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Figure 1.  Flow of Study Patients With Hypoxemia After Cardiac Surgery
Flow of Study Patients With Hypoxemia After Cardiac Surgery

BMI indicates body mass index, calculated as weight in kilograms divided by height in meters squared; LVEF, left ventricular ejection fraction; Pao2, partial pressure of arterial blood oxygen; Fio2, fraction of inspired oxygen.

Figure 2.  Severity of Postoperative Pulmonary Complications
Severity of Postoperative Pulmonary Complications

Each postoperative pulmonary complication, the worst each patient experienced throughout his/her hospital stay, was graded from 0 to 5. Grade 0 represents no symptoms or signals; grade 1, one of the following: dry cough, abnormal lung findings and temperature 37.5°C or higher with normal chest radiograph, or dyspnea without other documented cause; grade 2, two of the following: productive cough, bronchospasm, hypoxemia (Spo2 ≤ 90%) at room air, atelectasis with gross radiological confirmation (concordance of 2 independent experts) plus either temperature higher than 37.5°C, or abnormal lung findings, hypercarbia (Paco2>50 mm Hg) requiring treatment; grade 3, one of the following: pleural effusion resulting in thoracentesis, pneumonia, pneumothorax, extended noninvasive ventilation, or reintubation lasting less than 48 hours; grade 4, reintubation or invasive mechanical ventilation for 48 hours or more; and grade 5, death before hospital discharge.

Figure 3.  Kaplan-Meier Survival Analysis for Time to Hospital Discharge and Intensive Care Unit Discharge
Kaplan-Meier Survival Analysis for Time to Hospital Discharge and Intensive Care Unit Discharge
Figure 4.  Lung Function During the Postoperative Period
Lung Function During the Postoperative Period

A, Pressure-volume curves (slow-flow maneuvers) obtained immediately after intensive care (ICU) arrival (dashed lines) and after 4 hours of protective ventilation (solid lines) for both groups and starting from the same pressures and after the same lung-volume history. Data markers indicate the mean; error bars, 1 standard deviation. The test of the interaction term between strategy and time (repeated measures analysis of variance) showed P < .001, demonstrating that the intensive recruitment strategy presented a significantly larger increase in lung volumes, for the same pressures, after 4 hours.

B, Daily percentage of patients presenting hypoxemia and needing supplemental oxygen (measured by pulse oximetry, at room air), during the first 5 postoperative days. The intensive recruitment strategy group presented a lower percentage of patients needing supplemental oxygen (χ2 test) along the 5 days, with P = .009, after correction for multiple comparisons (original P value = .001).

