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The n e w e ng l a n d j o u r na l of m e dic i n e

original article

A Trial of Intraoperative Low-Tidal-Volume
Ventilation in Abdominal Surgery
Emmanuel Futier, M.D., Jean-Michel Constantin, M.D., Ph.D.,
Catherine Paugam-Burtz, M.D., Ph.D., Julien Pascal, M.D.,
Mathilde Eurin, M.D., Arthur Neuschwander, M.D., Emmanuel Marret, M.D.,
Marc Beaussier, M.D., Ph.D., Christophe Gutton, M.D., Jean-Yves Lefrant, M.D., Ph.D.,
Bernard Allaouchiche, M.D., Ph.D., Daniel Verzilli, M.D., Marc Leone, M.D., Ph.D.,
Audrey De Jong, M.D., Jean-Etienne Bazin, M.D., Ph.D., Bruno Pereira, Ph.D.,
and Samir Jaber, M.D., Ph.D., for the IMPROVE Study Group*

A BS T R AC T

From the Département d’Anesthésie et Ré­ BACKGROUND
animation, Hôpital Estaing (E.F., J.-M.C., Lung-protective ventilation with the use of low tidal volumes and positive end-
J.P., J.-E.B.), Université de Clermont-Fer-
rand, Retinoids, Reproduction, and Devel- expiratory pressure is considered best practice in the care of many critically ill
opmental Diseases Unit, Équipe Accueil patients. However, its role in anesthetized patients undergoing major surgery is
7281 (E.F., J.-M.C.), and the Biostatistics
Unit, Direction de la Recherche Clinique
not known.
(B.P.), Centre Hospitalier Universitaire
(CHU) de Clermont-Ferrand, Clermont- METHODS
Ferrand; Assistance Publique–Hôpitaux de In this multicenter, double-blind, parallel-group trial, we randomly assigned 400
Paris (AP-HP), Département d’Anesthé­
sie et Réanimation, Hôpital Beaujon, Hôpi-
adults at intermediate to high risk of pulmonary complications after major ab-
taux Universitaires Paris Nord Val de Seine dominal surgery to either nonprotective mechanical ventilation or a strategy of
and Université Paris Diderot, Sorbonne lung-protective ventilation. The primary outcome was a composite of major pul-
Paris Cité (C.P.-B., M.E., A.N.), Départe­
ment d’Anes­thé­sie et Réanimation, Hôpi-
monary and extrapulmonary complications occurring within the first 7 days after
tal Tenon (E.M.), and AP-HP, Départe­ surgery.
ment d’Anes­thé­sie et Réanimation,
Hô­pi­tal Saint-Antoine (M.B., C.G.), Paris; RESULTS
CHU de Nîmes, Section d’Anesthésie
and Dé­partement d’Anesthésie et Réani-
The two intervention groups had similar characteristics at baseline. In the inten-
mation, Nîmes (J.-Y.L.); CHU de Lyon, tion-to-treat analysis, the primary outcome occurred in 21 of 200 patients (10.5%)
Département d’Anesthésie et Réanima- assigned to lung-protective ventilation, as compared with 55 of 200 (27.5%) assigned
tion, Hôpi­tal Edouard Herriot, Lyon (B.A.);
CHU de Montpellier, Département d’Anes­
to nonprotective ventilation (relative risk, 0.40; 95% confidence interval [CI], 0.24
thésie et Réanimation B, Hôpital Saint- to 0.68; P = 0.001). Over the 7-day postoperative period, 10 patients (5.0%) assigned
Eloi, and INSERM Unité 1046 and Univer- to lung-protective ventilation required noninvasive ventilation or intubation for
sité Montpellier 1, Montpellier (D.V., A.D.J.,
S.J.); and Assistance Publique–Hôpital
acute respiratory failure, as compared with 34 (17.0%) assigned to nonprotective
de Marseille, Département d’Anesthésie ventilation (relative risk, 0.29; 95% CI, 0.14 to 0.61; P = 0.001). The length of the hospi-
et Réanimation, Hôpital Nord, Marseille tal stay was shorter among patients receiving lung-protective ventilation than among
(M.L.) — all in France. Address reprint re-
quests to Dr. Jaber at the Département those receiving nonprotective ventilation (mean difference, −2.45 days; 95% CI,
d’Anesthésie et Réanimation B (DAR B), −4.17 to −0.72; P = 0.006).
80 Ave. Augustin Fliche, 34295 Montpellier,
France, or at s-jaber@chu-montpellier.fr. CONCLUSIONS
* Additional investigators in the Intraop- As compared with a practice of nonprotective mechanical ventilation, the use of
erative Protective Ventilation (IMPROVE)
Study Group are listed in the Supplemen- a  lung-protective ventilation strategy in intermediate-risk and high-risk patients
tary Appendix, available at NEJM.org. undergoing major abdominal surgery was associated with improved clinical out-
N Engl J Med 2013;369:428-37. comes and reduced health care utilization. (IMPROVE ClinicalTrials.gov number,
DOI: 10.1056/NEJMoa1301082
Copyright © 2013 Massachusetts Medical Society.
NCT01282996.)

