Assuntos
Lesão Pulmonar Induzida por Ventilação Mecânica , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Humanos , Respiração Artificial/métodos , Respiração Artificial/efeitos adversos , Respiradores de Pressão NegativaRESUMO
PURPOSE: Sugammadex is a selective relaxant binding agent designed to encapsulate the aminosteroidal neuromuscular blocking agent rocuronium, thereby reversing its effect. Both sugammadex and the sugammadex-rocuronium complex are eliminated by the kidneys. This study investigated the effect of sugammadex on recovery of rocuronium-induced neuromuscular block in cats with clamped renal pedicles, as a model for acute renal failure. METHODS: Twelve male cats were divided into two groups and anesthetized with medetomidine, ketamine, and alpha-chloralose. The cats were intubated and ventilated with a mixture of oxygen and air. Neuromuscular monitoring was performed by single twitch monitoring. Rocuronium 0.5 mg/kg i.v. was administered. After spontaneous recovery from neuromuscular block, both renal pedicles were ligated. A second dose of rocuronium 0.5 mg/kg i.v. was given. One minute after disappearance of the twitches, in Group 1 placebo (0.9% saline) and in Group 2 sugammadex 5.0 mg/kg i.v. was administered. Onset time, duration of neuromuscular block, and time to recovery to 25, 50, 75, and 90% were determined. RESULTS: After renal pedicle ligation, sugammadex reversed rocuronium-induced neuromuscular block significantly faster than spontaneous recovery. Mean time (SEM) to 90% recovery of the twitch response was 4.7 (0.25) min (Group 2) versus 31.1 (5.0) min (Group 1) (p < 0.0001). No signs of recurrence of neuromuscular block were observed for 90 min after complete twitch restoration. Sugammadex caused no significant cardiovascular effects. CONCLUSION: Sugammadex rapidly and effectively reversed rocuronium-induced neuromuscular block in anesthetized cats, even when both renal pedicles were ligated and renal elimination of the drugs was no longer possible.
Assuntos
Androstanóis/farmacologia , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/farmacologia , Circulação Renal , gama-Ciclodextrinas/farmacologia , Animais , Gatos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Rocurônio , SugammadexRESUMO
BACKGROUND AND OBJECTIVE: 3-Desacetyl-vecuronium is an active metabolite of the neuromuscular blocking agent (NMBA) vecuronium, which might lead to residual paralysis after prolonged administration of vecuronium in critically ill patients with renal failure. This study investigated the ability of sugammadex to reverse 3-desacetyl-vecuronium-induced neuromuscular block (NMB) in the anaesthetised rhesus monkey. METHODS: Experiments were performed in anaesthetised female rhesus monkeys. After bolus intravenous injection of vecuronium (n = 8) or 3-desacetyl-vecuronium (n = 8) 10 µg kg(-1) (ED90), a continuous infusion of the same NMBA was started to maintain the first twitch of the train-of-four (TOF) at 10% of baseline value. The infusion was stopped and NMB recovered spontaneously. The procedure was repeated, but immediately after stopping the infusion, an intravenous bolus dose of sugammadex 0.5 or 1.0 mg kg(-1) was given. For each NMBA, four placebo experiments were performed, in which the second recovery from NMB was also spontaneous. For all experiments, time to recovery of the TOF ratio to 90% was retrieved. RESULTS: After administration of sugammadex for reversal of 3-desacetyl-vecuronium-induced NMB, recovery was significantly faster than spontaneous recovery. Mean time to recovery of TOF to 90% was 3.2 min (sugammadex 0.5 mg kg(-1)) and 2.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (17.6 min). For vecuronium-induced NMB, mean time to recovery of TOF to 90% was 17.1 min (0.5 mg kg(-1)) and 4.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (23.4 min). CONCLUSION: Sugammadex rapidly and effectively reversed 3-desacetyl-vecuronium-induced NMB in the rhesus monkey, at a lower dose than that needed to reverse vecuronium-induced NMB.
