentanila , Humanos , Isoflurano , Ketamina , Midazolam , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/metabolismo , Nutrição Parenteral , Medicação Pré-Anestésica
10.
Paediatr Anaesth ; 15(6): 484-90, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15910349

RESUMO

BACKGROUND: Clinical studies suggest low-dose ketamine may have preemptive effects on postoperative pain in adults. The objective of this study was to determine whether intraoperative low-dose S-ketamine reduces postoperative pain and morphine consumption in children undergoing major urological surgery. MATERIALS: Thirty children scheduled for major urological surgery were included in this prospective study. Anesthesia was performed as total intravenous anesthesia (TIVA) with alfentanil and propofol. Fifteen patients additionally received an intravenous bolus of S-ketamine (0.2 mg.kg-1) followed by a continuous infusion of 5 microg.kg-1.min-1, which was stopped immediately after skin closure (Ketamine Group). Another 15 patients received an infusion of saline (CONTROL group). After transfer to the PACU, pain intensity was evaluated using a numeric rating scale (NRS). First patient controlled analgesia (PCA) request, cumulative morphine consumption and pain intensities within the first 72 h were compared. RESULTS: Morphine consumption was not significantly different during the first 72 h ( CONTROL: 0.4 mg.kg-1, 0.24-0.51 mg.kg-1, Ketamine: 0.32 mg.kg-1, 0.19-0.61 mg.kg-1; median, 25-75% percentile; n.s.). However, differences were found in pain intensity during the first postoperative hour ( CONTROL: 4.0, 3.2-4.6, Ketamine: 2.5, 1.3-3.5; median, 25-75% percentile; P<0.05) and in the time to first PCA use ( CONTROL: 37, 28-46 min, Ketamine: 62, 38-68 min; median, 25-75% percentile; P<0.05). CONCLUSIONS: Intraoperative low-dose S-ketamine had no effect on morphine consumption during the first 72 h after surgery. The differences in pain intensity and time to first PCA use probably reflect additional sedation and antinociceptive effects of S-ketamine rather than a true 'prevention' of pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Anestésicos Dissociativos/uso terapêutico , Ketamina/uso terapêutico , Morfina/uso terapêutico , Dor Pós-Operatória/prevenção & controle , Procedimentos Cirúrgicos Urológicos , Alfentanil/administração & dosagem , Alfentanil/uso terapêutico , Analgésicos Opioides/administração & dosagem , Anestesia Geral , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Período Intraoperatório , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Masculino , Morfina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Tamanho da Amostra
11.
Can J Anaesth ; 52(1): 50-4, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15625256

RESUMO

PURPOSE: Priming is a known technique to accelerate onset of neuromuscular blockade (NMB). Its effect on NMB of the larynx has not been studied yet. METHODS: We compared a priming technique with a bolus application of rocuronium on the onset of NMB at the laryngeal adductor and the adductor pollicis muscles (AP). In 30 female patients, after induction of anesthesia a tube with a surface electrode was placed into the trachea prior to the administration of any neuromuscular blocking agent to monitor electromyography (EMG) of the laryngeal adductor muscles. Neuromuscular monitoring consisted of EMG of the laryngeal adductor muscles and the left AP. Patients were randomized into two groups. After transcutaneous stimulation of the recurrent laryngeal nerve and ulnar nerve, a bolus of rocuronium 0.6 mg x kg(-1) (Bolus group) or a priming dose of rocuronium 0.06 mg x kg(-1) followed by rocuronium 0.54 mg x kg(-1) three minutes later (Priming group) were injected. Lag time, onset 90%, onset time and peak effect of NMB were recorded and compared; a P < 0.05 was considered significant. RESULTS: The onset 90% and onset time measured at the laryngeal adductor muscles (onset: 44.7 +/- 7.4 vs 74.0 +/- 23.8 sec) and at the AP (onset: 105.4 +/- 29.9 vs 139.2 +/- 51.5 sec) were significantly shorter in the Priming group than in the Bolus group. Within groups, the onset times were significantly shorter at the laryngeal muscles in comparison to AP. CONCLUSION: Our results indicate that a priming technique with rocuronium significantly accelerates the onset of NMB at the laryngeal adductor muscles. Our results further support the use of rocuronium as an alternative to succinylcholine for rapid sequence induction.


Assuntos
Androstanóis , Músculos Laríngeos/efeitos dos fármacos , Bloqueio Nervoso/métodos , Fármacos Neuromusculares não Despolarizantes , Adulto , Androstanóis/administração & dosagem , Anestesia , Estimulação Elétrica , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Nervo Laríngeo Recorrente/fisiologia , Rocurônio , Transmissão Sináptica/efeitos dos fármacos , Glândula Tireoide/cirurgia
12.
Curr Opin Anaesthesiol ; 15(2): 187-91, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17019200

RESUMO

Trauma has a significant impact on pediatric morbidity and mortality. Depending on the emergency medical services and health care system, anesthesiologists may be involved in pediatric trauma care at the scene, in the emergency department, in the operating room, or in the intensive care unit. Familiarity with the pathophysiology of pediatric trauma and age-dependent anatomical and physiological features is, therefore, essential to every anesthesiologist. Fast and appropriate interventions with respect to the clinical status and the suspected injuries are the key to successful treatment. Due to the high incidence of head injury, airway management and hemodynamic stabilization are of utmost importance. For preclinical trauma care, however, evidence-based data showing a gold standard for pediatric trauma care are still lacking.

13.
Br J Clin Pharmacol ; 57(2): 153-61, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14748814

RESUMO

AIMS: We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791. METHODS: Nine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum. RESULTS: The concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results. CONCLUSION: Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.


Assuntos
Benzodiazepinas/farmacologia , Eletroencefalografia/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Midazolam/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinas/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Resistência a Medicamentos , Humanos , Hipnóticos e Sedativos/farmacocinética , Masculino , Midazolam/farmacocinética
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