Klinische Pharmakologie: Postoperative Übelkeit und Erbrechen

Zusammenfassung: Die "Dreierregel" beschreibt drei Schritte, die zur optimalen Kontrolle von postoperativer Übelkeit und Erbrechen ("postoperative nausea and vomiting", PONV) benötigt werden. Erstens sollte versucht werden, Hochrisikopatienten zu identifizieren. Risikofaktoren helfen mit, Patienten zu stratifizieren: Hochrisikopatienten profitieren am ehesten von einer Prävention; bei Niedrigrisikopatienten lohnt sich eine Prävention kaum. Zweitens sollte für Hochrisikopatienten eine Anästhesietechnik mit niedrigem emetogenen Potenzial gewählt werden. Und drittens sollten diese Patienten von einem präventiven antiemetischen Cocktail profitieren. Butyrophenone (z.B. Droperidol), 5-HT3-Rezeptoren-Antagonisten ("Setrone") und Steroide (z.B. Dexamethason) wirken am besten, wenn sie kombiniert werden. Sie gehören deshalb heute zu den logischen Komponenten eines antiemetischen Cocktails. Finanzielle Überlegungen können jedoch Zahl und Art der Antiemetika, die präventiv verabreicht werden sollen, beeinflussen. Die Identifizierung von Hochrisikopatienten bleibt der schwierigste Teil einer erfolgreichen PONV-Prävention. Zwar wurden Risikoscores vorgestellt, und diese wurden auch vielerorts in den klinischen Alltag integriert. Sensitivität und Spezifität dieser Scores sind jedoch ausgesprochen unbefriedigend, und ihre unkritische Anwendung bleibt somit unerwünscht. Solange keine zuverlässigeren Risikovoraussagen vorliegen, scheint bei manchen Patienten, eine aggressive Therapiestrategie sinnvoller und wahrscheinlich kosteneffizienter, als eine Präventio

How do authors of systematic reviews deal with research malpractice and misconduct in original studies? A cross-sectional analysis of systematic reviews and survey of their authors.

OBJECTIVES: To study whether systematic reviewers apply procedures to counter-balance some common forms of research malpractice such as not publishing completed research, duplicate publications, or selective reporting of outcomes, and to see whether they identify and report misconduct. DESIGN: Cross-sectional analysis of systematic reviews and survey of their authors. PARTICIPANTS: 118 systematic reviews published in four journals (Ann Int Med, BMJ, JAMA, Lancet), and the Cochrane Library, in 2013. MAIN OUTCOMES AND MEASURES: Number (%) of reviews that applied procedures to reduce the impact of: (1) publication bias (through searching of unpublished trials), (2) selective outcome reporting (by contacting the authors of the original studies), (3) duplicate publications, (4) sponsors' and (5) authors' conflicts of interest, on the conclusions of the review, and (6) looked for ethical approval of the studies. Number (%) of reviewers who suspected misconduct are reported. The procedures applied were compared across journals. RESULTS: 80 (68%) reviewers confirmed their data. 59 (50%) reviews applied three or more procedures; 11 (9%) applied none. Unpublished trials were searched in 79 (66%) reviews. Authors of original studies were contacted in 73 (62%). Duplicate publications were searched in 81 (69%). 27 reviews (23%) reported sponsors of the included studies; 6 (5%) analysed their impact on the conclusions of the review. Five reviews (4%) looked at conflicts of interest of study authors; none of them analysed their impact. Three reviews (2.5%) looked at ethical approval of the studies. Seven reviews (6%) suspected misconduct; only 2 (2%) reported it explicitly. Procedures applied differed across the journals. CONCLUSIONS: Only half of the systematic reviews applied three or more of the six procedures examined. Sponsors, conflicts of interest of authors and ethical approval remain overlooked. Research misconduct is sometimes identified, but rarely reported. Guidance on when, and how, to report suspected misconduct is needed

Rapid Sequence Induction With a Standard Intubation Dose of Rocuronium After Magnesium Pretreatment Compared With Succinylcholine: A Randomized Clinical Trial.