Assuntos
Junção Neuromuscular/efeitos dos fármacos , Fármacos Neuromusculares não Despolarizantes/farmacologia , Brometo de Vecurônio/análogos & derivados , gama-Ciclodextrinas/farmacologia , Potenciais de Ação , Animais , Estimulação Elétrica , Feminino , Infusões Intravenosas , Injeções Intravenosas , Macaca mulatta , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Recuperação de Função Fisiológica , Sugammadex , Fatores de Tempo , Brometo de Vecurônio/administração & dosagem , Brometo de Vecurônio/farmacologia , gama-Ciclodextrinas/administração & dosagemRESUMO
A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes pain symptoms similar to those noted in human osteoarthritis. Twenty rats were divided in two groups either receiving placebo or monosodium iodoacetate. Each group was subdivided in two groups either receiving pre-treatment with capsaicin two weeks before monosodium iodoacetate injection or not, resulting in four groups of five rats each. The impact of a single intra-articular administration of capsaicin (0.5%) on the generation of evoked mechanical pain (hind limb weight bearing, automated von Frey monofilament and RotaRod tests) and bone lesions (micro-CT scan radiographic analyses of bone structure) following monosodium iodoacetate-induced osteoarthritis in rats was determined. Evoked mechanical pain as monitored over a period of 4 weeks after monosodium iodoacetate injection was abolished in capsaicin pre-treated animals and pain values are comparable to those of capsaicin controls. Chronic joint pathological changes such as bone erosion and trabecular damage were significantly reduced by pre-treatment with a single administration of capsaicin. Decrease of bone volume was considerably ameliorated and trabecular connectivity was substantially better in capsaicin pre-treated animals. Capsaicin, an agonist activator of the vanilloid nociceptors (TRPV1), appears to be effective in protecting bone from arthritic damage. The present results support the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions in the monosodium iodoacetate-induced osteoarthritis rat model.
Assuntos
Osso e Ossos/patologia , Capsaicina/farmacologia , Osteoartrite/patologia , Dor/induzido quimicamente , Animais , Capsaicina/efeitos adversos , Capsaicina/uso terapêutico , Modelos Animais de Doenças , Membro Posterior/patologia , Humanos , Injeções Intra-Articulares , Iodoacetatos , Nociceptores/patologia , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Dor/patologia , Patela/patologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/fisiologia , Suporte de Carga/fisiologiaRESUMO
BACKGROUND: Intravenous opioid therapy is frequently used for postoperative pain management in children after orthopedic surgery but causes side effects such as respiratory depression, vomiting, sedation, and urinary retention. To investigate whether a continuous incisional fascia iliaca compartment (FIC) block provides more effective postoperative pain relief with fewer side effects than IV morphine, we performed a prospective, double-blind, randomized study to compare both techniques. METHODS: Thirty children (ASA physical status I-II) aged 3 mo to 6 yr undergoing a pelvic osteotomy were included in the study. The children were randomized for either morphine IV and placebo (saline) via a FIC catheter (Group M) or placebo (saline) IV and ropivacaine via a FIC catheter (Group R). All patients received general anesthesia using inhaled sevoflurane and IV fentanyl. Perioperatively, a FIC catheter was placed by the surgeon. All patients received either a bolus dose of morphine IV (Group M) or ropivacaine 0.75% via the FIC catheter (Group R) at the end of surgery. Postoperatively, Group M received morphine IV 20 microg x kg(-1) x h(-1) and Group R ropivacaine 0.2% 0.1 mL x kg(-1) x h(-1) via the FIC catheter. In both groups, saline was administered along the other route. All children were assessed for pain, sedation, time until first oral intake, and adverse effects for 48 h postoperatively. During this period, all children had a urinary catheter. RESULTS: The study was completed by 28 children. In the anesthetic recovery room, children in Group M had significantly higher pain scores. These children were also significantly more sedated during the study period. The incidence of vomiting did not differ between the groups; however, children in Group R had first oral intake significantly earlier than Group M. A local retrospective study revealed an incidence of urinary retention of 4.7% in the ropivacaine-treated patients and 39% in the morphine-treated patients. CONCLUSIONS: Continuous incisional FIC block provides excellent postoperative pain relief, less sedation, and better return of appetite than morphine IV after pelvic osteotomy in children.