428 n engl j med 369;5  nejm.org  august 1, 2013

The New England Journal of Medicine
Downloaded from nejm.org on February 21, 2017. For personal use only. No other uses without permission.
Copyright © 2013 Massachusetts Medical Society. All rights reserved.

19. Patients were screened and underwent random- diators. For personal use only. large cohort studies have shown that 20 to study protocol and statistical analysis plan were 30% of patients undergoing surgery with gen. All rights reserved. including the statistical analysis tidal volumes (10 to 15 ml per kilogram of pre.1 Postoperative pulmo. and recruitment maneuvers complications5 of more than 2. through systemic release of inflammatory me. postoperative pulmonary complications (see the n engl j med 369.5  nejm. Appendix. The members of considerable evidence from experimental and the steering committee (see the Supplementary observational studies that mechanical ventila. An independent data and safety moni- ommended to prevent hypoxemia and atelecta. PEEP. many critically ill patients.org) vouch for the tion — in particular. double-blind. at seven French university teaching hospitals. Intr aoper ative Low-Tidal-Volume Ventilation W orldwide. Mechanical ventilation with the use of high The protocol. ventilator-associated lung injury7 and contrib. available at NEJM. is available with the full text of this article at dicted body weight) has traditionally been rec.5 Saint-Etienne. We conducted the Intraoperative Protective were scheduled to undergo laparoscopic or non- Ventilation (IMPROVE) trial to determine wheth. stratified. The IMPROVE trial was an investigator-initiated. Copyright © 2013 Massachusetts Medical Society. There was no industry support or involvement in ute to extrapulmonary organ dysfunction the trial. 2017. uses risk classes that range from 1 to 5. which is a factor the acute respiratory distress syndrome11 and is that may influence outcomes.14 some physicians have questioned the collected data during surgery were aware of the benefits of using lung-protective ventilation in group assignments. and protective ventilation that combined low tidal had a preoperative risk index for pulmonary volumes. however. No other uses without permission. comes and health care utilization. Although the staff members who tion.3 Previ. the statistician. and the data and safety monitor- proach may be beneficial in a broader popula.6 There is. clinical trial. more than 230 million ME THODS patients undergoing major surgery each year require general anesthesia and TRIAL DESIGN AND OVERSIGHT mechanical ventilation.2 so preven. the use of low tidal volumes and positive end. and which may also randomization from each patient. and August 10. outcome assessors were un- the surgical setting. Randomization was performed with tion of these complications has become a the use of a computer-generated assignment se- measure of the quality of hospital care.9 ization between January 31. laparoscopic elective major abdominal surgery1 er a multifaceted strategy of prophylactic lung. Randomization was stratified accord- odic hyperinflation of the lungs). with an expected duration of at least 2 hours. fore surgery. plan. reviewed blinded safety data. The risk index could improve outcomes after abdominal sur. Lung-protective ventilation.15-18 especially since the use aware of these assignments throughout the study.10 has been ing to study site and the planned use or nonuse of shown to reduce mortality among patients with postoperative epidural analgesia.20 study if they were older than 40 years of age. which refers to 2012. research staff. toring committee oversaw the study conduct and sis in anesthetized patients. 2011. approved for all centers by a central ethics commit- eral anesthesia are at intermediate to high risk tee (Comité de Protection des Personnes Sud-Est I. with gery. France) according to French law.org on February 21. quence and a centralized telephone system. Written informed consent was obtained before expiratory pressure (PEEP). . 2013 429 The New England Journal of Medicine Downloaded from nejm. on the day be- include the use of recruitment maneuvers (peri.org  august 1. NEJM. parallel-group.21 Treatment assign- now considered best practice in the care of ments were concealed from patients.4. of high tidal volumes and no PEEP is still com- monplace and less than 20% of patients receive PATIENTS protective ventilation in routine anesthetic Patients were eligible for participation in the practice. for postoperative pulmonary complications. high tidal volumes that accuracy and completeness of the data and analy- cause alveolar overstretching — can initiate ses and the fidelity of the study to the protocol. The ous. nary complications adversely affect clinical out.13.8. ing committee. multicenter.org. as compared with the standard practice of higher risk classes indicating a higher risk of nonprotective mechanical ventilation.12 Although this ap.

