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1.
PLoS One ; 19(5): e0303256, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38758837

RESUMO

STUDY OBJECTIVE: During cesarean section, hypotension is a frequent side effect of spinal anesthesia. As a sitting or lateral position is required for spinal anesthesia performance, which of these two positions is more likely to cause intraoperative nausea, vomiting, and hypotension is still unknown. This meta-analysis compared the effects of these two positions on maternal hemodynamics and intraoperative nausea and vomiting. DESIGN: Systematic review and meta-analysis. SETTING: Operating room. PATIENTS: This study included 803 patients from 12 randomized controlled trials (RCTs). INTERVENTIONS: Neuraxial anesthesia in sitting position vs. lateral position. MEASUREMENTS: We chose RCTs comparing the effects of spinal anesthesia in the sitting and lateral positions on maternal hemodynamics by thoroughly searching PubMed, Embase, the Cochrane Library, and the Web of Science for articles published from database inception until October 31, 2022. The Cochrane Handbook was used to assess the methodological quality of each RCT; the results were analyzed using RevMan 5.4 software; and the Egger test was used to assess publication bias. MAIN RESULTS: 12 randomised controlled trials with 803 participants were ultimately included in the final analysis. No significant differences were observed between the two positions in terms of the incidence of hypotension(RR, 0.82; 95% CI, 0.58-1.16; P = 0.26; I2 = 66%), lowest systolic blood pressure(MD, -0.81; 95% CI, -7.38-5.75; P = 0.81; I2 = 86%), the dose of ephedrine(MD, -1.19; 95% CI, -4.91-2.52; P = 0.53; I2 = 83%), and number of parturients requiring ephedrine(RR, 0.97; 95% CI, 0.64-1.46; P = 0.88; I2 = 74%). For the incidence of intraoperative nausea and vomiting, there was no statistical difference between the two positions. CONCLUSION: Parturients undergoing elective cesarean section under spinal anesthesia in the sitting or lateral position experienced similar incidence of hypotension, and there were no significant differences between these two positions in terms of the amount of ephedrine administered or the number of patients needing ephedrine. In both positions, the frequency of nausea and vomiting was comparable. The ideal position for anesthesia can be chosen based on the preferences and individual circumstances of the parturient and anesthesiologist.


Assuntos
Raquianestesia , Cesárea , Hemodinâmica , Humanos , Cesárea/efeitos adversos , Feminino , Gravidez , Hemodinâmica/efeitos dos fármacos , Raquianestesia/efeitos adversos , Raquianestesia/métodos , Postura Sentada , Hipotensão/etiologia , Hipotensão/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Anestesia Obstétrica/efeitos adversos , Anestesia Obstétrica/métodos , Postura
2.
Clin Interv Aging ; 19: 219-227, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38352273

RESUMO

Background: Noradrenaline (NA) is commonly used intraoperatively to prevent fluid overload and maintain hemodynamic stability. Clinical studies provided inconsistent results concerning the effect of NA on postoperative outcomes. As aging is accompanied with various diseases and has the high possibility of the risk for postoperative complications, we hypothesized that intraoperative NA infusion in older adult patients undergoing major non-cardiac surgeries might potentially exert adverse outcomes. Methods: In this retrospective propensity score-matched cohort study, older adult patients undergoing major non-cardiac surgeries were selected, 1837 receiving NA infusion during surgery, and 1072 not receiving NA. The propensity score matching was conducted with a 1:1 ratio and 1072 patients were included in each group. The primary outcomes were postoperative in-hospital mortality and complications. Results: Intraoperative NA administration reduced postoperative urinary tract infection (OR:0.124, 95% CI:0.016-0.995), and had no effect on other postoperative complications and mortality, it reduced intraoperative crystalloid infusion (OR:0.999, 95% CI:0.999-0.999), blood loss (OR: 0.998, 95% CI: 0.998-0.999), transfusion (OR:0.327, 95% CI: 0.218-0.490), but increased intraoperative lactate production (OR:1.354, 95% CI:1.051-1.744), and hospital stay (OR:1.019, 95% CI:1.008-1.029). Conclusion: Intraoperative noradrenaline administration reduces postoperative urinary tract infection, and does not increase other postoperative complications and mortality, and can be safely used in older adult patients undergoing major non-cardiac surgeries.