Assuntos
Amidas/administração & dosagem , Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Fáscia/inervação , Morfina/administração & dosagem , Bloqueio Nervoso/métodos , Osteotomia/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Ossos Pélvicos/cirurgia , Analgésicos Opioides/efeitos adversos , Período de Recuperação da Anestesia , Apetite/efeitos dos fármacos , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Infusões Intravenosas , Morfina/efeitos adversos , Bloqueio Nervoso/efeitos adversos , Medição da Dor , Dor Pós-Operatória/etiologia , Estudos Prospectivos , Ropivacaina , Sono/efeitos dos fármacos , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
OBJECTIVE: To determine if treatment of longstanding complex regional pain syndrome type 1, focusing on functional improvement only while neglecting pain, results in clinical improvement of this syndrome. DESIGN: Prospective description of a case series of 106 patients. SETTING: Outpatient clinic for rehabilitation. INTERVENTIONS: Physical therapy of the affected limb directed at a functional improvement only while neglecting the pain, was performed following an extensive explanation. Normal use of the limb between the treatments was encouraged despite pain. A maximum of five of these sessions were performed in three months. MEASURES: Radboud Skills Test was used to monitor functional improvement of the arms. Speed and walking distance was used as the measure of outcome for the legs. RESULTS: The function of the affected arm or leg improved in 95 patients. Full functional recovery was experienced in 49 (46%) of them. A reduction in pain presented in 75 patients. In 23 patients functional recovery was reached despite an increase in pain. Four patients stopped early due to pain increase. CONCLUSIONS: Our results suggest that 'pain exposure physical therapy' is effective and safe for patients who are unresponsive to accepted standard therapies. Avoiding the use of a limb due to pain will result in loss of function. Forced usage of limbs restores the function, reverses these adaptive processes and leads to regain of control by practice with a reduction of pain in most cases.
Assuntos
Terapia por Exercício , Distrofia Simpática Reflexa/terapia , Adolescente , Adulto , Idoso , Estudos de Viabilidade , Humanos , Pessoa de Meia-Idade , Medição da Dor , Estudos Prospectivos , Recuperação de Função Fisiológica , Distrofia Simpática Reflexa/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Fos expression in the lumbar spinal cord, resulting from a noxious electrical stimulus at the hindpaw, is hypothesized to originate from three sources: direct sensory input of the noxious stimulus, local interactions in the spinal cord, and input of modulating signals from supraspinal regions. Our aim in this study was to discriminate among these sources by eliminating the supraspinal input. METHODS: Therefore, a spinal block was administered in male Wistar rats by administering a local anesthetic (bupivacaine) through an intrathecal catheter at the mid-thoracic level. This thoracic spinal block completely suppressed the noxious stimulation-induced withdrawal reflex that is normally elicited by electrical stimulus. Fos immunoreactivity (Fos-IR) was quantified in all laminae of the L4 segment of the spinal cord. RESULTS: Noxious stimulation resulted in a general and strong increase in Fos-IR in the ipsilateral dorsal horn, mainly in Laminae I, II, and V. Thoracic spinal block caused a remarkable increase in the amount of Fos-IR in Lamina V, but had no significant effect on the Fos-IR in Laminae I and II. CONCLUSIONS: The increase in Fos-IR in Lamina V may have resulted from the interruption of a pain-modulating descending mechanism from the brain. A known modulating descending mechanism is the serotonergic system, controlled by the periaqueductal gray. This system inhibits the neurons in the superficial laminae. Another nonserotonergic system originates in the anterior pretectal nucleus. The latter facilitates neurons in the superficial laminae, while neurons in Lamina V are inhibited. We conclude that both systems are probably involved in the observed effects of the peripheral noxious stimulation given in the present model.