Table 1.  Baseline Characteristicsa
Baseline Characteristicsa
Table 2.  Intraoperative Characteristics
Intraoperative Characteristics
Table 3.  Outcome Analyses
Outcome Analyses
1.
Güldner  A, Kiss  T, Serpa Neto  A,  et al.  Intraoperative protective mechanical ventilation for prevention of postoperative pulmonary complications: a comprehensive review of the role of tidal volume, positive end-expiratory pressure, and lung recruitment maneuvers.  Anesthesiology. 2015;123(3):692-713.PubMedGoogle ScholarCrossref
2.
Sundar  S, Novack  V, Jervis  K,  et al.  Influence of low tidal volume ventilation on time to extubation in cardiac surgical patients.  Anesthesiology. 2011;114(5):1102-1110.PubMedGoogle ScholarCrossref
3.
Zupancich  E, Paparella  D, Turani  F,  et al.  Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: a randomized clinical trial.  J Thorac Cardiovasc Surg. 2005;130(2):378-383.PubMedGoogle ScholarCrossref
4.
Hulzebos  EH, Helders  PJ, Favié  NJ, De Bie  RA, Brutel de la Riviere  A, Van Meeteren  NL.  Preoperative intensive inspiratory muscle training to prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a randomized clinical trial.  JAMA. 2006;296(15):1851-1857.PubMedGoogle ScholarCrossref
5.
Miranda  DR, Gommers  D, Papadakos  PJ, Lachmann  B.  Mechanical ventilation affects pulmonary inflammation in cardiac surgery patients: the role of the open-lung concept.  J Cardiothorac Vasc Anesth. 2007;21(2):279-284.PubMedGoogle ScholarCrossref
6.
Bartz  RR, Ferreira  RG, Schroder  JN,  et al.  Prolonged pulmonary support after cardiac surgery: incidence, risk factors and outcomes: a retrospective cohort study.  J Crit Care. 2015;30(5):940-944.PubMedGoogle ScholarCrossref
7.
Neto  AS, Hemmes  SN, Barbas  CS,  et al; PROVE Network Investigators.  Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data.  Lancet Respir Med. 2016;4(4):272-280.PubMedGoogle ScholarCrossref
8.
Bashour  CA, Yared  JP, Ryan  TA,  et al.  Long-term survival and functional capacity in cardiac surgery patients after prolonged intensive care.  Crit Care Med. 2000;28(12):3847-3853.PubMedGoogle ScholarCrossref
9.
Wrigge  H, Uhlig  U, Baumgarten  G,  et al.  Mechanical ventilation strategies and inflammatory responses to cardiac surgery: a prospective randomized clinical trial.  Intensive Care Med. 2005;31(10):1379-1387.PubMedGoogle ScholarCrossref
10.
García-Delgado  M, Navarrete-Sánchez  I, Colmenero  M.  Preventing and managing perioperative pulmonary complications following cardiac surgery.  Curr Opin Anaesthesiol. 2014;27(2):146-152.PubMedGoogle ScholarCrossref
11.
Serpa Neto  A, Cardoso  SO, Manetta  JA,  et al.  Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis.  JAMA. 2012;308(16):1651-1659.PubMedGoogle ScholarCrossref
12.
Severgnini  P, Selmo  G, Lanza  C,  et al.  Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function.  Anesthesiology. 2013;118(6):1307-1321.PubMedGoogle ScholarCrossref
13.
Futier  E, Constantin  JM, Paugam-Burtz  C,  et al; IMPROVE Study Group.  A trial of intraoperative low-tidal-volume ventilation in abdominal surgery.  N Engl J Med. 2013;369(5):428-437.PubMedGoogle ScholarCrossref
14.
Hemmes  SN, Gama de Abreu  M, Pelosi  P, Schultz  MJ; PROVE Network Investigators for the Clinical Trial Network of the European Society of Anaesthesiology.  High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial.  Lancet. 2014;384(9942):495-503.PubMedGoogle ScholarCrossref
15.
Reis Miranda  D, Struijs  A, Koetsier  P,  et al.  Open lung ventilation improves functional residual capacity after extubation in cardiac surgery.  Crit Care Med. 2005;33(10):2253-2258.PubMedGoogle ScholarCrossref
16.
Kroenke  K, Lawrence  VA, Theroux  JF, Tuley  MR.  Operative risk in patients with severe obstructive pulmonary disease.  Arch Intern Med. 1992;152(5):967-971.PubMedGoogle ScholarCrossref
17.
The Acute Respiratory Distress Syndrome Network.  Ventilation 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(18):1301-1308.PubMedGoogle ScholarCrossref
18.
Amato  MB, Meade  MO, Slutsky  AS,  et al.  Driving pressure and survival in the acute respiratory distress syndrome.  N Engl J Med. 2015;372(8):747-755.PubMedGoogle ScholarCrossref
19.
Rothen  HU, Sporre  B, Engberg  G, Wegenius  G, Reber  A, Hedenstierna  G.  Prevention of atelectasis during general anaesthesia.  Lancet. 1995;345(8962):1387-1391.PubMedGoogle ScholarCrossref
20.
Rothen  HU, Sporre  B, Engberg  G, Wegenius  G, Högman  M, Hedenstierna  G.  Influence of gas composition on recurrence of atelectasis after a reexpansion maneuver during general anesthesia.  Anesthesiology. 1995;82(4):832-842.PubMedGoogle ScholarCrossref
21.
Rothen  HU, Sporre  B, Engberg  G, Wegenius  G, Hedenstierna  G.  Re-expansion of atelectasis during general anaesthesia: a computed tomography study.  Br J Anaesth. 1993;71(6):788-795.PubMedGoogle ScholarCrossref
22.
Paparella  D, Yau  TM, Young  E.  Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update.  Eur J Cardiothorac Surg. 2002;21(2):232-244.PubMedGoogle ScholarCrossref
23.
Zarbock  A, Mueller  E, Netzer  S, Gabriel  A, Feindt  P, Kindgen-Milles  D.  Prophylactic nasal continuous positive airway pressure following cardiac surgery protects from postoperative pulmonary complications: a prospective, randomized, controlled trial in 500 patients.  Chest. 2009;135(5):1252-1259.PubMedGoogle ScholarCrossref
24.
Reis Miranda  D, Klompe  L, Mekel  J,  et al.  Open lung ventilation does not increase right ventricular outflow impedance: an echo-Doppler study.  Crit Care Med. 2006;34(10):2555-2560.PubMedGoogle ScholarCrossref
25.
Lim  SC, Adams  AB, Simonson  DA,  et al.  Transient hemodynamic effects of recruitment maneuvers in three experimental models of acute lung injury.  Crit Care Med. 2004;32(12):2378-2384.PubMedGoogle ScholarCrossref
26.
Miranda  DR, Klompe  L, Cademartiri  F,  et al.  The effect of open lung ventilation on right ventricular and left ventricular function in lung-lavaged pigs.  Crit Care. 2006;10(3):R86.PubMedGoogle ScholarCrossref
27.
Goligher  EC, Kavanagh  BP, Rubenfeld  GD, Ferguson  ND.  Physiologic responsiveness should guide entry into randomized controlled trials.  Am J Respir Crit Care Med. 2015;192(12):1416-1419.PubMedGoogle ScholarCrossref
Preliminary Communication
Caring for the Critically Ill Patient
April 11, 2017