Assuntos
Norepinefrina , Procedimentos Cirúrgicos Operatórios , Idoso , Humanos , Estudos de Coortes , Norepinefrina/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Pontuação de Propensão , Estudos Retrospectivos , Infecções Urinárias/complicações
3.
Front Oncol ; 13: 1083000, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37056343

RESUMO

Background: Regional anesthesia have been successfully performed for pain management in breast cancer surgery, but it is unclear which is the best regional anesthesia technique. The aim of the present network meta-analysis was to assess the analgesic efficacy and disadvantages of regional anesthesia techniques. Methods: Multiple databases were searched for randomized controlled trials (RCTs). The association between regional anesthesia and analgesic efficacy was evaluated by Bayesian network meta-analysis. Results: We included 100 RCTs and 6639 patients in this study. The network meta-analysis showed that paravertebral nerve block, pectoral nerve-2 block, serratus anterior plane block, erector spinae plane block, rhomboid intercostal block, and local anesthetic infusion were associated with significantly decreased postoperative pain scores, morphine consumption and incidence of postoperative nausea and vomiting compared with no block. Regarding the incidence of chronic pain, no significance was detected between the different regional anesthesia techniques. In the cumulative ranking curve analysis, the rank of the rhomboid intercostal block was the for postoperative care unit pain scores, postoperative 24-hour morphine consumption, and incidence of postoperative nausea and vomiting. Conclusion: Regional anesthesia techniques including, paravertebral nerve block, pectoral nerve-2 block, serratus anterior plane block, erector spinae plane block, rhomboid intercostal block, and local anesthetic infusion, can effectively alleviate postoperative acute analgesia and reduce postoperative morphine consumption, but cannot reduce chronic pain after breast surgery. The rhomboid intercostal block might be the optimal technique for postoperative analgesia in breast cancer surgery, but the strength of the evidence was very low. Systematic review registration: https://www.crd.york.ac.uk/prospero/(PROSPERO), identifier CRD 42020220763.

4.
Perioper Med (Lond) ; 12(1): 4, 2023 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-36890549

RESUMO

BACKGROUND: Dexamethasone is commonly used for antiemesis in surgical patients. It has been confirmed that long-term steroid use increases blood glucose level in both diabetic and non-diabetic patients, it is unclear how a single dose of intravenous dexamethasone used pre/intraoperatively for postoperative nausea and vomiting (PONV) prophylaxis would influence the blood glucose and wound healing in diabetic patients. METHODS: The Pubmed, Cochrane Library, Embase, Web of Science databases, CNKI and Google Scholar were searched. The articles reporting a single dose dexamethasone administered intravenously for antiemesis in surgical patients with diabetes mellitus (DM) were included. RESULTS: Nine randomized controlled trials (RCTs) and 7 cohort studies were included in our meta-analysis. The results showed that dexamethasone increased glucose level intraoperatively (MD: 0.439, 95% CI: 0.137-0.581, I2 = 55.7%, P = 0.004), at the end of surgery (MD: 0.815, 95% CI: 0.563-1.067, I2 = 73.5%, P = 0.000), on postoperative day (POD) 1 (MD: 1.087, 95% CI: 0.534-1.640, I2 = 88%, P = 0.000), on POD 2 (MD: 0.501, 95% CI: 0.301-0.701, I2 = 0%, P = 0.000), and increased peak glucose level within 24 hours of surgery (MD: 2.014, 95% CI: 0.503-3.525, I2 = 91.6%, P = 0.009) compared with control. It indicated that dexamethasone caused the increase of perioperative glucose level at different time points by 0.439 to 1.087 mmol/L (7.902 to 19.566 mg/dL), and the increase of peak glucose level within 24 hours of surgery by 2.014 mmol/L (36.252 mg/dL) compared with control. Dexmethasone had no impact on wound infection (OR: 0.797, 95%CI: 0.578-1.099, I2 = 0%, P = 0.166) and healing (P < 0.05). CONCLUSION: Dexamethasone could increase blood glucose by only 2.014 mmol/L (36.252 mg/dL) of peak glucose level within 24 hours of surgery in surgery patients with DM, the increase of glucose level at each time point perioperatively was even lower, and had no effect on wound healing. Thus, dexamethasone with a single dose could be safely used for PONV prophylaxis in diabetic patients. TRIAL REGISTRATION: The protocol of this systematic review was registered in INPLASY with the registration number INPLASY202270002.