Assuntos
Extremidades/inervação , Bloqueio Nervoso/métodos , Dor/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Medula Espinal/metabolismo , Anestésicos Locais/administração & dosagem , Animais , Bupivacaína/administração & dosagem , Estimulação Elétrica , Injeções Espinhais , Vértebras Lombares , Masculino , Inibição Neural , Dor/fisiopatologia , Dor/prevenção & controle , Ratos , Ratos Wistar , Reflexo Anormal , Medula Espinal/fisiopatologia , Vértebras Torácicas , Regulação para CimaRESUMO
BACKGROUND: Mechanical ventilation (MV) can induce lung injury. Proinflammatory cytokines have been shown to play an important role in the development of ventilator-induced lung injury. Previously, the authors have shown a role for Toll-like receptor 4 signaling. The current study aims to investigate the role of Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-beta (TRIF), a protein downstream of Toll-like receptors, in the development of the inflammatory response after MV in healthy mice. METHODS: Wild-type C57BL6 and TRIF mutant mice were mechanically ventilated for 4 h. Lung tissue and plasma was used to investigate changes in cytokine profile, leukocyte influx, and nuclear factor-kappaB activity. In addition, experiments were performed to assess the role of TRIF in changes in cardiopulmonary physiology after MV. RESULTS: MV significantly increased messenger RNA expression of interleukin (IL)-1beta in wild-type mice, but not in TRIF mutant mice. In lung homogenates, MV increased levels of IL-1alpha, IL-1beta, and keratinocyte-derived chemokine in wild-type mice. In contrast, in TRIF mutant mice, only a minor increase in IL-1beta and keratinocyte-derived chemokine was found after MV. Nuclear factor-kappaB activity after MV was significantly lower in TRIF mutant mice compared with wild-type mice. In plasma, MV increased levels of IL-6 and keratinocyte-derived chemokine. In TRIF mutant mice, no increase of IL-6 was found after MV, and the increase in keratinocyte-derived chemokine appeared less pronounced. TRIF deletion did not affect cardiopulmonary physiology after MV. CONCLUSIONS: The current study supports a prominent role for TRIF in the development of the pulmonary and systemic inflammatory response after MV.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Inflamação/genética , Inflamação/fisiopatologia , Respiração Artificial , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Animais , Citocinas/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/fisiologia , Oligonucleotídeos/genética , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismoRESUMO
Isoflurane (ISO) can be a valuable alternative for alpha-chloralose (ACL) anesthesia in functional MRI (fMRI) studies. Therefore, we compared the efficacy of the blood oxygen level dependent (BOLD) effect in fMRI studies during ISO and ACL anesthesia sequentially in the same animals. After non-invasive instrumentation for ventilation and monitoring, series of T2* weighted MR images were acquired during forepaw stimulation, first under ISO, then followed by ACL anesthesia. The results demonstrated that ISO and ACL were both suitable to perform this fMRI experiment. The center of activation was at the same stereotactic position for both anesthetics and matched the primary somatosensory cortex (S1). Under the applied conditions, the BOLD response during ISO anesthesia declined in magnitude during the first stimulation period, as compared to ACL. From this study, we conclude that since ISO has several positive properties in comparison to ACL, including fast pharmacokinetics and suitability for repeated measurements, it is a valuable alternative for anesthesia in fMRI studies of rats.