Effect of Intensive vs Moderate Alveolar Recruitment Strategies Added to Lung-Protective Ventilation on Postoperative Pulmonary Complications: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Anesthesia and Intensive Care, Heart Institute (InCor), Hospital Das Clínicas da FMUSP, University of São Paulo, São Paulo, Brazil
  • 2Cardio-Pulmonary Department, Heart Division, Heart Institute (Incor), Hospital Das Clínicas da FMUSP - University of São Paulo, São Paulo, Brazil
  • 3Departament of Applied Physiotherapy, Federal University of Triângulo Mineiro, Uberaba, Brazil
  • 4Cardio-Pulmonary Department, Pulmonary Division, Heart Institute (Incor), Hospital Das Clínicas da FMUSP, University of São Paulo, São Paulo, Brazil
JAMA. 2017;317(14):1422-1432. doi:10.1001/jama.2017.2297
Key Points

Question  Is there any extra benefit to applying more intensive alveolar recruitment strategies for high-risk surgical patients already receiving perioperative small tidal volumes and protective lung ventilation?

Findings  An intensive recruitment strategy compared with a moderate recruitment strategy to treat patients with hypoxemia after cardiac surgery resulted in significantly lower severity of pulmonary complications during the hospital stay. The strategy caused a consistent shift to lower scores that favored use of an intensive recruitment strategy.

Meaning  A more intensive alveolar recruitment strategy applied postoperatively may reduce the severity of pulmonary complications in patients with hypoxemia after cardiac surgery.

Abstract

Importance  Perioperative lung-protective ventilation has been recommended to reduce pulmonary complications after cardiac surgery. The protective role of a small tidal volume (VT) has been established, whereas the added protection afforded by alveolar recruiting strategies remains controversial.

Objective  To determine whether an intensive alveolar recruitment strategy could reduce postoperative pulmonary complications, when added to a protective ventilation with small VT.

Design, Setting, and Participants  Randomized clinical trial of patients with hypoxemia after cardiac surgery at a single ICU in Brazil (December 2011-2014).

Interventions  Intensive recruitment strategy (n=157) or moderate recruitment strategy (n=163) plus protective ventilation with small VT.

Main Outcomes and Measures  Severity of postoperative pulmonary complications computed until hospital discharge, analyzed with a common odds ratio (OR) to detect ordinal shift in distribution of pulmonary complication severity score (0-to-5 scale, 0, no complications; 5, death). Prespecified secondary outcomes were length of stay in the ICU and hospital, incidence of barotrauma, and hospital mortality.

Results  All 320 patients (median age, 62 years; IQR, 56-69 years; 125 women [39%]) completed the trial. The intensive recruitment strategy group had a mean 1.8 (95% CI, 1.7 to 2.0) and a median 1.7 (IQR, 1.0-2.0) pulmonary complications score vs 2.1 (95% CI, 2.0-2.3) and 2.0 (IQR, 1.5-3.0) for the moderate strategy group. Overall, the distribution of primary outcome scores shifted consistently in favor of the intensive strategy, with a common OR for lower scores of 1.86 (95% CI, 1.22 to 2.83; P = .003). The mean hospital stay for the moderate group was 12.4 days vs 10.9 days in the intensive group (absolute difference, −1.5 days; 95% CI, −3.1 to −0.3; P = .04). The mean ICU stay for the moderate group was 4.8 days vs 3.8 days for the intensive group (absolute difference, −1.0 days; 95% CI, −1.6 to −0.2; P = .01). Hospital mortality (2.5% in the intensive group vs 4.9% in the moderate group; absolute difference, −2.4%, 95% CI, −7.1% to 2.2%) and barotrauma incidence (0% in the intensive group vs 0.6% in the moderate group; absolute difference, −0.6%; 95% CI, −1.8% to 0.6%; P = .51) did not differ significantly between groups.