5.
J Cardiothorac Vasc Anesth ; 36(12): 4393-4402, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36155718

RESUMO

OBJECTIVES: To develop and validate a nomogram for predicting postoperative pulmonary infection (PPI) in patients undergoing lung surgery. DESIGN: Single-center retrospective cohort analysis. SETTING: A university-affiliated cancer hospital PARTICIPANTS: A total of 1,501 adult patients who underwent lung surgery from January 2018 to December 2020. INTERVENTIONS: Observation for PPI within 7 days after lung surgery. MEASUREMENTS AND MAIN RESULTS: A complete set of demographics, preoperative variables, and postoperative follow-up data was recorded. The primary outcome was PPI; a total of 125 (8.3%) out of 1,501 patients developed PPI. The variables with p < 0.1 in univariate logistic regression were included in the multivariate regression, and multivariate logistic regression analysis showed that surgical procedure, surgical duration, the inspired fraction of oxygen in one-lung ventilation, and postoperative pain were independent risk factors for PPI. A nomogram based on these factors was constructed in the development cohort (area under the curve: 0.794, 95% CI 0.744-0.845) and validated in the validation cohort (area under the curve: 0.849, 95% CI 0.786-0.912). The calibration slope was 1 in the development and validation cohorts. Decision curve analysis indicated that when the threshold probability was within a range of 0.02-to-0.58 and 0.02-to-0.42 for the development and validation cohorts, respectively, the nomogram model could provide a clinical net benefit. CONCLUSIONS: The authors developed and validated a nomogram for predicting PPI in patients undergoing lung surgery. The prediction model can predict the development of PPI and identify high-risk groups.


Assuntos
Neoplasias Pulmonares , Nomogramas , Adulto , Humanos , Estudos Retrospectivos , Pulmão , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia
6.
Medicine (Baltimore) ; 100(43): e27668, 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34713863

RESUMO

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a very common event in elderly noncardiac surgical patients. The effects of inhalational anaesthetics and propofol on the incidence of POCD and postoperative cognitive status at different time points after surgery are currently unclear. METHODS: We searched the Embase, Medline, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs), in which inhalation anaesthesia and propofol anaesthesia were compared. The incidence of POCD or postoperative cognitive status was assessed in elderly patients undergoing noncardiac surgery. RESULTS: Fifteen RCTs with 1854 patients were included in this meta-analysis. The incidence of POCD on postoperative Days 2-6 after propofol anaesthesia was markedly lower than that after inhalation anaesthesia (risk ratio (RR): 0.37, 95% confidence interval (CI): 0.15-0.88, P = .025), and Mini-Mental State Examination (MMSE) scores after propofol anaesthesia were substantially higher than those after inhalation anaesthesia (standard mean difference (SMD): 0.59, 95% CI: 0.07-1.11, P = .026). The levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were much lower after propofol anaesthesia than after inhalation anaesthesia (SMD: -2.027, 95% CI: -3.748- -0.307, P = .021; SMD: -0.68, 95% CI: -0.93- -0.43, P < .001). CONCLUSIONS: The moderate evidence from this meta-analysis shows that, in elderly noncardiac surgical patients, propofol anaesthesia is superior to inhalation anaesthesia for attenuating of early POCD incidence, and low-level evidence shows that cognitive status is higher and systemic inflammation is less severe after propofol anaesthesia in the early days after surgery. LIMITATIONS: The sample size was not sufficiently large for systemic inflammation, and the tools to identify POCD were not uniform in the included studies.