Assuntos
Anestesia , Cloralose/administração & dosagem , Cloralose/farmacologia , Isoflurano/administração & dosagem , Isoflurano/farmacologia , Animais , Estimulação Elétrica , Imageamento por Ressonância Magnética , Masculino , Modelos Animais , Oxigênio/sangue , Ratos , Ratos Wistar , Técnicas EstereotáxicasRESUMO
BACKGROUND: Mechanical ventilation (MV) can induce ventilator-induced lung injury. A role for proinflammatory pathways has been proposed. The current studies analyzed the roles of Toll-like receptor (TLR) 4 and TLR2 involvement in the inflammatory response after MV in the healthy lung. METHODS: Wild-type (WT) C57BL6, TLR4 knockout (KO), and TLR2 KO mice were mechanically ventilated for 4 h. Bronchoalveolar lavage fluid was analyzed for presence of endogenous ligands. Lung homogenates were used to investigate changes in TLR4 and TLR2 expression. Cytokines were measured in lung homogenate and plasma, and leukocytes were counted in lung tissue. RESULTS: MV significantly increased endogenous ligands for TLR4 in bronchoalveolar lavage fluid and relative messenger RNA expression of TLR4 and TLR2 in lung tissue. In lung homogenates, MV in WT mice increased levels of keratinocyte-derived chemokine, interleukin (IL)-1alpha, and IL-1beta. In TLR4 KO mice, MV increased IL-1alpha but not IL-1beta, and the increase in keratinocyte-derived chemokine was less pronounced. In plasma, MV in WT mice increased levels of IL-6, keratinocyte-derived chemokine, and tumor necrosis factor alpha. In TLR4 KO mice, MV did not increase levels of IL-6 or tumor necrosis factor alpha, and the response of keratinocyte-derived chemokine was less pronounced. MV in TLR2 KO mice did not result in different cytokine levels compared with WT mice. In WT and TLR2 KO mice, but not in TLR4 KO mice, MV increased the number of pulmonary leukocytes. CONCLUSIONS: The current study supports a role for TLR4 in the inflammatory reaction after short-term MV in healthy lungs. Increasing the understanding of the innate immune response to MV may lead to future treatment advances in ventilator-induced lung injury, in which TLR4 may serve as a therapeutic target.
Assuntos
Inflamação/etiologia , Respiração Artificial/efeitos adversos , Receptor 4 Toll-Like/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Contagem de Células , Células Cultivadas , Quimiocinas/sangue , Quimiocinas/imunologia , Citocinas/sangue , Citocinas/imunologia , Citocinas/metabolismo , Inflamação/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Leucócitos/imunologia , Ligantes , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Valores de Referência , Respiração Artificial/métodos , Volume de Ventilação Pulmonar , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Mechanical ventilation with small tidal volumes reduces the development of ventilator-induced lung injury and mortality, but may increase PaCO2. It is not clear whether the beneficial effect of a lung-protective strategy results from reduced ventilation pressures/tidal volumes or is mediated by the effects of hypercapnic acidosis on the inflammatory response involved in the pathogenesis of ventilator-induced lung injury. OBJECTIVE: To analyze whether hypercapnic acidosis affects lung tissue cytokine levels and leukocyte influx in healthy ventilated mice. STUDY DESIGN: Analysis of lung tissue and plasma concentrations of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-10, and keratocyte-derived chemokine after 2 hrs of mechanical ventilation (V(t) 8 mL/kg, positive end-expiratory pressure 4 cm H2O) with 0.06% CO2 (room air), 2% CO2, or 4% CO2. SUBJECTS: Healthy C57BL6 mice (n = 40). MEASUREMENTS/RESULTS: PaCO2 and pH were within normal range when ventilated with 0.06% CO2 and significantly changed with 2% and 4% CO2: (mean +/- SD) pH 7.23 +/- 0.06 and 7.15 +/- 0.04, PaCO2 7.9 +/- 1.4 and 10.8 +/- 0.7 kPa, respectively (p < 0.005). Blood pressure remained within normal limits in all animals. Quantitative microscopic analysis showed a 4.7 +/- 3.7-fold increase (p < 0.01) in pulmonary leukocyte influx in normocapnic ventilated animals and a significant reduction in leukocyte influx of 57 +/- 32% (p < 0.01) and 67 +/- 22% (p < 0.01) when ventilated with 2% and 4% CO2, respectively. Normocapnic ventilation induced a significant elevation of lung tissue IL-1beta (1516 +/- 119 ng/mL), TNF-alpha (344 +/- 88 ng/mL), IL-6 (6310 +/- 807 ng/mL), IL-10 (995 +/- 152 ng/mL), and keratocyte-derived chemokine (36,966 +/- 15,294 ng/mL) (all p-values <0.01). Hypercapnic acidosis with 2% respectively 4% CO2 significantly attenuated this increase with 25 +/- 32% and 54 +/- 32% (IL-1beta, p < 0.01); 17 +/- 36% and 58 +/- 33% (TNF-alpha, p < 0.02); 22 +/- 34% and 89 +/- 6% (IL-6, p < 0.01); 20 +/- 31% and 67 +/- 17% (IL-10, p < 0.01) and 16 +/- 44% and 45 +/- 30% (keratocyte-derived chemokine, p = 0.07). CONCLUSION: Hypercapnic acidosis attenuates the mechanical ventilation-induced immune response independent from reduced tidal volumes/pressures and may protect the lung from ventilator induced lung injury.