assuming a 20% rate of the use of PEEP. Copyright © 2013 Massachusetts Medical Society. The n e w e ng l a n d j o u r na l of m e dic i n e Supplementary Appendix). tory failure. 430 n engl j med 369. at a two- in patients assigned to nonprotective ventilation. fined according to consensus criteria). analysis was conducted after the enrollment of erative and postoperative periods. the first 200 patients. use of statistical analysis plan. reoperation (all defined according to consensus The predicted body weight was calculated for criteria22. a transient increase in the fraction of in. For personal use only.org on February 21. Major extrapulmonary complications were de- square of the height in meters) of 35 or higher. administration of fluids. each patient with the use of previously defined formulas. severe sepsis and septic shock.22 or death. surgical complications. acute lung injury. or low-up period were the incidence of pulmonary had a progressive neuromuscular illness. the need for invasive or 8 ml per kilogram of predicted body weight.05. anastomotic leakage. defined ac- recruitment maneuver consisted of applying a cording to standard criteria (see the Supplementary continuous positive airway pressure of 30 cm of Appendix). 2017. in the 2 weeks preceding surgery. occurring by day 7 after surgery. a plateau the systemic inflammatory response syndrome pressure of no more than 30 cm of water was (SIRS). had a require. Secondary outcomes within the 30-day fol- ment for intrathoracic or emergency surgery. pneumonia. were made by the attending uation of the trial on the basis of that analysis. No other uses without permission. and recruitment ma. <2 hours).11 For episodes of arterial desaturation STATISTICAL ANALYSIS (defined as a peripheral oxygen saturation of We calculated that a sample of 400 patients ≤92%). an interim other aspects of patient care during the intraop. The data and safety mon- prophylactic antibiotic agents. and targeted in each group. had a body-mass or noninvasive ventilation for acute respiratory fail- index (the weight in kilograms divided by the ure. with no PEEP and no re. the development of postoperative neuvers repeated every 30 minutes after tracheal atelectasis. and the intubation (the protective-ventilation group). in particular. sided alpha level of 0. would provide 80% power to detect a relative dif- spired oxygen (Fio2) to 100% was permitted. a noninvasive ventilation because of acute respira- PEEP of 6 to 8 cm of water. fined as sepsis. if required.25 For safety reasons. tary Appendix). or lung. graded on a scale from 0 (no pulmonary complications) to 4 (the INTERVENTIONS most severe complications)23 (see the Supplemen- Patients were assigned to receive volume-con. During anesthesia. severe sepsis and septic shock (de- had a history of respiratory failure or sepsis with. un- of two strategies: nonprotective ventilation with expected need for admission to the intensive a tidal volume of 10 to 12 ml per kilogram of care unit (ICU). Extrapulmonary complications in­cluded water for 30 seconds.24). and unplanned (see the Supplementary Appendix).org  august 1. recruitment maneuvers. as previously described20 of death from any cause 30 days after surgery. Each acute respiratory distress syndrome. surgery was stopped prematurely in 2 of the 3 pa- OUTCOMES tients because of extensive illness (duration of sur- The primary outcome was a composite of major gery. and 1 had undergone random- pulmonary and extrapulmonary complications ization in error (violation of exclusion criteria). see the if they had received mechanical ventilation within Supplementary Appendix) or the need for invasive the 2 weeks preceding surgery.5  nejm. Pulmonary complications were analyzed sepa- protective ventilation with a tidal volume of 6 to rately. and ference of 50% in the primary outcome. All rights reserved. . 2013 The New England Journal of Medicine Downloaded from nejm. including gen. complications due to any cause. (the nonprotective-ventilation group). of 3 patients were excluded after randomization. physician according to the expertise of the staff and 400 patients were therefore included. according to the a priori eral anesthesia. A total at each center and routine clinical practice. and the rate cruitment maneuvers. durations of ICU and hospital stays. Major pulmo. including intraabdomi- cedures were identical in the two study groups nal abscess. Patients were ineligible (defined according to standard criteria. Decisions about all ventilation group. sepsis. ventilation-related adverse events trolled mechanical ventilation according to one during surgery. and postoperative itoring committee did not recommend discontin- pain management. postoperative gas exchange. All other ventilation pro. or both postoperative complications in the nonprotective- was allowed. extrapulmonary complications. predicted body weight. An additional 3 patients were thus randomly as- nary complications were defined as pneumonia signed to a study group to obtain the full sample.

