Produção Nacional
Revisado por pares
Sigh in Patients With Acute Hypoxemic Respiratory Failure and ARDS
2020; Elsevier BV; Volume: 159; Issue: 4 Linguagem: Inglês
10.1016/j.chest.2020.10.079
ISSN1931-3543
AutoresTommaso Mauri, Giuseppe Foti, Carla Fornari, Giacomo Grasselli, Riccardo Pinciroli, Federica Lovisari, Daniela Tubiolo, Carlo Alberto Volta, Savino Spadaro, Roberto Rona, Egle Rondelli, Paolo Navalesi, Eugenio Garofalo, Rihard Knafelj, Vojka Gorjup, Riccardo Colombo, Andrea Cortegiani, Zhou Jian-xin, Rocco D’Andrea, Italo Calamai, Ánxela Vidal González, Oriol Roca, Domenico Luca Grieco, Tomas Jovaiša, Dimitrios Bampalis, Tobias Becher, Denise Battaglini, Huiqing Ge, Mariana Luz, Jean‐Michel Constantin, Marco Ranieri, Claude Guérin, Jordi Mancebo, Paolo Pelosi, Roberto Fumagalli, Laurent Brochard, Antonio Pesenti, Plug working group of ESICM, Alessandra Papoff, Raffaele Di Fenza, Stefano Gianni, Elena Spinelli, Alfredo Lissoni, Chiara Abbruzzese, Alfio Bronco, Silvia Villa, Vincenzo Russotto, Arianna Iachi, Lorenzo Ball, Nicoló Patroniti, Rosario Spina, Romano Giuntini, Simone Peruzzi, Luca S. Menga, Tommaso Fossali, Antonio Castelli, Davide Ottolina, Marina García-de-Acilu, Manel M. Santafé, Dirk Schädler, Norbert Weiler, Emilia Rosas Carvajal, César Calvo, Evangelia Neou, Yumei Wang, Yimin Zhou, Federico Longhini, Andrea Bruni, Mariacristina Leonardi, Cesare Gregoretti, Mariachiara Ippolito, Zelia Milazzo, Lorenzo Querci, Serena Ranieri, Giulia Insom, Jernej Berden, Marko Noč, Urša Mikuž, Matteo Arzenton, Marta Lazzeri, Arianna Villa, Bruna Brandão Barreto, Marcos Nogueira Oliveira Rios, Dimitri Gusmao-Flores, Mandeep Phull, Tom Barnes, Hussain Musarat, Sara Conti,
Tópico(s)Cardiac Arrest and Resuscitation
ResumoBackgroundSigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant.Research QuestionIs the clinical application of sigh during pressure support ventilation (PSV) feasible?Study Design and MethodsWe conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm H2O for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days.ResultsTwo-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, –7%; 95% CI, –18% to 4%; P = .015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P = .852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P = .337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P = .300) for the sigh vs no-sigh group.InterpretationAmong hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk.Trial RegistryClinicalTrials.gov; No.: NCT03201263; URL: www.clinicaltrials.gov Sigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant. Is the clinical application of sigh during pressure support ventilation (PSV) feasible? We conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm H2O for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days. Two-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, –7%; 95% CI, –18% to 4%; P = .015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P = .852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P = .337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P = .300) for the sigh vs no-sigh group. Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk. ClinicalTrials.gov; No.: NCT03201263; URL: www.clinicaltrials.gov Take-home PointsStudy Question: The aim of this randomized clinical trial was to determine the feasibility of the application of sigh during pressure support ventilation (PSV).Results: The study showed that in mechanically ventilated patients with acute hypoxemic respiratory failure or ARDS, addition of sigh in comparison with no sigh during PSV was feasible and safe: there was no increase in patients failing to remain on assisted ventilation (23% vs 30%, respectively), and there were similar proportions of adverse events (12% vs 13%, respectively).Interpretation: Addition of sigh to PSV is feasible and safe in intubated ICU patients with