Assuntos
Anestesia por Inalação/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Anestésicos Intravenosos/efeitos adversos , Complicações Cognitivas Pós-Operatórias/induzido quimicamente , Propofol/efeitos adversos , Anestésicos Inalatórios/uso terapêutico , Anestésicos Intravenosos/uso terapêutico , Humanos , Testes de Estado Mental e Demência , Propofol/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/métodos
7.
J Pain Res ; 14: 2165-2177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295185

RESUMO

BACKGROUND: General anaesthesia is the commonly provided for breast cancer surgery, but the effects of inhalational anaesthesia and propofol-based intravenous anaesthesia on short- and long-term outcomes after breast cancer surgery are not clear. In this study, we conduct a meta-analysis of randomized controlled trials (RCTs) to explore the superior anaesthetic for breast cancer surgery patients. METHODS: We searched the Embase, Medline, Cochrane Library, Web of Science, CNKI, and Wanfang databases (up to January, 2021) for RCTs in which inhalational anaesthesia and propofol-based intravenous anaesthesia were compared and short- and long-term outcomes were assessed in breast cancer surgical patients. The meta-analysis was performed by Stata 12.0. RESULTS: Twenty RCTs with a total of 2201 patients were included. Compared with inhalational anaesthesia, propofol-based intravenous anaesthesia was associated with more postoperative rescue analgesia (I2 =0%, RR: 1.18, 95% CI: 1.07-1.30, P=0.001) but a lower incidence of postoperative nausea and vomiting (PONV) (I2 =25.5%, RR: 0.71, 95% CI: 0.62-0.81, P<0.001) and postoperative rescue antiemetics (I2 =0%, RR: 0.69, 95% CI: 0.58-0.82, P<0.001). Propofol-based intravenous anaesthesia preserved nature killer cell cytotoxicity (I2 =86.2%, SMD: 0.76, 95% CI: 0.13-1.39, P=0.018), decreased IL-6 level (I2 =98.0%, SMD: -3.09, 95% CI: -5.70- -0.48, P=0.021) and neutrophil-to-lymphocyte ratio (I2 =0%, SMD: -0.28, 95% CI: -0.53- -0.03, P=0.030), and increased 2-year recurrence-free survival rate (I2 =0%, RR: 1.10, 95% CI: 1.00-1.20, P=0.043) but did not affect recurrence or the overall survival rate (P>0.05). CONCLUSION: Propofol-based intravenous anaesthesia increases postoperative rescue analgesia but reduces PONV compared with inhalational anaesthesia in breast cancer surgery. The benefit of propofol over inhalational anaesthetics in the preservation of anti-cancer immunity is obvious, but it is difficult to conclude that propofol can exert long-term benefits due to the small sample size.