2017. A total of 1803 patients awaiting abdominal surgery were assessed preoperatively for trial eligibility by the research staff. and 1 had undergone randomization in error. owing to extensive illness.org on February 21. 3 patients were excluded. All rights reserved.org  august 1. An un­ Fisher’s exact test. cedure was used to adjust for multiple testing of ysis was used to identify relevant baseline covariates components of the composite primary outcome. 2013 431 The New England Journal of Medicine Downloaded from nejm. in addition Adjusted analyses were performed with the use to the stratification variables (use or nonuse of of the same adjustment variables that were used epidural analgesia and study center). Con- tested in the model were selected if the P value tinuous variables were compared with the use of was less than 0. 2 patients were excluded because surgery was stopped prematurely (duration. 1). An addi- tional 3 patients were then enrolled in the study.10 and if they were clinically rel. and Follow-up of Patients. Randomization.27 associated with the primary outcome. n engl j med 369. evant. No other uses without permission. Adjusted analyses were performed with the Adjusted analyses were performed with the use 1803 Patients were scheduled to undergo elective abdominal surgery 1202 Were ineligible 47 Were ≤40 yr of age 102 Had expected duration of surgery of <2 hr 1053 Had preoperative risk index for pulmonary complications of <2 601 Underwent screening 198 Were excluded 49 Declined to participate 149 Met exclusion criteria 400 Underwent randomization 3 Were excluded after randomization 2 Had extensive illness (surgery <2 hr) 1 Had violation of exclusion criteria (age ≤40 yr) An additional 3 underwent randomization 200 Were assigned to receive nonprotective 200 Were assigned to receive lung-protective mechanical ventilation mechanical ventilation 200 (100%) Were included in 30-day analysis 200 (100%) Were included in 30-day analysis Figure 1. an unpaired t-test or the Mann–Whitney U test. For personal use only. Multiple logistic-regression anal. A total of 400 patients were included in the modified intention-to-treat analysis and were followed for 30 days after surgery. . Assessment. Copyright © 2013 Massachusetts Medical Society. The Hochberg pro- outcome analysis. Intr aoper ative Low-Tidal-Volume Ventilation All analyses were conducted on data from the use of robust Poisson generalized-linear-model re­ modified intention-to-treat population. gression26 and are presented as relative risks with cluded all patients who underwent randomization 95% confidence intervals. Variables in the robust Poisson regression analysis. A chi-square test (or except the three who were excluded (Fig. <2 hours). as appropriate) was used for adjusted chi-square test was used for the primary secondary binary outcomes.5  nejm. which in. After randomization.

5) INTRAOPERATIVE PROCEDURES Type of surgery — no.5) ventilation but was included in the analysis for Any alcohol intake 10 (5. No other uses without permission.0) 44 (22. 6 to 12).0) 47 (23.0%) in the nonprotective-ventilation group and previous 6 mo in 159 (79.5) 116 (58.0) 99 (49. and values remained within tar- Diagnosis — no. Mean (±SD) tidal volumes Liver resection 52 (26.0) 8 (4. (%) 88 (44. 50+0.11 of these measures was 0 (interquartile range. Cancer 164 (82.3±9. group differences in type and duration of sur- § The preoperative risk index for pulmonary complications5 uses risk classes that range from 1 to 5. volume of fluids administered. 0 to ‡ The body-mass index is the weight in kilograms divided by the square of the 0) (Table 2).6±11. (%) get ranges throughout the intraoperative period. There were no significant between- height in meters.5) PEEP was 6 cm of water (interquartile range.0) 155 (77.0) group (P<0. (%) 121 (60.0) 45 (22.0) 6 (3.05).4).0 169. and need for ble for participation in the study.0) of daily living Baseline characteristics were similar between the Chronic obstructive pulmonary 20 (10. 45. (%) 44 (22. All rights reserved.4±0.5) of 1803 patients awaiting abdominal surgery were Preoperative risk index — no.91(height in centimeters − 152. Open laparotomy. Laparoscopic surgery — no.0) 21 (10. Five patients in the ¶ All factors listed as coexisting conditions were included in the preoperative risk index as predictors of postoperative pulmonary complications. was performed in 156 patients Loss of >10% of body weight in 44 (22. For personal use only.8±3. Copyright © 2013 Massachusetts Medical Society. blood postoperative complications. Data on the primary outcome were available for all patients.0) 40 (20.8 24. Age — yr 63.4±10.0) (78. Patients with a risk class of 2 or more were eligi.05 was considered to indicate Body weight — kg statistical significance.org on February 21.001).2 Predicted† 63. A total of 400 pa- Risk class 2 100 (50.0) 41 (20. in the the two groups (P>0.5  nejm. A two-sided Height — cm 169.5) tive-ventilation group.8 Colorectal resection 40 (20. 6 to 8). and the median number of recruitment maneu- * Plus–minus values are means ±SD.0) 20 (10.0) 93 (46. Baseline Characteristics of the Patients.0) 101 (50. . The time-to-event Nonprotective Lung-Protective curves were calculated with the Kaplan–Meier Ventilation Ventilation method. There were no significant differences between vers was 9 (interquartile range.7 R E SULT S Body-mass index‡ STUDY POPULATION Mean 24. (%)¶ tective-ventilation group received lung-protective Current smoking 50 (25.8 From January 2011 through August 2012.0) Stata software.5) tients were included in the modified intention- Risk class 3 94 (47.0 All analyses were conducted with the use of Male sex — no. (%)§ assessed for trial eligibility.80). The n e w e ng l a n d j o u r na l of m e dic i n e of the same adjustment variables that were used Table 1. 2013 The New England Journal of Medicine Downloaded from nejm.0) 7 (3.5) 15 (7. One patient in the nonpro- Coexisting condition — no.4). a total 25–35 — no. Details regarding the handling of missing Characteristic (N = 200) (N = 200) data are provided in the Supplementary Appendix.* in the linear-regression model. use or nonuse of epidural analgesia.3±13.5) (P = 0.0) 84 (42. nonprotective-ventilation group. version 12 (StataCorp).1±1.9 71.0) operative procedures.5) 10 (5.5) the group to which he was assigned.5%) in the protective-ventilation group Long-term glucocorticoid use 4 (2. as compared with 6.8 P value of less than 0. Actual 71.8±9.4±14. loss.0) two groups (Table 1). 2017.7±3.9 63.91(height in centimeters − 152. the value for each † The predicted body weight was calculated as follows: for men.org  august 1. vasopressor administration.0 61.5) to-treat analysis and were followed for 30 days Risk class 4 or 5 6 (3. 1).0) were 11.0) after surgery (Fig.5) In the protective-ventilation group. the median Diagnosis other than cancer 36 (18. (%) Table 2 shows the distribution of the main intra- Pancreaticoduodenectomy 80 (40. and for women.1±8.1 ml per kilogram in the nonprotec- Gastrectomy 17 (8. with higher risk classes indicating a higher risk of gery.5) ml per kilogram in the protective-ventilation Other procedure 11 (5.5±9. mainly ­disease for cancer resection. nonprotective-ventilation group required at least one intraoperative rescue therapy for arterial de- 432 n engl j med 369.0) 51 (25. Not fully independent in activities 8 (4.5 + 0.