acute hypoxemic respiratory failure or ARDS. Study Question: The aim of this randomized clinical trial was to determine the feasibility of the application of sigh during pressure support ventilation (PSV). Results: The study showed that in mechanically ventilated patients with acute hypoxemic respiratory failure or ARDS, addition of sigh in comparison with no sigh during PSV was feasible and safe: there was no increase in patients failing to remain on assisted ventilation (23% vs 30%, respectively), and there were similar proportions of adverse events (12% vs 13%, respectively). Interpretation: Addition of sigh to PSV is feasible and safe in intubated ICU patients with acute hypoxemic respiratory failure or ARDS. Mechanical ventilation is a vital support for intubated patients with acute hypoxemic respiratory failure (AHRF) and ARDS.1Brower R.G. Matthay M.A. Morris A. et al.Acute Respiratory Distress Syndrome NetworkVentilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.N Engl J Med. 2000; 342: 1301-1308Crossref PubMed Scopus (10449) Google Scholar,2Mauri T. Cambiaghi B. Spinelli E. Langer T. Grasselli G. Spontaneous breathing: a double-edged sword to handle with care.Ann Transl Med. 2017; 5: 292Crossref PubMed Scopus (42) Google Scholar Early switch to assisted ventilation modes carries significant benefits, including reduced sedation and improved hemodynamics.2Mauri T. Cambiaghi B. Spinelli E. Langer T. Grasselli G. Spontaneous breathing: a double-edged sword to handle with care.Ann Transl Med. 2017; 5: 292Crossref PubMed Scopus (42) Google Scholar Approximately 30% of invasively ventilated patients breathe spontaneously by day 1 from intubation and, by day 7, pressure support ventilation (PSV) is the most widely used mode of ventilation worldwide.3Bellani G. Laffey J.G. Pham T. et al.Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.JAMA. 2016; 315: 788-800Crossref PubMed Scopus (2949) Google Scholar Multiple physiologic studies showed that use of sighs could be an interesting addition to pressure support ventilation. Sigh may improve lung function through improved lung elastance,4Patroniti N. Foti G. Cortinovis B. et al.Sigh improves gas exchange and lung volume in patients with acute respiratory distress syndrome undergoing pressure support ventilation.Anesthesiology. 2002; 96: 788-794Crossref PubMed Scopus (102) Google Scholar decreased regional heterogeneity,5Mauri T. Eronia N. Abbruzzese C. et al.Effects of sigh on regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing assisted mechanical ventilation.Crit Care Med. 2015; 43: 1823-1831Crossref PubMed Scopus (50) Google Scholar increased release of active surfactant,6Massaro G.D. Massaro D. Morphologic evidence that large inflations of the lung stimulate secretion of surfactant.Am Rev Respir Dis. 1983; 127: 235-236PubMed Google Scholar and decreased effort,5Mauri T. Eronia N. Abbruzzese C. et al.Effects of sigh on regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing assisted mechanical ventilation.Crit Care Med. 2015; 43: 1823-1831Crossref PubMed Scopus (50) Google Scholar the latter being protective also for the diaphragm. Moreover, sigh has been shown to allow a reduction in tidal volume and respiratory rate, reducing the ventilation load applied to the lungs.4Patroniti N. Foti G. Cortinovis B. et al.Sigh improves gas exchange and lung volume in patients with acute respiratory distress syndrome undergoing pressure support ventilation.Anesthesiology. 2002; 96: 788-794Crossref PubMed Scopus (102) Google Scholar,5Mauri T. Eronia N. Abbruzzese C. et al.Effects of sigh on regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing assisted mechanical ventilation.Crit Care Med. 2015; 43: 1823-1831Crossref PubMed Scopus (50) Google Scholar,7Nacoti M. Spagnolli E. Bonanomi E. Barbanti C. Cereda M. Fumagalli R. Sigh improves gas exchange and respiratory mechanics in children undergoing pressure support after major surgery.Minerva Anestesiol. 