Conclusions and Relevance  Among patients with hypoxemia after cardiac surgery, the use of an intensive vs a moderate alveolar recruitment strategy resulted in less severe pulmonary complications while in the hospital.

Trial Registration  clinicaltrials.gov Identifier: NCT01502332

Introduction

Quiz Ref IDPostoperative pulmonary complications are common after cardiac surgery, often increasing postoperative morbidity and mortality.1,2 The extracorporeal circulation3 and the development of massive atelectasis after open-chest surgery4,5 commonly activate lung inflammation, both amplifying the harm associated with perioperative mechanical ventilation. This harmful sequence may be accompanied by hypoxemia, pneumonia, ventilator-induced lung injury, and acute respiratory distress syndrome (ARDS).6-9 These complications may result in increased resources utilization, delayed mobilization, prolonged need of supplemental oxygen or mechanical ventilation,10 and a longer hospital stay.

Recent studies have shown that intraoperative lung-protective ventilation may reduce postoperative pulmonary complications.2,11-13 Different strategies for lung protection have been tested, either a simple reduction of tidal volume (VT),2 or a low VT in combination with alveolar recruitment strategies (moderate positive end-expiratory pressure [PEEP] aided by recruiting maneuvers12,13). In all these studies, however, the control group received nonprotective mechanical ventilation, with no PEEP and high VT (9-11 mL/kg of predicted body weight [PBW]). Thus, the specific role (“extra benefit”) of alveolar recruitment strategies was not directly tested. From 2011 to 2013, a study specifically testing the extra benefit of a more intensive alveolar recruitment strategy involving patients already receiving low-VT ventilation during open abdominal surgery failed to show benefits. In fact, it caused more adverse effects.14 Only a small physiological study supports the benefit of more intensive alveolar recruitment strategies for patients also receiving low-VT ventilation. That study, however, showed a decreased inflammation5 and some improvement in lung function15 but without any significant effects on hard outcomes.

This clinical trial evaluated the specific role of a more intensive alveolar recruitment strategy for reducing the severity of pulmonary complications in patients with hypoxemia already receiving protective ventilation with low VT after cardiac surgery.

Methods
Study Design

This was a single-center, randomized clinical trial performed at the Heart Institute (Incor) from the University of São Paulo in Brazil. Patients were enrolled between December 2011 and February 2014 (Figure 1). The study protocol was approved by the local ethics and research committee (Supplement 1). Written informed consent was obtained from all participants.

Participants

Quiz Ref IDPatients were assessed for eligibility and gave consent on the eve of their surgery. Patients were included if they were undergoing elective cardiac surgery (coronary artery bypass graft surgery, valve surgery, or both, with or without cardiopulmonary bypass) and had hypoxemia when they were admitted to the intensive care unit (ICU). Hypoxemia is defined as an arterial partial pressure of oxygen:fraction of inspired oxygen (Pao2:Fio2) ratio of less than 250 mm Hg, collected during PEEP (≥5 cm H2O). Patients were excluded if they were younger than 18 years or older than 80 years; had previous lung disease (documented history or preoperative tests suggesting airway obstruction, defined as the ratio of forced expiratory volume in the first second of expiration to forced vital capacity [FEV1:FVC] <70%); had previous cardiac surgery or neuromuscular disease; had a mean pulmonary artery blood pressure of more than 35 mm Hg; had left ventricular ejection fraction of less than 35%; body mass index (BMI) of less than 20 or more than 40 (BMI is calculated as weight in kilograms divided by height in meters squared); needed emergency surgery or ventricular assist device; needed more than 2 μg/kg/min of norepinephrine; had refractory hypotension or arrhythmia at entry; had pneumothorax or air leak syndrome at entry; or were enrolled in another study.

Study Protocol

Full details of the surgical and anesthetic techniques are given in Supplement 2. All postoperative patients were admitted to the ICU; received volume-controlled ventilation; and had a VT of 6 mL/kg of predicted body weight (PBW), Fio2 of 0.60, and PEEP of 5 cm H2O. Quiz Ref IDAfter confirming entry or exclusion criteria, patients were randomly assigned to 1 of 2 strategies: lung-protective ventilation plus intensive alveolar recruitment strategy or lung-protective ventilation plus moderate alveolar recruitment strategy. Randomization was performed only after patient enrollment, with a computer-generated list (1:1 allocation ratio), generated online by a web-based program that ensured allocation concealment (Figure 1). All patients were then sedated with standard intravenous boluses of fentanyl or midazolam and shortly paralyzed with cisatracurium during lung-mechanics measurements.