7 <0.5 15.1±1.6 0. Detailed data on intraoperative procedures are given in Table S2 in the Supplementary Appendix.001 PEEP — cm of water Baseline <0.61 * Plus–minus values are means ±SD.2±7.6 <0.0 1. † The duration of surgery was calculated as the time between skin incision and closure of the incision.001 Median 0 6 Interquartile range 0–0 6–8 No. of recruitment maneuvers <0.6 <0. n engl j med 369.8 <0.0 0.4±17.25–1.95 2–4 hr 76/192 (39. Intraoperative Procedures.8 55.org  august 1.5 Interquartile range 1. and PEEP positive end-expiratory pressure.5) 0.84 Epidural analgesia — no.5) >4–6 hr 75/192 (39.org on February 21. For personal use only.5 Interquartile range 0.9 319±139.6 46.0 Colloid 0. (%) 77 (38.9 55.0±4.0) >6 hr 41/192 (21.001 Fio2 — % 47.8 406. All rights reserved.5  nejm.5 0.97 Median 0. .5) 83 (41.4±0.001 Tidal volume — ml/kg of predicted body weight 11.0 Duration of surgery — no.9±3.3 15.001 Median 0 9 Interquartile range 0–0 6–12 Peak pressure — cm of water Baseline 20.2±2.0–3.* Nonprotective Lung-Protective Ventilation Ventilation Variable (N = 200) (N = 200) P Value Tidal volume — ml 719. Fio2 denotes inspired oxygen fraction.6±3.1 6.9 18.0 0.4±7.4 20.001 Respiratory system compliance — ml/cm of water Baseline 48./total no.02 End of surgery 16.50–1.5 2.4) 44/195 (22.0 0.1±12.0±127.1) 76/195 (39. Copyright © 2013 Massachusetts Medical Society.27 Volume of fluids administered — liters Crystalloid 0. No other uses without permission.04 End of surgery 20.06 End of surgery 45.1±4. 2013 433 The New England Journal of Medicine Downloaded from nejm.2±26.6 0.47 Median 2.6) 75/195 (38.7±75.15 Plateau pressure — cm of water Baseline 16.001 Median 0 6 Interquartile range 0–0 6–8 End of surgery <0.2±26.5–3.3 0. 2017.2±3.4 0. (%)† 0.6±4.1±4.6) Duration of mechanical ventilation — min 344±127. Intr aoper ative Low-Tidal-Volume Ventilation Table 2.