8.
Int J Clin Pract ; 73(10): e13394, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31332896

RESUMO

BACKGROUND: Intra-operative hypotension might induce poor postoperative outcomes in non-cardiac surgery, and the relationship between the level or duration of Intra-operative hypotension (IOH) and postoperative adverse events is still unclear. In this study, we performed a meta-analysis to determine how IOH could affect acute kidney injury (AKI), myocardial injury and mortality in non-cardiac surgery. METHODS: We searched PubMed (Medline), Embase, Springer, The Cochrane Library, Ovid and Google Scholar, and retrieved the related clinical trials on intra-operative hypotension and prognosis in non-cardiac surgery. RESULTS: Fifteen observational studies were included. The meta-analysis showed that in non-cardiac surgery, intra-operative hypotension (mean arterial pressure [MAP]) <60 mm Hg for more than 1 minute was associated with an increased risk of postoperative acute kidney injury(AKI) [1-5 minutes: odds ratio (OR) = 1.13, 95% CI (1.04, 1.23), I2  = 0, P = .003; 5-10 minutes: OR = 1.18, 95% CI (1.07, 1.31), I2  = 0, P = .001; >10 minutes: OR = 1.35, 95% CI (1.1, 1.67), I2  = 52.6%, P = .004] and myocardial injury [1-5 minutes: OR = 1.16, 95% CI (1.01, 1.33), I2  = 30.6%, P = .04; 5-10 minutes: OR = 1.34, 95% CI (1.01, 1.77), I2  = 70.4%, P = .046; >10 minutes: OR = 1.43, 95% CI (1.18, 1.72), I2  = 39.4%, P < .0001]. Intra-operative hypotension (MAP < 60 mm Hg) for 1-5 minutes was not associated with postoperative 30-day mortality [OR = 1.15, 95% CI (0.95, 1.4), I2  = 0, P = .154], but intra-operative hypotension (MAP < 60 mm Hg) for more than 5 min was associated with an increased risk of postoperative 30-day mortality [OR = 1.11, 95% CI (1.06, 1.17), I2  = 51.9%, P < .0001]. CONCLUSION: Intra-operative hypotension was associated with an increased risk of postoperative AKI, myocardial injury and 30-day mortality in non-cardiac surgery. Intra-operative MAP < 60 mm Hg more than 1 minute should be avoided.


Assuntos
Injúria Renal Aguda/mortalidade , Hipotensão/mortalidade , Complicações Intraoperatórias , Infarto do Miocárdio/mortalidade , Injúria Renal Aguda/complicações , Humanos , Hipotensão/complicações , Infarto do Miocárdio/complicações
9.
World J Surg Oncol ; 17(1): 7, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611274

RESUMO

BACKGROUND: Perioperative transfusion can reduce the survival rate in colorectal cancer patients. The effects of transfusion on the short- and long-term prognoses are becoming intriguing. OBJECTIVE: This systematic review and meta-analysis aimed to define the effects of perioperative transfusion on the short- and long-term prognoses of colorectal cancer surgery. RESULTS: Thirty-six clinical observational studies, with a total of 174,036 patients, were included. Perioperative transfusion decreased overall survival (OS) (hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.24 to 0.41; P < 0.0001) and cancer-specific survival (CSS) (HR, 0.34; 95% CI, 0.21 to 0.47; P < 0.0001), but had no effect on disease-free survival (DFS) (HR, 0.17; 95% CI, - 0.12 to 0.47; P = 0.248). Transfusion could increase postoperative infectious complications (RR, 1.89, 95% CI, 1.56 to 2.28; P < 0.0001), pulmonary complications (RR, 2.01; 95% CI, 1.54 to 2.63; P < 0.0001), cardiac complications (RR, 2.20; 95% CI, 1.75 to 2.76; P < 0.0001), anastomotic complications (RR, 1.51; 95% CI, 1.29 to 1.79; P < 0.0001), reoperation(RR, 2.88; 95% CI, 2.05 to 4.05; P < 0.0001), and general complications (RR, 1.86; 95% CI, 1.66 to 2.07; P < 0.0001). CONCLUSION: Perioperative transfusion causes a dramatically negative effect on long-term prognosis and increases short-term complications after colorectal cancer surgery.


Assuntos
Transfusão de Sangue , Neoplasias Colorretais/cirurgia , Cirurgia Colorretal/efeitos adversos , Assistência Perioperatória , Complicações Pós-Operatórias , Humanos , Prognóstico
10.
Minerva Anestesiol ; 84(11): 1287-1297, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29756694