Subsequently, a low-flow pressure-volume curve was performed (PV-Tool, Galileo Gold ventilator [Hamilton Medical]). In both groups, the maneuver started from a baseline PEEP of 5 cm H2O, with airway pressures progressively increased up to 30 cm H2O (ramp-speed of 2 cm H2O per second), followed by gradual decrease back to 5 cm H2O (equivalent ramp-speed). After 4 hours of mechanical ventilation according to each randomized strategy, a second pressure-volume curve was performed.

Before each of the pressure-volume curves, baseline ventilator settings were reestablished for 5 minutes, to homogenize lung history. However, after each pressure-volume curve (baseline and 4 hours later), patients received alveolar recruitment maneuvers defined according to randomization, during which they were monitored with invasive arterial pressure lines. The maneuvers were followed by immediate application of the randomized PEEP (8 cm H2O for the moderate recruitment strategy, 13 cm H2O for intensive recruitment strategy).

In the intensive strategy group, patients received 3 cycles of lung inflation (60 seconds each), consisting of PEEP of 30 cm H2O, pressure-controlled ventilation, driving pressure of 15 cm H2O, respiratory rate of 15/min, inspiratory time of 1.5 seconds, and Fio2 of 0.40. During the intervals (60 seconds) among inflation cycles and subsequently, patients received assist-controlled or pressure-controlled ventilation, with driving pressures adjusted to obtain a VT of 6 mL/kg of PBW, inspiratory time of 1 second, PEEP of 13 cm H2O, and minimum respiratory rate to maintain Paco2 between 35 and 45 mm Hg.

In the moderate strategy group, patients received 3 sustained inflations (30 seconds each) under continuous positive airway pressure (CPAP) mode at 20 cm H2O and Fio2 of 0.60. During the intervals (60 seconds) among sustained insufflations and subsequently, patients received assist or control volume-controlled ventilation (decelerating-flow waveform), VT of 6 mL/kg of PBW, inspiratory time of 1 second, PEEP of 8 cm H2O, Fio2 of 0.60, and minimum respiratory rate adjusted to maintain Paco2 between 35 and 45 mm Hg.

For both groups, dynamic hyperinflation was minimized by visual inspection of flow tracings. Also, the recruiting maneuvers were started only if patients were hemodynamically stable, characterized by 2 necessary conditions: good functional hemodynamics (negative leg-raising test) and optimized vascular tonus (vasopressors in use titrated to achieve mean-arterial pressures ≥80 mm Hg before the recruiting maneuvers for the intensive-strategy group or 70 mm Hg or more for the moderate-strategy groups). Inflation cycles of at least 15 seconds were applied during the recruiting maneuvers for both strategies. In case of interruption because of hemodynamic concerns, the maneuver was reestablished after 5 minutes of stabilization (eFigure 3 in Supplement 2).

After 4 hours under the randomized ventilation strategy, patients received a second recruiting maneuver (right after the second pressure volume curve) and were subsequently weaned from mechanical ventilation according to the institutional protocol (progressively reduced levels of pressure support, until a minimum of 5 cm H2O), with the exception of PEEP, which was maintained constant until patient extubation, at the level defined by randomization.

Both groups received similar care and physical therapy in the postoperative period. Aided lung expansion with positive-pressure mask ventilation was applied in both groups whenever signals of hypoxemia plus abundant airway secretions were present. In a second step, noninvasive ventilation with CPAP of 10 cm H2O or more was applied (aided by inspiratory pressure support of 5-10 cm H2O, if necessary), only to those patients still fulfilling all the following criteria: (1) oxygen saturation (Spo2) 90% or less under supplemental oxygen, (2) need of supplemental oxygen of 5 L/min or more; and (3) respiratory rate 30/min or more.

Because of different ventilator settings, the research staff participating in the first few hours of protocol could not be blinded to treatment assignments. After extubation, however, all other clinical staff, investigators, research team, patients, and families were unaware of the treatment assignments for the duration of the trial.

Data Collection and Outcomes Measurements

The primary outcome was the severity of postoperative pulmonary complications during hospital stay, scored on an ordinal scale ranging from 0 to 5, using a modified definition of pulmonary complications from Kroenke et al16 (eMethods in Supplement 2), for which grade 0 represents no symptoms or signals; grade 4, reintubation or invasive mechanical ventilation for 48 hours or more; and grade 5, death before hospital discharge. Bedside chest radiographs were obtained for all patients at the first, third, and fifth postoperative days, in addition to those requested by staff physicians. They were independently analyzed by 2 pulmonary specialists, blinded to treatment assignment. Only concordant assessments (an abnormal opacity at the same location) were integrated to clinical findings for the final score of pulmonary complications (details in Supplement 2). The occurrence and severity of pulmonary complications was assessed daily, until hospital discharge, using the worst score during the hospital stay for the main analysis.