003) (Table 3).36.29 Our lung- vs. which are associated with The proportion of patients who required post.83). 95% confidence interval [CI]. 18.ent study and findings in other trials of lung- tion or noninvasive ventilation for postoperative protective ventilation during high-risk surgery. the protective-ventilation group and the nonpro- tective-ventilation group with respect to the pro- OUTCOMES portion of patients who were unexpectedly ad- Primary Outcome mitted to the ICU during the 30-day period after Major pulmonary and extrapulmonary complica. 95% CI. respectively. No other uses without permission. 2017. the Secondary Outcomes median hospital stay was shorter in the protec- One or more pulmonary complications developed tive-ventilation group than in the nonprotective- within the first 7 days after surgery in 35 patients ventilation group (Table 3). have focused on different (and not than among those who received nonprotective necessarily clinically relevant) outcomes. P = 0.5  nejm.5%) in the protective-ventilation group. 0. 19 had postoperative pneumonia and tilation or intubation) for acute respiratory failure 47 had respiratory failure requiring intubation was lower in the protective-ventilation group than or noninvasive ventilation.protective ventilation.In this trial. with no patients in the protective-ventilation There was no significant difference between group (P = 0. as compared with non­ tive-ventilation group had major (grade ≥3) pul. protective ventilation strategy resulted in a 69% 95% CI.001).49.67). 1. dominal procedures. surgery.001 by the log-rank test) (Fig. nor was there a significant tilation group.28 and mortality. Of the 400 patients operative ventilatory assistance (noninvasive ven. 95% CI.40. For personal use only.Previous trials have included small numbers of tients who received lung-protective ventilation patients. 0.org  august 1. 95% CI. 0. More patients in the non. There were no relevant between. In addition.5%.0. led to improved clinical monary complications (Table 3.postoperative complications in our study was ing the 30 days after surgery (P<0.32 to 0.0%) in the nonprotective-ventila. However. as well as the large pro- and on day 1 after surgery (Table S5 in the Supple. respectively. The n e w e ng l a n d j o u r na l of m e dic i n e saturation (PEEP in one patient. These rates are con- in the nonprotective-ventilation group during the sistent with previously reported rates of pulmo- first 7 days after surgery (10 of 200 patients [5.en­rolled.5%.portion of patients who underwent major ab- mentary Appendix). and both in two). (17.surgery (11.tive risk with protective ventilation.61. gery in 21 patients (10.001 by the log. 0. S1 neuvers in two.0 and 12.74. 2).06). P = 0. and the proportion reduction in the number of patients requiring was also lower with protective ventilation during ventilatory support within the first 7 days after the first 13 days after surgery (6.29. All rights reserved. 0.13.ventilation (P<0. adjusted relative risk with protective ventilation.49 to 1.25 This was due. Several hypotheses could explain some of P = 0.19 to 0.in part. to the exclusion of patients with a low group differences in gas exchange after extubation risk of complications.slightly higher than predicted.70. DISCUSSION tion group (adjusted relative risk.5% vs.0% and 3.5%) in the protective-ven.001) (Table 3). 34 of 200 [17. 95% CI. 0.36 to 3.chanical ventilation. as compared in the Supplementary Appendix). 0. the cumulative the differences between the results of the pres- 30-day probability of an event requiring intuba. The results of associated group was similar to that in the nonprotective- univariate and multivariate analyses are provided ventilation group (3.org on February 21. 2013 The New England Journal of Medicine Downloaded from nejm.5%) in the between-group difference in the rate of adverse nonprotective-ventilation group (adjusted relative events (Table S3 in the Supplementary Appendix). 0. nary complications25. 0. P = 0. . risk. intraoperative lung-protective me- protective-ventilation group than in the protec.001). acute respiratory failure was lower among pa. as compared with 55 (27. Copyright © 2013 Massachusetts Medical Society.17 and 434 n engl j med 369.14 to 0.59. P<0. adjusted relative risk.68.0%].increased morbidity rates. and Tables S3 and outcomes and reduced health care utilization S4 in the Supplementary Appendix) and major after abdominal surgery. rank test) (Fig.0%].88. P = 0. recruitment ma. adjusted rela- tions occurred within the first 7 days after sur.5%. in Table S1 in the Supplementary Appendix. 0.24 to Mortality at 30 days in the protective-ventilation 0. adjusted relative risk.61. as com- pared with 72 (36. The observed rate of pulmonary and extrapulmonary complications dur.