2012; 78: 920-929PubMed Google Scholar These studies generated the hypothesis that addition of sigh to PSV might improve clinical outcomes of patients with AHRF and ARDS. However, no randomized clinical trial (RCT) on sigh addition to PSV has ever been performed, and, before conducting a larger trial aimed at verifying improved survival, we first conceived a pilot RCT to verify the clinical feasibility of sigh in comparison with standard PSV8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar and to have preliminary estimates of adverse events, loss to follow-up, outcomes, and its variabilities. A noninferiority approach was chosen to demonstrate that application of sigh in the clinical setting is as feasible as standard PSV, which is the most widely adopted assisted ventilation mode. In the present trial, sigh was applied early after switching to PSV in intubated patients with AHRF or ARDS and maintained until successful weaning, death, or day 28. The study aimed at attesting the noninferiority of sigh, as compared with standard PSV without sigh, in terms of failure of assisted ventilation. Failure was defined as the occurrence of any of the following conditions: switch back to controlled ventilation, use of rescue therapies for refractory hypoxemia, and reintubation. Secondary outcomes included comparison between the two study arms in the incidence of adverse events, physiologic parameters, survival, and ventilator-free days. The present study was a pilot RCT conducted between December 2017 and May 2019 at the ICUs of 20 hospitals from eight countries: Italy, Spain, United Kingdom, Germany, Slovenia, Greece, China, and Brazil. Centers were recruited through a call to members of the Pleural Pressure Working Group (PLUG) of the European Society of Intensive Care Medicine (ESICM) and through publication of the protocol on the ESICM website. The ESICM also endorsed and funded, in part, the study. The study design and statistical analysis plan have been published.8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico (international leading coordination center, June 6, 2017, No. 318). The institutional review boards of all centers approved the trial. The study was registered at ClinicalTrials.gov.9National Institutes of Health Clinical Center. Sigh in Acute Hypoxemic Respiratory Failure (PROTECTION). NCT03201263. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; https://clinicaltrials.gov/ct2/show/NCT03201263. Updated July 2, 2017.Google Scholar Informed consent was obtained for all individual participants included in the study, in accordance with local regulations. The trial enrolled patients admitted to each participating ICU and receiving invasive ventilation for > 24 h and ≤ 7 days, undergoing PSV for ≥ 4 and ≤ 24 h, with a Pao2/Fio2 ratio ≤ 300 mm Hg and clinical positive end-expiratory pressure (PEEP) ≥ 5 cm H2O. The Richmond Agitation-Sedation Scale10Sessler C.N. Gosnell M.S. Grap M.J. et al.The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients.Am J Respir Crit Care Med. 2002; 166: 1338-1344Crossref PubMed Scopus (2380) Google Scholar value at enrollment had to be between –2 and 0. Exclusion criteria can be found in e-Appendix 1. After enrollment, all patients underwent a 30-min test of addition of sigh to clinical PSV to assess the prevalence of sigh responders vs nonresponders as defined by improved oxygenation. Briefly, the ventilator Fio2 was titrated to obtain a peripheral oxygen saturation (Spo2) of 90% to 96%, while keeping the same clinical PEEP and PSV levels. Sigh was then added as a pressure control phase set at total end-inspiratory pressure of 30 cm H2O for a 3-s insufflation time, once per minute. At the beginning and after 30 min, the Spo2/Fio2 ratio was determined. On the basis of a previous physiologic