The prespecified secondary outcomes were length of ICU stay, length of hospital stay, hospital mortality, and incidence of barotrauma.

For an exploratory analysis, we also investigated the following post hoc end points: comparison of the proportion of patients with severe pulmonary complications (score ≥3) in the intensive and moderate recruitment strategies groups; daily comparison of pulmonary complications during 5 postoperative days; daily need of supplemental oxygen (defined as room air oxygen saturation ≤90% in a pulse oximeter) during any of the first 5 postoperative days; duration of invasive mechanical ventilation; extended use of noninvasive ventilation (NIV); incidence of pneumonia, wound infection, or postoperative bleeding; and cardiovascular complications during the hospital stay.

Physiological parameters were collected at baseline and during or after the first 4 hours of protective mechanical ventilation, including a pressure-volume curve and common respiratory and hemodynamic variables. In addition, ventilation maps were obtained in the last 33 consecutive patients by electrical impedance tomography. We used the Enlight monitor and obtained cross-sectional images at the fourth and fifth intercostal space, checking if differences in the pattern of ventilation, atelectasis, or both could be detected between the 2 protective strategies.

Statistical Analysis

The study was designed to have a 90% power to detect a difference in the incidence of major (grade ≥3) pulmonary complications between the moderate (expected incidence of 30%4,13) and intensive recruitment strategy (expected incidence of 15%, based on low-range estimates of effect size for this population4,15), at a 2-sided α error of 5% (see eAppendix in the Study Protocol in Supplement 1). Although the primary outcome was a global shift in the ordinal scores of pulmonary complications, we dichotomized the pulmonary severity score outcomes for sample size calculations, aiming to observe frequent enough complications of high severity, affecting clinical management. This generated the sample size of 322 patients, rounded to 320.

An independent data and safety monitoring committee performed a blinded and planned interim analysis after enrollment of 50% of patients (n = 160) to evaluate adverse events. A stopping rule for adverse events (P < .01) was used, only considering the outcomes of hospital mortality and barotrauma. There was no stopping rule for efficacy when considering the primary outcome. The committee recommended that the study should be continued.

We compared the baseline characteristics, follow-up measures, and clinical outcomes on an intention-to-treat basis according to randomized study strategy. Continuous variables were compared using t tests or repeated analysis of variance measures. The scores of pulmonary complications were analyzed through Mann-Whitney U tests and multivariable ordinal logistic regression by estimating the common odds ratio for a shift in the direction of a better outcome on the modified scale of pulmonary complications. Categorical variables were compared using the Fisher exact test or likelihood ratio tests. Adjustments for multiplicity of comparisons (Bonferroni) were applied for the post hoc secondary outcomes. The duration of ICU and hospital stay was compared using Kaplan-Meier curves and log-rank tests. The censoring was performed at 28 days, and the time to event was the time from surgery to ICU and hospital discharge. Patients who died before leaving the ICU or hospital were censored as nondischarged at day 28. A 2-sided P value <.05 was considered statistically significant. The statistical analysis was performed using SPSS version 19.0 (SPSS Inc).

Results
Study Population

A total of 4483 patients were screened for eligibility. After checking the inclusion-exclusion criteria, and after excluding those with absence of consent, we ultimately enrolled and randomized 320 patients: 163 assigned to the moderate and 157 to the intensive recruitment strategy (Figure 1). All patients completed the study and were followed up until death or hospital discharge. Baseline characteristics and intraoperative procedures are presented in Table 1 and Table 2.

Primary Outcome

The pulmonary complications score was a mean 1.8 (95% CI, 1.7-2.0) and a median 1.7 (IQR, 1.0-2.0) for the intensive recruitment strategy group vs a mean 2.1 (95% CI, 2.0 to 2.3) and median 2.0 (IQR, 1.5-3.0) for the moderate strategy group. Quiz Ref IDThe severity and occurrence of postoperative pulmonary complications, computed during whole hospital stay, was reduced in the intensive recruitment strategy group compared with those in the moderate strategy group with a shift in the distribution of the primary outcome scores in favor of the intensive recruitment strategy, with a common odds ratio for lower scores of 1.86 (95% CI, 1.22 to 2.83; P = .003;Figure 2 and Table 3). Post hoc analysis revealed that major pulmonary complications (grade ≥3) occurred in 24 patients (15.3%) receiving the intensive and in 43 patients (26.4%) receiving the moderate recruitment strategy (absolute difference, −11.1%; 95% CI, −19.8% to −2.2%).