Succinylcholine remains the muscle relaxant of choice for rapid sequence induction (RSI) but has many adverse effects. High-dose rocuronium bromide may be an alternative to succinylcholine for RSI but recovery times are nearly doubled compared with a standard intubating dose of rocuronium. Magnesium sulfate significantly shortens the onset time of a standard intubating dose of rocuronium. We set out to investigate whether intravenous (IV) pretreatment with MgSO4 followed by a standard intubating dose of rocuronium achieved superior intubation conditions compared with succinylcholine. Adults were randomized to receive a 15-minute IV infusion of MgSO4 (60 mg·kg-1) immediately before RSI with propofol 2 mg·kg-1, sufentanil 0.2 μg·kg-1 and rocuronium 0.6 mg·kg-1, or a matching 15-minute IV infusion of saline immediately before an identical RSI, but with succinylcholine 1 mg·kg-1. Primary end point was the rate of excellent intubating conditions 60 seconds after administration of the neuromuscular blocking agent and compared between groups using multivariable log-binomial regression model. Secondary end points were blood pressure and heart rate before induction, before and after intubation, and adverse events up to 24 hours postoperatively. Among 280 randomized patients, intubating conditions could be analyzed in 259 (133 MgSO4-rocuronium and 126 saline-succinylcholine). The rate of excellent intubating conditions was 46% with MgSO4-rocuronium and 45% with saline-succinylcholine. The analysis adjusted for gender and center showed no superiority of MgSO4-rocuronium compared with saline-succinylcholine (relative risk [RR] 1.06, 95% confidence interval [CI], 0.81-1.39, P = .659). The rate of excellent intubating conditions was higher in women (54% [70 of 130]) compared with men (37% [48 of 129]; adjusted RR 1.42, 95% CI, 1.07-1.91, P = .017). No significant difference between groups was observed for systolic and diastolic blood pressures. Mean heart rate was significantly higher in the MgSO4-rocuronium group. The percentage of patients with at least 1 adverse event was lower with MgSO4-rocuronium (11%) compared with saline-succinylcholine (28%) (RR 0.38, 95% CI, 0.22-0.66, P < .001). With saline-succinylcholine, adverse events consisted mainly of postoperative muscle pain (n = 26 [19%]) and signs of histamine release (n = 13 [9%]). With MgSO4-rocuronium, few patients had pain on injection, nausea and vomiting, or skin rash during the MgSO4-infusion (n = 5 [4%]). IV pretreatment with MgSO4 followed by a standard intubating dose of rocuronium did not provide superior intubation conditions to succinylcholine but had fewer adverse effects

Dexamethasone for the treatment of established postoperative nausea and vomiting: A randomised dose finding trial.

Dexamethasone is widely used for the prevention of postoperative nausea and vomiting (PONV) but little is known about its efficacy for the treatment of established PONV. To test the antiemetic efficacy of intravenous dexamethasone for the treatment of established PONV in adults undergoing surgery under general anaesthesia and to determine whether there is dose-responsiveness. The DexPonv trial is a multicentre, placebo-controlled, randomised, double-blind, dose-finding study. Inclusion of patients was between September 2012 and November 2017. Follow-up for PONV symptoms was for 24 h. Thirty days postoperatively, patients were contacted by study nurses for any information on postoperative bleeding and infection. Four public hospitals in Switzerland. A total of 803 adults scheduled for elective surgery without any antiemetic prophylaxis signed the consent form; 714 were included. Among those, 319 had PONV and 281 patients were eventually randomised (intention to treat population and safety set). The per protocol set consisted of 260 patients. Patients with PONV symptoms (including retching) were randomised to a single intravenous dose of dexamethasone 3, 6 or 12 mg or matching placebo. The primary endpoint was the absence of further nausea or vomiting (including retching), within 24 h after administration of the study drug. Dexamethasone was ineffective during the first 24 h, whatever the dosage, compared to placebo, even when the model was adjusted for known risk factors (P = 0.170). There were no differences in the time to treatment failure or the quality of sleep during the first night. There was a positive correlation between the dose of dexamethasone and blood glucose concentrations (P < 0.001), but not with bleeding risk, wound infections or other adverse effects. This randomised trial failed to show anti-emetic efficacy of any of the tested intravenous regimens of dexamethasone for the treatment of established PONV in adults undergoing surgery under general anaesthesia. clinicaltrials.gov (NCT01975727)