study, the expected prevalence of sigh responders (ie, patients improving Spo2/Fio2 by > 1%) was estimated to be 50%.5Mauri T. Eronia N. Abbruzzese C. et al.Effects of sigh on regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing assisted mechanical ventilation.Crit Care Med. 2015; 43: 1823-1831Crossref PubMed Scopus (50) Google Scholar After completion of the sigh test, patients were randomized by a 1:1 ratio to a strategy of PSV titrated according to a predefined protocol with addition of sigh (sigh group) or to a strategy of PSV titrated according to the same protocol but without sigh (no-sigh group). The local investigators randomized patients using a central, dedicated, password-protected, web-based, automated randomization system. The randomization sequence was generated using a permuted blocks randomization scheme (block size of six). After randomization, in the sigh group, PSV was targeted to a tidal volume of 6 to 8 mL/kg of predicted body weight (PBW), with a respiratory rate 20 to 35 breaths/min (bpm) and clinical PEEP. Fio2 was left as selected during the prerandomization sigh test. Sigh was promptly added as a pressure control breath at total end-inspiratory pressure of 30 cm H2O for 3 s delivered once per minute. Ventilators were switched to biphasic synchronized positive airway pressure mode (also known as synchronized intermittent mandatory ventilation combining pressure control and PSV) with the lower pressure level set at clinical PEEP and the higher pressure level set at 30 cm H2O with a 3-s inspiratory time. Sigh settings were left unchanged until switch to controlled ventilation, day 28, death, or performance of a successful spontaneous breathing trial (SBT; see below). In the no-sigh group, after randomization, PSV was set to obtain the same targets as above with clinical PEEP and the Fio2 selected during the prerandomization sigh test. Then, in both groups at least every 8 h, the PSV level was adjusted to maintain a tidal volume of 6 to 8 mL/kg PBW and respiratory rate of 20 to 35 bpm, while PEEP and Fio2 were managed to keep the Spo2 at 90% to 96%. In both groups, switch to protective controlled ventilation was indicated when patients fulfilled specific predefined criteria.8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar Patients switched to controlled ventilation were reassessed at least every 8 h and switched back to the sigh or no-sigh group as soon as predefined criteria for improvement were met.8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar Patients with Spo2 ≥ 90% on Fio2 ≤ 0.4 and PEEP ≤ 5 cm H2O, no agitation, and who were hemodynamically stable underwent an SBT. For patients in the sigh group, the attending physician withdrew sigh, waited 60 min, confirmed the above-mentioned criteria, and performed the SBT; if criteria were no longer met, sigh was reintroduced and this procedure was repeated after at least 8 h. The SBT lasted at least 60 min with a combination of PEEP of 0 to 5 cm H2O and PSV level of 0 to 5 cm H2O. Criteria for success vs failure of the SBT were predefined by study protocol.8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar Subjects successfully completing the SBT were promptly extubated or, in the presence of tracheostomy, mechanical ventilation was discontinued. Patients who failed the SBT were switched back to the sigh or no-sigh group, and criteria for SBT were checked again after at least 6 h. After extubation, reintubation was performed if at least one of the criteria predefined by the study protocol was present.8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar The primary end point of this trial8Mauri T. Foti G. Fornari C. et al.PROTECTION Study GroupPressure support ventilation + sigh in acute hypoxemic respiratory failure patients: study protocol for a pilot randomized controlled trial, the PROTECTION trial.Trials. 