Prespecified Secondary Outcomes

The mean number of days patients in the moderate recruitment strategy group spent in the hospital was 12.4 (median, 9 days) vs 10.9 (median, 8 days) in the intensive group (absolute difference, −1.5 days; 95% CI, −3.1 to −0.3; P = .04, log-rank test; Figure 3 and Table 3). The mean number of days patients in the moderate recruitment strategy groups spent in the ICU was 4.8 days vs 3.8 days in the intensive group (absolute difference, −1.0 day; 95% CI, −1.6 to −0.2; P = .01, log-rank test). Hospital mortality (absolute difference, −2.4%; 95% CI, −7.1% to 2.2%; P = .27) and barotrauma incidence (absolute difference, −0.6%; 95% CI, −1.8% to 0.6%; P = .51) were not significantly different between study groups (Table 2).

Exploratory Analyses and Outcomes

The proportion of patients with hypoxemia at room air (arterial oxygen saturation <90%) and who needed supplemental oxygen for more than 24 hours was significantly lower in the intensive recruitment strategy group (absolute difference, −17.5 percentage points; 95% CI, −27.2 to −7.2 percentage points; P = .009; Table 3 and Figure 4; panel B). This difference was observed despite the less frequent application of aided lung expansion with positive-pressure mask ventilation in the intensive recruitment strategy group (eTable 3 in Supplement 2). Furthermore, the number of patients meeting the predefined criteria for extended noninvasive ventilation was lower in the intensive recruitment strategy group (absolute difference, −11.5 percentage points; 95% CI, −17.2 to −5.2 percentage points; P = .004). The daily comparison of scores of pulmonary complications showed a residual benefit of the intensive recruitment strategy up to the fifth postoperative day (P = .006; eFigure 5 in Supplement 2).

Despite the higher intensity of the maneuvers, patients in the intensive recruitment strategy has a nonsignificant (≈1.1 hours) shorter time requiring mechanical ventilation after ICU arrival (absolute difference, −1.1 hour; 95% CI, −1.7 to −0.3 hour; P = .15; multiplicity corrected, Table 3).

Hemodynamic Variables

Quiz Ref IDImmediately after the inflation cycles of recruiting maneuvers, the decrease in systolic, diastolic, and mean arterial pressures was greater in the intensive recruitment strategy (P ≤ .001, interaction factor). However, 5 minutes after ceasing the maneuvers, arterial pressures recovered, without significant differences between both groups (eFigure 1 in Supplement 2). The same pattern of transient hemodynamic impairment was apparent 4 hours later, during the second recruiting maneuvers (before extubation). Heart rate between groups during or after recruitment maneuvers did not differ (eFigure 2 in Supplement 2). Severe hypotension (mean arterial blood pressure <60 mm Hg) or arrhythmia was not observed during the maneuvers (eFigure 3 in the Supplement 2). Despite the different PEEP strategies in each group, the hemodynamic parameters were not significantly different during the 4 hours of mechanical ventilation (eTable 2 in Supplement 2).

Lung Function

Evolution of respiratory variables is shown in eTable 1 in Supplement 2. At admission to the ICU, there were no significant differences in baseline respiratory variables in either group, including Pao2:Fio2 ratios (both groups using PEEP at 5 cm H2O), arterial pH, and respiratory-system compliance. Soon after randomization, a marked difference was observed, with patients in the intensive recruitment strategy group developing significantly higher Pao2:Fio2 ratios (P < .001), lower Paco2 (P < .001), higher respiratory-system compliance (P < .001), and lower driving-pressures (P < .001). There was no significant difference in VT between both groups ( ≈ 6.1 mL/kg, P = .49, between-groups factor).

After 4 hours of treatment, pressure-volume curves were significantly improved in the intensive recruitment strategy group (accommodating a higher volume for equivalent pressures), but unchanged in the moderate recruitment strategy group (P < .001, interaction between strategy and time; Figure 4, panel A).

The electrical impedance tomographic analysis showed that from ICU admission until extubation, the intensive recruitment strategy group gained significantly more ventilation and compliance in dependent lung regions (P = .003) compared with the moderate recruitment strategy group (eFigure 4 in Supplement 2).