36) 0.58 0. .65) 0.19–0.86 (0.29–2. No other uses without permission.18 One strength of the present trial is our flammatory response30 and can synergize with use of a robust composite outcome that is highly the response induced by major surgery at both pertinent to this high-risk surgical population.0) 1 (0. sex.24–0.001 0.68) 0. preoperative risk index for postoperative pulmonary complications.12 0.73) <0. ¶ Postoperative pulmonary complications were scored with the use of a graded scale23 from 0 (no pulmonary complications) to 4 (the most severe complications) (see the Supplementary Appendix).12–0. Results of Unadjusted and Adjusted Outcome Analyses.61) <0.67 (0.23 (0.06) 0. ARDS denotes acute respiratory distress syndrome.26) 0.66) <0.14 Need for ventilation within 7 days Invasive 7 (3.0) 86 (43.04 0. nonatelectatic lung.38 (0.61) 0.5) 0.93) 0.32) 0.26 Noninvasive 29 (14.35–2.04 to −0.5  nejm.63) 0.40 (0.84) 0. (%) Pulmonary complication within 7 days¶ Grade 1 or 2 30 (15. This amplification of n engl j med 369.28–0.37 (0.5) 13 (6.5) 0.87 (0.40 (0.21–0.21 (0.38 (0.45 (−4.006 0.004 Pneumonia within 7 days 16 (8.0) 13 (6.5) 0.19 (0.29 (0.0) 0.02 0. 2013 435 The New England Journal of Medicine Downloaded from nejm.71) 0.org on February 21.49) <0. and need for blood transfusion (yes or no). and differences between groups are shown for the duration of stays in the hospital and ICU.98 to 7.47) −2.009 Acute lung injury or ARDS within 7 days 6 (3.05–0.15–0.40) Interquartile range 4–9 4–8 * All postoperative complications were defined according to consensus criteria (see the Supplementary Appendix).72) Interquartile range 8–20 8–15 ICU 0. septic shock.0) 25 (12.31 (0.21 (−4. and SIRS systemic inflammatory response syndrome. Copyright © 2013 Massachusetts Medical Society.001 0.48 (0.19 (0. hilum. or hemidiaphragm toward the affected area and compensatory overinflation in the adjacent.11–0.15.17) 0.0) 3 (1. or death) within the first 7 days after surgery.24 (0.25–0. ‖ Atelectasis was defined as opacification of the lung with shift of the mediastinum.17 (0.46) <0.51) 0.5) 9 (4.66) 0.89 (0.001 Secondary outcomes — no.5) 0. Intr aoper ative Low-Tidal-Volume Ventilation Table 3.29 (0.16.16 Grade ≥3 42 (21. ICU intensive care unit.65–1.83 Duration of stay in hospital and ICU — days Hospital 0.43 (0.42–1.01 0.5) 2 (1.05–0.5) 8 (4.64) 0.* Unadjusted Adjusted Relative Risk or Relative Risk or Nonprotective Lung-Protective ­Between-Group ­Between-Group Ventilation Ventilation ­Difference ­Difference Variable (N = 200) (N = 200) (95% CI) P Value† (95% CI)‡ P Value Primary composite outcome — no.24–0.69 Median 7 6 −1.5 local and systemic levels. All rights reserved.51–4.06–1.13) 0.97) 0. duration of surgery.5) 6 (3.001 0. For additional data on postoperative outcomes. † Adjustment was performed for stratification variables (use or nonuse of epidural analgesia and study center).69 (0.17 to −0.02–1.5) 21 (10. Relative risks are shown for outcome variables.08–1. (%) Within 7 days§ 55 (27.80 1.0) 25 (12.28–0.80 1. CI confi- dence interval.0) 0.5) 0. have used either very low levels of PEEP or no Mechanical ventilation itself can induce an in- PEEP.03 Severe sepsis or septic shock 9 (4.5) 0.51 0.86 (0.13 (0.45 (0. 2017.001 Within 30 days 58 (29.45 (0.0) 0.47 Death within 30 days 7 (3.39–1.5) 0.70–1.0) 10 (5.001 Atelectasis within 7 days‖ 34 (17.0) 0.14 0. For personal use only. ‡ The Hochberg procedure was used to adjust for multiple testing of components of the composite primary outcome.48 (−6.91) −1.006 Median 13 11 −2.001 0.70) 0.002 Extrapulmonary complication within 7 days SIRS 100 (50.org  august 1.25 (−4.37) 0.48 (0. see Tables S3 and S4 in the Supplementary Appendix.36–3.27 § The primary outcome was a composite of major pulmonary complications (defined as pneumonia or need for invasive or noninvasive ventilation for acute respiratory failure) and extrapulmonary complications (defined as sepsis.87 to 3.5) 0.13–0.02–1.37 Sepsis 29 (14.73) 0.24–0.16) 0.0) 0.16 0.