Assuntos
Acidose/metabolismo , Citocinas/metabolismo , Leucócitos/metabolismo , Pulmão/metabolismo , Acidose/imunologia , Animais , Gasometria , Camundongos , Camundongos Endogâmicos C57BL , Respiração Artificial/efeitos adversos , Volume de Ventilação PulmonarRESUMO
BACKGROUND: Although our understanding of nociceptive processing during anesthesia has increased greatly over the last decade, many patients still experience hyperalgesia and acute pain postoperatively. The noxious-induced withdrawal reflex (NIWR) model is specifically designed and validated to quantitatively study the reaction on painful, multimodal stimuli in animals under anesthetic conditions. Since the anesthetic mechanisms differ between inhaled anesthetics and opioids, we evaluated the differential effects of isoflurane and fentanyl on c-fos expression at the lumbar level as a measure of nociceptive information transfer during general anesthesia. METHODS: The experimental setup consisted of a randomized block design with four experimental groups: two light (3/4) minimum alveolar concentration (MAC) isoflurane anesthesia groups (unstimulated/NIWR-stimulated) and two NIWR-stimulated surgical anesthesia groups (1(1/2) MAC isoflurane anesthesia and (3/4) MAC isoflurane anesthesia combined with fentanyl 400-600 microg x kg(-1) x h(-1)). After 2 h of intermittent electrical stimulation of the hind paw of the rat, the number of Fos immunoreactive (Fos-IR) neurons in the dorsal horn was measured quantitatively. RESULTS: The main suppressive effects on lumbar c-fos expression of isoflurane were observed in the superficial lamina II (P = 0.02), whereas fentanyl showed the strongest effects in lamina V (P = 0.05). CONCLUSIONS: This study demonstrates that the NIWR model combined with spinal Fos-immunoreactivity is a suitable and useful model for evaluating the differential effects of inhaled anesthetics and opioids on nociceptive information transfer during general anesthesia.
Assuntos
Fentanila/uso terapêutico , Isoflurano/uso terapêutico , Dor/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Medula Espinal/fisiologia , Analgésicos/uso terapêutico , Anestesia , Animais , Quimioterapia Combinada , Estimulação Elétrica , Vértebras Lombares , Masculino , Dor/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacosAssuntos
Androstanóis/farmacocinética , Fármacos Neuromusculares não Despolarizantes/farmacocinética , gama-Ciclodextrinas/farmacocinética , Androstanóis/administração & dosagem , Androstanóis/antagonistas & inibidores , Animais , Cálculos da Dosagem de Medicamento , Humanos , Macaca mulatta , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Rocurônio , Sugammadex , gama-Ciclodextrinas/administração & dosagemRESUMO
BACKGROUND: Mechanical ventilation (MV) may activate the innate immune system, causing the release of cytokines. The resulting proinflammatory state is a risk factor for ventilator-induced lung injury. Cytokine increase results from direct cellular injury but may also result from cyclic stretch alone as demonstrated in vitro: mechanotransduction. To study mechanotransduction in vivo, the authors used an animal MV model with clinically relevant ventilator settings, avoiding alveolar damage. METHODS: Healthy C57BL6 mice (n = 82) were ventilated (tidal volume, 8 ml/kg; positive end-expiratory pressure, 4 cm H2O; fraction of inspired oxygen, 0.4) for 30, 60, 120, and 240 min. Assigned animals were allowed to recover for 2 days after MV. Both pulmonary tissue and plasma interleukin (IL)-1alpha, IL-1beta, tumor necrosis factor alpha, IL-6, IL-10, and keratinocyte-derived chemokine levels were measured. Histopathologic appearance of lung tissue was analyzed by light microscopy and electron microscopy. RESULTS: In lung tissue, all measured cytokines and keratinocyte-derived chemokine levels increased progressively with MV duration. Light