2018; 19: 460Crossref PubMed Scopus (2) Google Scholar was to assess noninferiority of sigh feasibility vs no sigh by comparing the number of patients in each group experiencing at least one of the following criteria for failure of assisted ventilation: switch to controlled ventilation for ≥ 24 h (consecutive); use of rescue therapy; and reintubation within 48 h. Secondary outcomes included the following: comparison of selected physiologic variables during the first 7 days from randomization in the two study groups; evaluation of the clinical safety of sigh vs no sigh by comparing the incidence of predefined adverse events; quantification of responders and nonresponders to the prerandomization sigh test; 28-day mortality and ventilator-free days in the two study groups and in responders and nonresponders. On the basis of previous data,11Xirouchaki N. Kondili E. Vaporidi K. et al.Proportional assist ventilation with load-adjustable gain factors in critically ill patients: comparison with pressure support.Intensive Care Med. 2008; 34: 2026-2034Crossref PubMed Scopus (114) Google Scholar we computed that a sample size of 258 patients (with 129 patients per study arm) was sufficient to assess feasibility of the sigh strategy (primary outcome), using a noninferiority test with a tolerance of 5%, power of 0.8, α 0.05, and 22% and 15% as the expected rate of failure of assisted ventilation in patients undergoing no-sigh and sigh treatment, respectively. Failure of assisted ventilation in patients treated with sigh was compared with patients with no sigh, using a one-tailed noninferiority test for proportions with a 5% tolerance. In details, noninferiority of sigh was established when failure in the sigh group was lower than failure of no sigh plus 5%. This is the standard alternative hypothesis for noninferiority tests.12Walker E. Nowacki A.S. Understanding equivalence and noninferiority testing.J Gen Intern Med. 2011; 26: 192-196Crossref PubMed Scopus (504) Google Scholar Thus, in this study, a P value less than .05 (type I error) for the noninferiority test would reject inferiority of the new treatment (sigh) compared with no sigh. Survival at day 28 was analyzed using Kaplan-Meier curves, and the log-rank test was used to test differences between curves. Continuous variables are described by mean and SD when normally distributed or as median and interquartile range otherwise. Categorical variables are reported as number and proportion (%). Statistical significance of differences between the two study groups (sigh vs no sigh) was tested using χ2 or Fisher exact test for categorical variables, t-test for continuous normally distributed variables, and Wilcoxon signed-rank test for nonnormally distributed continuous variables. To test differences in time trends of physiologic and clinical parameters between the two study groups we used generalized estimating equation models to account for repeated measures. One thousand and sixty-four intubated ICU patients undergoing PSV were screened. A total of 806 were not enrolled, of whom 726 (90%) met at least one of the exclusion criteria and 80 (10%) were eligible but could not be enrolled for various reasons (Fig 1). Two hundred and fifty-eight patients completed the sigh test and were subsequently randomized, 129 to the sigh group and 129 to the no-sigh group. None of the patients withdrew consent after randomization. Sigh was applied for 4 (2-9) days in the sigh group. Follow-up until day 28 was complete for all patients. Data for 258 subjects (129 in each group) were considered for the primary intention-to-treat analysis (Fig 1). Three patients in the sigh group and two patients in the PSV group were not included in the per-protocol analysis because of switch to the other study arm, due to adverse event, discomfort, and hypoxemia; 126 patients in the sigh group and 127 in the no-sigh group were kept