RESUMO

INTRODUCTION: There is a high incidence of postoperative cardiopulmonary complications after thoracic surgery with one lung ventilation (OLV), the effect of general anesthetics on intraoperative cardiopulmonary function and postoperative complications is still unclear. EVIDENCE ACQUISITION: We searched the Embase, PubMed, Cochrane Library, Springer, Wiley, CNKI, VIP and Wanfang databases for randomized controlled trials (RCTs) in which inhalation anesthesia and intravenous anesthesia were compared; intraoperative cardiopulmonary function and postoperative complications were assessed in patients undergoing thoracic surgery with intraoperative one-lung ventilation (OLV). EVIDENCE SYNTHESIS: Twenty-three RCTs with a total of 1349 patients were included. Compared with intravenous anesthesia, inhalation anesthesia significantly increased pulmonary shunt fraction (Qs/Qt) (mean: 5.72, 95% CI: 3.93 to 7.51, P<0.0001), and improved Cardiac Index (CI) (mean difference [MD]: 0.19, 95% CI: 0.10 to 0.28, P<0.0001), but decreased Oxygenation Index (OI) during OLV intraoperatively (MD: -27.37, 95% CI: -43.92 to -10.82, P=0.001). Inhalation anesthesia could reduce postoperative pulmonary complications (RR: 0.47, 95% CI: 0.33 to 0.66, P<0.0001), but did not reduce postoperative cardiac adverse events (P>0.05). CONCLUSIONS: Inhalation anesthesia can preserve intraoperative cardiac function and reduce postoperative pulmonary complications in patients undergoing thoracic surgery with OLV; although it decreases intraoperative pulmonary function, inhalation anesthesia may be superior to intravenous anesthesia in thoracic surgery. Publication bias existed in some included studies, and the sample size was not large enough in CI and cardiac adverse events.


Assuntos
Anestesia por Inalação , Anestesia Intravenosa , Coração/fisiologia , Pulmão/fisiologia , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Torácicos , Testes de Função Cardíaca , Humanos , Monitorização Intraoperatória , Ventilação Monopulmonar , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes de Função Respiratória
11.
Minerva Anestesiol ; 83(7): 749-761, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28402094

RESUMO

INTRODUCTION: Postoperative major adverse cardiac events (MACEs) are the main cause of postoperative mortality, and controversies exist regarding the effects of anesthesia methods on postoperative MACEs and mortality in high-risk cardiac patients after non-cardiac surgeries. EVIDENCE ACQUISITION: A Meta-analysis about the effect of anesthesia methods on postoperative MACEs and mortality in high-risk cardiac patients undergoing intermediate- or high-risk non-cardiac surgeries was conducted; Chinese databases (SinoMed, CNKI, Wanfang, and VIP) and English databases (Medline, EMBASE, PubMed, Springer, Ovid, the Cochrane Library, and Google scholar) were searched. EVIDENCE SYNTHESIS: Twenty-seven randomized controlled trials (RCTs) were included and 35340 patients were involved. The cardiac troponin I level (cTnI) on postoperative day 1 (MD: -0.39, 95% CI: -0.45--0.34, P<0.00001) and the incidence of myocardial ischaemia (OR: 0.43, 95% CI: 0.27-0.68, P=0.0004) within 3 postoperative days were significantly lower after sevoflurane anesthesia than propofol anesthesia. There were no differences in postoperative MACEs or in mortality within either 30 days or 1 year between sevoflurane and propofol anesthesia, or between N2O and non-N2O anesthesia. The cTnI on postoperative day 3 was significantly lower from epidural anesthesia combined with general anesthesia (GA) than from GA alone (MD: -0.61, 95% CI: -0.75--0.47, P<0.00001). However, there were no differences in myocardial infarction or mortality between epidural anesthesia combined with GA and GA alone, or between spinal anesthesia alone and GA alone. CONCLUSIONS: Sevoflurane anesthesia, or epidural combined with general anesthesia can provide short-term myocardial protective effect in high-risk cardiac patients undergoing intermediate- or high-risk non-cardiac surgeries.


Assuntos
Anestesia/métodos , Cardiopatias/mortalidade , Complicações Pós-Operatórias/mortalidade , Anestesia/efeitos adversos , Cardiopatias/etiologia , Humanos , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
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