microscopy showed increased leukocyte influx but no signs of alveolar leakage or albumin deposition. Electron microscopy revealed intact epithelial cell and basement membranes with sporadically minimal signs of partial endothelial detachment. In plasma, increased levels of IL-1alpha, tumor necrosis factor alpha, IL-6, and keratinocyte-derived chemokine were measured after MV. In the recovery animals, cytokine levels had normalized and no histologic alterations could be found. CONCLUSIONS: Mechanical ventilation induces reversible cytokine increase and leukocyte influx with preserved tissue integrity. This model offers opportunities to study the pathophysiologic mechanisms behind ventilator-induced lung injury and the contribution of MV to the "multiple-hit" concept.
Assuntos
Citocinas/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Alvéolos Pulmonares/fisiopatologia , Respiração Artificial/efeitos adversos , Animais , Gasometria/métodos , Pressão Sanguínea , Quimiocinas/sangue , Citocinas/biossíntese , Interleucinas/sangue , Queratinócitos , Leucócitos/metabolismo , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica/métodos , Modelos Animais , Valores de Referência , Respiração Artificial/métodos , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangueRESUMO
Steroidal neuromuscular blocking agents (NMBAs), such as rocuronium, are widely used in clinical anesthesia and emergency medicine to facilitate endotracheal intubation and artificial ventilation and to allow surgical access to body cavities. Reversal of neuromuscular blockade is important for the acceleration of patient recovery and prevention of postoperative residual neuromuscular blockade and reduces the incidence of severe morbidity and mortality associated with anesthesia management. Sugammadex is the first selective relaxant binding agent (SRBA) and has been designed to reverse the steroidal neuromuscular blocking drug rocuronium. Encapsulation of the rocuronium molecule by sugammadex results in a rapid decrease in free rocuronium in the plasma and subsequently at the nicotinic receptor at the motor endplate. After encapsulation, rocuronium is not available to bind to the nicotinic receptor in the neuromuscular junction. This promotes the liberation of acetylcholine receptors, and muscle activity reappears. This new concept of reversal of neuromuscular block induced by rocuronium (or vecuronium) led to impressive results in animal and phase 1 and 2 studies. Sugammadex is currently in phase 3 clinical studies and may be commercially available by 2008.
RESUMO
BACKGROUND: Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic gamma-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the anesthetized rhesus monkey using train-of-four stimulation. METHODS: Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-microg/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-microg/kg dose of rocuronium was injected. Up to this point, all three experiments in a single monkey were identical. One minute after this rocuronium injection, either one of the two tested dosages of sugammadex (1.0 or 2.5 mg/kg) was injected or saline was injected. RESULTS: Injection of 100 microg/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 microg/kg. In all experiments, a 100% neuromuscular blockade was achieved at this dose. After injection of the high rocuronium dose, the 90% recovery of the train-of-four ratio took 28 min (SD = 7 min) after saline, 26 min (SD = 9.5 min) after 1 mg/kg sugammadex, and 8 min (SD = 3.6 min) after 2.5 mg/kg sugammadex. Signs of residual blockade or recurarization were not observed. Injection of sugammadex had no significant effects on blood pressure or heart rate. CONCLUSIONS: Chemical encapsulation of rocuronium by sugammadex is a new therapeutic mechanism allowing effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.