RESUMEN
BACKGROUND: Postoperative agitation is a frequent and stressful condition for a child, their family, and their health-care providers, and prevention would be of benefit. We aimed to assess the effects of intravenous clonidine administered intraoperatively on the incidence of postoperative agitation, pain, and adverse events. METHODS: We did this randomised, placebo-controlled, double-blind trial (PREVENT AGITATION) at one tertiary-level hospital and two urban-district hospitals in Denmark. Children aged 1-5 years, with an American Society of Anesthesiologists physical classification score of 1-2, who were scheduled for anaesthesia with sevoflurane and fentanyl were randomly assigned (1:1) in blocks of ten by computer-generated centralised randomisation, stratified by age (<2 years or ≥2 years) and site, to receive either intravenous clonidine 3 µg/kg or an equal quantity of isotonic saline in identical vials, administered around 20 min before the completion of surgery. Data were collected from the postoperative care unit (24 h) and at follow-up (30 days). Our primary outcome was the proportion of patients with one or more episodes of postoperative agitation, measured every 15 min in the postoperative care unit (POCU) with the four-point Watcha scale (ie, Watcha >2). We analysed by intention to treat. The trial is registered with ClinicalTrials.gov (number NCT02361476). FINDINGS: Between January and December, 2015, of the 379 eligible children, we randomly assigned 191 to receive clonidine treatment and 188 to receive placebo; 75 were girls (20%). Nine were excluded from the primary outcome analysis because of missing data points. 46 (25%) of 187 clonidine participants compared with 86 (47%) of 183 placebo participants had one or more episodes of postoperative agitation (Watcha score >2; relative risk 0·56, 95% CI 0·43-0·73; p<0·0001). 30 (20%) of 150 boys in the clonidine group were agitated compared with 69 (47%) of 147 boys in the placebo group (0·43, 0·30-0·61; p<0·0001). The observed effect was not significant in girls. Incidence of adverse events was similar in the clonidine and placebo groups. INTERPRETATION: On the basis of our results, clonidine might be used to safely prevent postoperative agitation in boys anaesthetised with sevoflurane. FUNDING: Danish Society of Anaesthesia and Intensive Care.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2 , Anestésicos por Inhalación , Clonidina , Agitación Psicomotora , Sevoflurano , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Anestésicos por Inhalación/uso terapéutico , Niño , Preescolar , Clonidina/administración & dosificación , Método Doble Ciego , Humanos , Lactante , Masculino , Agitación Psicomotora/prevención & control , Sevoflurano/uso terapéuticoRESUMEN
INTRODUCTION: Post-operative agitation (PA) is a common problem (20-70%) in children anaesthetised with sevoflur-ane. Clonidine is widely used off-label in children for several indications, including PA, but the current level of evidence is limited. Our aim is to investigate the impact of prophylactic intravenous (IV) clonidine administered at the end of surgery on the incidence and degree of PA. Furthermore, the pharmacokinetic profile of IV clonidine in children is not well established and our aim is to obtain pharmacokinetic data relating hereto. METHODS: This is a multicentre, randomised and blinded clinical trial in which we will be enrolling 380 children aged 1-5 years who are planned for anaesthesia with sevoflurane and fentanyl. Inclusion is based on computer-generated randomisation (1:1) and stratified by age and site. The study drug is administered IV approximately 20 min. before the expected completion of surgery (intervention: clonidine 3 µg per kg; placebo: equal quantity of saline). CONCLUSION: The primary outcome is PA measured on the Watcha scale. The secondary outcomes include post-operative pain relief and adverse effects, including a 30-day follow-up. In total, 40 children will be allocated to drug assay sampling, enabling a compartmental pharmacokinetic analysis. FUNDING: Funded by the participating departments and by two unrestricted scientific grants from the Danish Society of Anaesthesia and Intensive. TRIAL REGISTRATION: This study was approved by the Danish Health and Medicines Authority (EudraCT number 2014-001466-10), the Ethics Committee of the Capital Region of Denmark (H-2-2014-072) and registered with Clinicaltrials.gov (NCT02361476).
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Anestésicos por Inhalación/efectos adversos , Clonidina/farmacocinética , Delirio del Despertar/prevención & control , Éteres Metílicos/efectos adversos , Complicaciones Posoperatorias/prevención & control , Simpaticolíticos/farmacocinética , Adyuvantes Anestésicos , Anestesia , Preescolar , Clonidina/uso terapéutico , Fentanilo , Humanos , Lactante , Dimensión del Dolor , Sevoflurano , Método Simple Ciego , Simpaticolíticos/uso terapéuticoRESUMEN
The objective of this study was to assess the influence of oral contraceptives (OCs) on the risk of venous thromboembolism (VTE) in young women. A 5-year case-control study including all Danish hospitals was conducted. All women 15-44 years old, suffering a first ever deep venous thrombosis or a first pulmonary embolism (PE) during the period January 1, 1994, to December 30, 1998, were included. Controls were selected annually, 600 per year in 1994-1995 and 1200 per year 1996-1998. Response rates for cases and controls were 87.2% and 89.7%, respectively. After exclusion of nonvalid diagnoses, pregnant women, and women with previous thrombotic disease, 987 cases and 4054 controls were available for analysis. A multivariate, matched analysis was performed. Controls were matched to cases within 1-year age bands. Adjustment was made for confounding influence (if any) from the following variables: age, year, body mass index, length of OC use, family history of VTE, cerebral thrombosis or myocardial infarction, coagulopathies, diabetes, years of schooling, and previous birth. The risk of VTE among current users of OCs was primarily influenced by duration of use, with significantly decreasing odds ratios (OR) over time: <1 year, 7.0 (5.1-9.6); 1-5 years, 3.6 (2.7-4.8); and >5 years, 3.1 (2.5-3.8), all compared with nonusers of OCs. After adjustment for confounders, current use of OCs with second- (levonorgestrel or norgestimate) and third- (desogestrel or gestodene) generation progestins when compared with nonuse resulted in ORs for VTE of 2.9 (2.2-3.8) and 4.0 (3.2-4.9), respectively. After adjusting for progestin types and length of use, the risk decreased significantly with decreasing estrogen dose. With 30-40 microg as reference, 20 and 50 microg products implied ORs of 0.6 (0.4-0.9) and 1.6 (0.9-2.8), respectively (p(trend) = 0.02). After correction for duration of use and differences in estrogen dose, the third/second-generation risk ratio was 1.3 (1.0-1.8; p <0.05). In conclusion, use of OCs was associated significantly to the risk of VTE. The risk among current users was reduced by more than 50% during the first years of use. The risk increased more than 100% with increasing estrogen dose, and the difference in risk between users of third- and second-generation OCs, after correction for length of use and estrogen dose, was 33%.