36 should be used with caution 0. and Philips. Astute Medical. However. sistance the study would never have been completed. it was rec- Nonprotective 200 182 163 145 142 142 ommended that the study centers follow clinical- ventilation practice guidelines.20 tation is unlikely to have affected our results. Jaber reports receiving consult- nature of the trial protocol.00 1 3 7 15 30 supported in the literature. Dr Constantin reports receiving consulting fees from Baxter.29 the full text of this article at NEJM. Dräger. and reimburse- that combined low tidal volumes. P<0. Allaouchiche re- methods used to minimize bias (blinded and ports receiving consulting fees from Fresenius Kabi and lecture centralized randomization. Baxter. and Hospal. Dräger. complete follow-up. Dr. Leone reports receiving and intention-to-treat analyses).6. Dr. lecture fees and ate levels of PEEP to prevent further collapse. Probability of Event There are several limitations to our study.8. The n e w e ng l a n d j o u r na l of m e dic i n e ment maneuvers. with routine practice ing fees from Dräger France and Maquet France. in which hemodynamic effects 0. 436 n engl j med 369.35 Consequently. No other potential conflict of interest relevant to this article was reported.37. and temic organ failure. Fresenius Kabi. Baxter. Astellas. receiving consulting fees from Fresenius Kabi. at Risk for noninvasive ventilation. Dr. and General Electric Medi- trials may have promoted the repeated opening cal Systems. and the enrollment of pa. of educational presentations from Dräger. Lung-protective ventilation since the volume of fluids administered was 0. and moder.5  nejm. Baxter. the pragmatic consulting fees from LFB Biomedicaments and lecture fees from Fresenius Kabi and Novartis.32 reimbursement of travel expenses from Fisher and Paykel The use of very low levels of PEEP in previous Healthcare. Fresenius Kabi. Dräger. Disclosure forms provided by the authors are available with comes after major surgery.30 trial design did not include standardization of the administration of fluids. payment for expert testimony from Baxter. Merck Sharp & Dohme.001 by the log-rank test for the tective ventilation during surgery. Abbott.33 We used a multi. 2017. leading to atelec. General Electric faceted strategy of lung-protective ventilation Medical Systems. All rights reserved. as compared between-group difference in the probability of the primary outcome.10 similar in the two groups. our study provides evidence that acute respiratory failure. Kaplan–Meier Estimates of the Probability of the Composite tion of noninvasive ventilation in our trial is ­Primary Outcome. fees from Novartis and Astellas. Singer for valuable advice during the preparation of the manuscript. payment for the development pulmonary complications.20 The trial protocol Days since Randomization did not include standardization of requirements No. Copyright © 2013 Massachusetts Medical Society.org  august 1. patients enrolled in other studies analyzing out.40 in patients with hemodynamic instability.19. the clinical and research staff at all the trial sites.34 reimbursement of travel expenses from Astellas. . recruit. Paugam-Burtz reports maneuvers to open collapsed alveoli. without whose as- tion of transient arterial hypotension during re. The Nonprotective ventilation 0. Dr. lecture fees from General Electric Medical tasis. which can precipitate the development of Systems.38 and postoperative care Lung-protective 200 192 184 179 176 175 ventilation was conducted by health care workers who were unaware of the study assignments. For personal use only. and closing of small airways. and re- tients with characteristics similar to those of imbursement of travel expenses from Pfizer. The utiliza- Figure 2. however. from Fisher and Paykel Healthcare. and death. 2013 The New England Journal of Medicine Downloaded from nejm. results in fewer postoperative complica- tions and reduced health care utilization. and Fresenius Kabi. Hospal. Futier reports receiving consulting fees from General subsequent development of lung injury31 and sys­ Electric Medical Systems. lecture fees being maintained.37 We Data for the Kaplan–Meier estimates of the probability of the composite primary outcome of major pulmonary or extrapulmonary complications therefore consider it unlikely that any imbalance were censored at 30 days after surgery. Major extrapulmonary complications were ­sepsis. septic shock.org on February 21.50 are potentially influenced by the applied level of alveolar pressure. a multifaceted strategy of prophylactic lung-pro- severe sepsis. and Mervyn cruitment maneuvers. this limi- 0. recruitment ment of travel expenses from Bird. ­included pneumonia or the need for invasive or noninvasive ventilation for In conclusion. and LFB Biomedicaments. with a practice of nonprotective mechanical ven- tilation. close to that reported in earlier studies. and Fresenius Kabi.org. Our findings are consistent with the observa. We thank all the patients who participated in the study. No other uses without permission. and payment Other strengths of the present trial include the for the development of educational presentations from LFB Bio- medicaments and Merck Sharp & Dohme. lecture fees from Fresenius Kabi. the inflammation cascade contributes to the Dr. Major pulmonary complications in interventions affected our results. The definition of nonprotective ventilation was arbitrary but is 0. Fresenius Kabi.

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