Efeito da N-acetilcisteína oral na bronquite crónica: uma revisão sistematizada quantitativa

RESUMO: O papel da N-acetilcesteína (NAC) no tratamento da bronquite crónica não está estabelecido.Dado que vários estudos foram publicados sobre este assunto, os autores propuseram-se fazer uma revisão sistematizada de alguns desses estudos.Efectuaram a revisão de ensaios randomizados comparando a NAC oral com placebo em doentes com doença pulmonar obstrutiva crónica (DPOC). Foram pesquisados artigos publicados em diversas línguas, em Medline, Embase e Cochrane Library.Onze artigos envolvendo 2011 doentes preen-cheram os critérios de selecção.O tratamento com NAC consistia em terapêutica oral de 400 a 600 mg por dia sendo a duração superior a 3 meses na maioria dos estudos. Os factores de risco de exacerbação bem como a caracterização da gravidade da DPOC através do estudo funcional não foram avaliados em todos os estudos.O papel da NAC na redução do número de exacerbações foi avaliado em 9 dos 11 estudos, sendo exacerbação definida como o aumento da tosse, da expectação mucopurulenta e/ou dispneia. Os resultados mostraram que 48,5% dos doentes medicados com NAC (351 de 723) não tiveram exacerbações comparativamente com 31,2% dos doentes sob placebo (229 de 733). O benefício relativo da NAC foi de 1,56.Em 5 estudos foram usadas escalas de auto-avaliação do tratamento, sendo possível seleccionar os doentes que referiam melhoria dos seus sintomas, o que se verificou em 61,4% dos doentes medicados com NAC (286 de 466) comparativamente a 34,6% dos doentes sob placebo (160 de 462). O benefício relativo da NAC foi de 1,78.Em relação aos efeitos adversos, 6 estudos relataram queixas gastrointestinais que se repartiram por 68 em 666 (10,2%) dos doentes tratados com NAC, comparativamente a 73 em 671 (10,9%) dos doentes medicados com placebo.Alguns estudos analisaram outras variáveis. Num estudo com DPOC grave o FEV1 melhorou significativamente nos doentes tratados com NAC, embora o ensaio decorresse em apenas 4 semanas. Noutro, com DPOC ligeira, os doentes recebendo NAC durante 24 semanas mostraram também melhoria significativa do FEV1.Os autores concluem que em períodos de tratamento de 12-24 semanas a NAC reduz o risco de exacerbações e melhora os sintomas em doentes com DPOC, comparativamente ao placebo e sem aumentar o risco de efeitos secundários.Os autores interrogam-se este benefício é suficiente para justificar o uso regular a longo termo em todos os doentes com bronquite crónica. COMENTÁRIO: Há evidência crescente de que a DPOC pode estar relacionada com o aumento do stress oxidativo e inflamatório1.A NAC pode reduzir o stress oxidativo ao potenciar a produção intracelular de glutatião, que é um dos mais importantes anti-oxidantes celulares.Tem sido também sugerido que a NAC poderá actuar na adesividade bacteriana, reduzindo a possibilidade de colonização/infecção na DPOC2.Embora a maioria dos autores admitam que a NAC reduz o número de exacerbações e a queda do FEV1 nos doentes com bronquite crónica, os resultados dos ensaios são pouco precisos e há até mesmo resultados controversos 3,4.Em relação à meta-análise resumida, os resultados são favoráveis ao uso de NAC mas também passíveis de crítica.Primeiro, não distingue a eficácia entre doentes com maior ou menor risco de exacerbação e do mesmo modo não foi avaliada a eficácia em relação a diferentes graus de gravidade da DPOC.Em segundo lugar o parâmetro avaliado exacerbação de DPOC não é consensual como factor major de aceleração da perda progressiva da função pulmonar.Finalmente, a duração do tratamento não foi além de 6 meses, o que se pode questionar ser pouco tempo para uma droga dirigida à área preventiva, dado propôr-se ser eficaz em reduzir o número de exacerbações e a queda do FEV1.Na tentativa de encontrar respostas para as questões sobre a eficácia da NAC na DPOC, encontrase em curso um estudo internacional, multicêntrico, randomizado, duplamente cego e controlado com placebo - BRONCUS - Bronchitis, Randomised, On Nac & Cost-Utility Study.Consiste num estudo prospectivo de 3 anos, em doentes com DPOC moderada a grave relacionada com o tabaco, cujos objectivos primários são determinar se o uso de NAC a longo termo reduz a queda anual do FEV1 pós broncodilatação e/ou o número de exacerbações. Em adição avalia-se também o efeito da NAC na qualidade de vida e o seu custo-benefício.Neste estudo multinacional participam 4 centros portugueses Porto, Gaia, Coimbra e Lisboa coordenados pelo Prof. Dr. R. Ávila.Os primeiros resultados revelam que foram recrutados, entre Junho de 1997 e Dezembro de 1999, 523 doentes com média de idade de 63 anos sendo 46% fumadores, com valor médio de FEV1 de 57% 5.Os resultados finais do BRONCUS, disponíveis dentro de 2 anos, poderão trazer as respostas. Palavras-chave: N-acetilcisteína (NAC), Doença Pulmonar Obstrutiva Crónica (DPOC), Exacerbação de DPO