for the per-protocol analysis. Baseline characteristics were well balanced between the two study groups (Table 1). Men represented 67% (87 patients) and 71% (92 patients) in the sigh group and in the no-sigh group, respectively. The mean age of patients was 63 ± 15 years, with no significant difference between groups. The prevalence of comorbidities and general severity at admission were comparable (Table 1). The prevalence of the diagnosis of ARDS was 46% in the sigh group and 53% in the no-sigh group, with nonsignificant difference (Table 1).Table 1Baseline CharacteristicsCharacteristicsSigh(n = 129)No Sigh(n = 129)P ValueaTests for differences between PSV plus sigh vs PSV: t-test or Wilcoxon, χ2, or Fisher, as appropriate.Demographics Men, No. (%)87 (67)92 (71).499 Age, mean (SD), y63 (17)63 (14).676 Height, median (Q1, Q3), cm170 (165, 178)170 (160, 176).298 Predicted body weight, median (Q1, Q3), kg80 (67, 90)78 (65, 86).432 BMI, median (Q1, Q3), kg/m226.1 (23.4, 31.0)26.2 (23.5, 29.7).967Comorbidities, No. (%) Chronic cardiovascular disease66 (51)79 (61).103 Chronic pulmonary disease19 (15)27 (21).193 Diabetes26 (20)28 (22).735 Chronic renal disease14 (11)24 (19).079 Cancer13 (10)18 (14).338No. of comorbidities, No. (%) 040 (34)32 (25).199 148 (37)44 (35) 223 (18)31 (24) ≥ 314 (11)21 (16)Recent medical history In-hospital days, median (Q1, Q3)5 (3, 8)5 (3, 8).785 ICU days, median (Q1, Q3)3 (2, 5)3 (2, 5).513 Intubation days, median (Q1, Q3)3 (2, 5)3 (2, 4).358 SAPS II, median (Q1, Q3)42 (32, 55)42 (32, 56).796 SOFA, median (Q1, Q3)7 (5, 10)7.5 (5, 9).857 RASS, No. (%)–264 (50)72 (56).588–127 (21)25 (19)038 (29)32 (25)Diagnosis of sepsis, No. (%) Sepsis43 (33)39 (30).144 Septic shock20 (15)35 (27) No sepsis60 (47)51 (40) Not specified6 (5)4 (3)Etiology Pneumonia, No. (%)79 (61)75 (58).612 Aspiration of gastric content, No. (%)15 (12)11 (9).408 Vasculitis, No. (%)1 (1)1 (1)1.000 Nonpulmonary sepsis, No. (%)20 (16)24 (19).508 Trauma, No. (%)8 (6)6 (5).583 Pancreatitis, No. (%)4 (3)4 (3)1.000 Burns, No. (%)1 (1)1 (1)1.000 TRALI, No. (%)3 (2)4 (3).702 Other, No. (%)15 (12)16 (12).848Pulmonary infiltrates, No. (%) None28 (22)22 (17).427 Unilateral42 (33)38 (30) Bilateral (ARDS diagnosis)59 (46)69 (53)PEEP, median (Q1, Q3), cm H2O10 (8, 12)10 (8, 11).487PSV, median (Q1, Q3), cm H2O10 (8, 12)10 (8, 12).967RR, median (Q1, Q3), bpm18 (10, 30)18 (15, 23).445pH, mean (SD)7.43 (0.05)7.43 (0.06).510Pao2/Fio2, median (Q1, Q3), mm Hg222 (192, 252)228 (187, 251).991Paco2, median (Q1, Q3), mm Hg44 (38, 49)43 (39, 47).695Continuous data are reported as median (Q1, Q3) or mean (SD). Categorical data are reported as No. (%). bpm = breaths/min; PEEP = positive end-expiratory pressure; PSV = pressure support ventilation; RASS = Richmond Agitation-Sedation Scale; RR = respiratory rate; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment; TRALI = transfusion-related acute lung injury.a Tests for differences between PSV plus sigh vs PSV: t-test or Wilcoxon, χ2, or Fisher, as appropriate. Open table in a new tab Continuous data are reported as median (Q1, Q3) or mean (SD). Categorical data are reported as No. (%). bpm = breaths/min; PEEP = positive end-expiratory pressure; PSV = pressure support ventilation; RASS = Richmond Agitation-Sedation Scale; RR = respiratory rate; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment; TRALI = transfusion-related acute lung injury. Twenty-eight days after randomization, 30 patients (23%) in the sigh group vs 39 (30%) in the no-sigh group (Table 2) experienced at least one criterion for failure of assisted ventilation. The sigh treatment group was therefore noninferior to the no-sigh treatment group in terms of failure of assisted ventilation (absolute difference, –7%; 95% CI, –18% to 4%; P = .015 for noninferiority test) (Fig 2). Specific reasons for failure of assisted ventilation and type of rescue treatment are shown in Table 2. Per-protocol analysis showed similar results with 29 patients (23%) failing to remain on assisted ventilation in the sigh group vs 37 (29%) in the no-sigh group (absolute difference, –6%; 95% CI, –17% to 5%; P = .022 for noninferiority test).Table 2Study OutcomesOutcomesSigh(n = 129)No Sigh(n = 129)P ValueaTests for differences between sigh and no sigh: noninferiority for "failure of assisted ventilation"; χ2 or Fisher for other variables.Failure of assisted ventilation, No. (%), noninferiority test30 (23)39 (30).015Reasons for failure Switch to controlled MV ≥ 24 h, No. (%)15 (12)26 (20).061 Rescue treatment for hypoxemia, No. (%)14 (11)19 (15).351 Reintubation within 48 h, No. (%)13 (9)12 (9).833Type of rescue treatment, No. (%) Recruitment maneuver9 (7)14 (11).735 PEEP ≥ 15 cm H2O3 (2)2 (2) Prone position2 (2)3 (2)Reasons for switch to MV, No. (%) Support > 20 cm H2O or arterial pH < 7.34 (3)8 (6).262 PEEP ≥ 15 cm H2O or Pao2/Fio2 ≤ 100 mm Hg8 (6)8 (6) Hypotension or hypertension0 (0)1 (1) Active cardiac ischemia or unstable arrhythmias0 (0)1 (1) RASS < –3 or RASS > 23 (2)5 (4) Necessity to perform diagnostic test0 (0)3 (2)Adverse events, No. (%)16 (12)17 (13).852Type of adverse event, No. (%) Hemodynamic instability5 (4)6 (5)1.00 Arrhythmias2 (2)2 (2) Barotrauma9 (7)9 (7)Sigh responders,bSpo2/Fio2 increase > 1% during the prerandomization sigh test. No. (%)73 (56)83 (64).609Tracheostomy, No. (%)22 (17)19 (15).441Deaths at 28 d, No. (%)21 (16)27 (21).337VFDs, median (Q1, Q3)22 (7, 26)22 (3, 25).300Length of ICU stay, median (Q1, Q3), d7 (3, 13)7 (5, 11).695Continuous data are reported as median (Q1, Q3) or mean (SD). Categorical data are reported as No. (%). MV = mechanical ventilation; PEEP = positive end-expiratory pressure; PSV = pressure support ventilation; RASS = Richmond Agitation-Sedation Scale; VFDs = ventilator-free days.a Tests for differences between sigh and no sigh: noninferiority for "failure of assisted ventilation"; χ2 or Fisher for other variables.b Spo2/Fio2 increase > 1% during the prerandomization sigh test. Open table in a new tab Continuous data are reported as median (Q1, Q3) or mean (SD). Categorical data are reported as No. (%). MV = mechanical ventilation; PEEP = positive end-expiratory pressure; PSV = pressure support ventilation; RASS = Richmond Agitation-Sedation Scale; VFDs = ventilator-free days. Adverse events (ie, hemodynamic instability, arrhythmias, and barotrauma) did not differ between the two study groups (16 patients [12%] in the sigh group vs 17 patients [13%] in the no-sigh group; P = .852). Types of adverse events are described in Table 2. Twenty-one patients (16%) died by day 28 in the sigh group vs 27 patients (21%) in the no-sigh group (P = .337) (Table 2). Survival was analyzed by Kaplan-Meier curves (Fig 3) (P = .342 by log-rank test). Ventilator-free days on day 28 were 22 (7-26) days in the sigh group and 22 (3-25) in the no-sigh group (P = .300) (Table 2). The number of patients failing an SBT was 23 (18%) in the sigh group and 21 (16%) in the no-sigh group (P = .741). The number of SBTs failed was 1 (1-2) per patient for both groups, with no significant difference. Sigh responders, defined as patients in whom the Spo2/Fio2 ratio increased by > 1% during the sigh prerandomization test, numbered 156 (60%): 73 (47%) in the sigh group and 83 (53%) in the no-sigh group. Thus, nonresponders numbered 102: 56 (55%) in the sigh group and 46 (45%) in the no-sigh group. Baseline demographics and clinical characteristics did not differ between the study groups both for responders and nonresponders (e-Table 1, e-Table 2). In responders, mortality was 16% (n = 12) in the sigh group vs 13% (n = 11) in the no-sigh group (P = .575). In nonresponders, mortality was 16% (n = 9) in the sigh group vs 35%
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