Impact of Study Design on Reported Incidences of Acute Mountain Sickness: A Systematic Review.

UNLABELLED: Waeber, Baptiste, Bengt Kayser, Lionel Dumont, Christopher Lysakowski, Martin R. Tramèr, and Nadia Elia. Impact of study design on reported incidences of acute mountain sickness: A systematic review. High Alt Med Biol 16:204-215, 2015.- AIMS: Published incidences of acute mountain sickness (AMS) vary widely. Reasons for this variation, and predictive factors of AMS, are not well understood. We aimed to identify predictive factors that are associated with the occurrence of AMS, and to test the hypothesis that study design is an independent predictive factor of AMS incidence. We did a systematic search (Medline, bibliographies) for relevant articles in English or French, up to April 28, 2013. Studies of any design reporting on AMS incidence in humans without prophylaxis were selected. Data on incidence and potential predictive factors were extracted by two reviewers and crosschecked by four reviewers. Associations between predictive factors and AMS incidence were sought through bivariate and multivariate analyses for different study designs separately. Association between AMS incidence and study design was assessed using multiple linear regression. RESULTS: We extracted data from 53,603 subjects from 34 randomized controlled trials, 44 cohort studies, and 33 cross-sectional studies. In randomized trials, the median of AMS incidences without prophylaxis was 60% (range, 16%-100%); mode of ascent and population were significantly associated with AMS incidence. In cohort studies, the median of AMS incidences was 51% (0%-100%); geographical location was significantly associated with AMS incidence. In cross-sectional studies, the median of AMS incidences was 32% (0%-68%); mode of ascent and maximum altitude were significantly associated with AMS incidence. In a multivariate analysis, study design (p=0.012), mode of ascent (p=0.003), maximum altitude (p<0.001), population (p=0.002), and geographical location (p<0.001) were significantly associated with AMS incidence. Age, sex, speed of ascent, duration of exposure, or history of AMS were inconsistently reported and therefore not further analyzed. CONCLUSIONS: Reported incidences and identifiable predictive factors of AMS depend on study design