Discussion

Among patients with hypoxemia after cardiac surgery, the use of an intensive alveolar recruitment strategy compared with a moderate recruitment strategy resulted in less severe pulmonary complications during the hospital stay. Patients in the intensive alveolar recruitment strategy group also had shorter hospital and shorter ICU lengths of stay but no difference in hospital mortality or incidence of barotrauma than did patients in the moderate alveolar recruitment strategy group. Physiological parameters explored in post hoc analysis indicated a faster recovery of lung function after the first recruitment maneuver was applied in the ICU, resulting in physiological benefits that lasted through extubation and beyond. Further lung function benefits were observed in the next days following extubation, resulting in a significantly lower use of supplemental oxygen and lower use of extended noninvasive mechanical ventilation.

To our knowledge, this is the first study to show a significant effect of lung recruitment maneuvers on clinical outcomes, which objectively resulted in modest reductions in ICU and hospital length of stay with no difference in in-hospital mortality or the occurrence of barotrauma. This is especially noteworthy considering that the control group was also receiving protective lung ventilation with low VT and moderate PEEP levels. Thus, the major difference between treatment groups was the intensity of lung recruitment.

The moderate recruitment strategy used in this study was similar to the lung-protective strategy applied intraoperatively in the recent Intraoperative Protective Ventilation in Abdominal Surgery (IMPROVE) trial.13 Enrolling patients undergoing abdominal surgery, the IMPROVE trial had already demonstrated a 76% reduction in postoperative pulmonary complications (grade ≥3) compared with a control group receiving nonprotective ventilation (0 PEEP and median VT, 11 mL/kg of PBW). Thus, the present study suggests that a step further in postoperative lung protection is possible. Patients in the intensive recruitment strategy group showed greater reversal of atelectasis (suggested by electrical impedance tomography maps, eFigure 4 in Supplement 2), with a better respiratory-system compliance and lower driving-pressure18 applied to the inflamed lung (eTable 1 in Supplement 2). After several hours, they also showed a better lung inflation profile (suggested by the enhanced P-V loops, Figure 4, panel A), and, subsequently, a better gas-exchange during the weaning time, as well as along the subsequent days. This long-lasting improvement in lung function prevented pulmonary complications and the need of more intensive therapies, allowing the patients to be discharged earlier from the ICU and hospital.

Contrasting the results presented in the present trial, a recent multicenter study by Hemmes et al14 (Protective Ventilation During General Anesthesia for Open Abdominal Surgery [PROVHILO]) showed no benefit from a more intensive alveolar recruitment strategy involving patients undergoing abdominal surgery. Variations in study methods might explain the different outcomes. For instance, 100% of patients in this present study were extubated at low Fio2 (≤0.40) compared with only half of patients in the PROVHILO study. Thus, it is possible that a greater reabsorption of atelectasis promoted by higher intra-alveolar Fio219,20 may have abrogated the effects of that ventilation strategy. Second, the maneuvers used in the present trial transiently reached inspiratory pressures of 45 cm H2O, likely more effective to reverse atelectasis,21 whereas the PROVHILO study did not use pressures greater than 35 cm H2O. Third, the population in this study had higher chances of developing atelectasis, presenting higher body mass indexes (28 vs 25.5; calculated as weight in kilograms divided by height in meters squared), more frequent extracorporeal support3,22 and more open-chest surgeries with direct lung contact. Considering the lower VT used in this study (6.1 mL/kg of PBW; eTable 1 in Supplement 2) compared with approximately 7.2 mL/kg of PBW in their study, all such differences may have converged to amplify the relative importance of recruiting maneuvers.

In contrast with some of previous investigations,5,14,15 the lung recruitment performed in this study was not done intraoperatively or after extubation.23 Although such procedures might have enhanced the benefits of an intensive recruitment strategy,5 it is otherwise possible that the selective application of recruitment strategy, only at the postoperative phase, offers a good compromise between safety and efficacy. Possibly, this lung-rescue procedure replaced or avoided the intraoperative recruitment strategy application in the context of bleeding and reduced peripheral vascular tonus, a situation that might decrease protocol adhesion or promote frequent hypotension. By performing the procedure in the ICU, hemodynamic optimization might be easier, and ventilator disconnections during transportation could be counterbalanced.

Adverse Effects and Resource Utilization

A larger decrease in arterial blood pressure was observed in the intensive recruitment strategy group, although blood pressure never decreased to less than 60 mm Hg and was limited to the duration of the recruitment maneuver. Five minutes later, there were no significant differences in arterial pressure between groups, despite the higher PEEP in the intensive group. This fast recovery is consistent with clinical studies showing improved right ventricular function after the maneuver24 and also with experimental studies in which a short recruiting maneuver (<1 minute) was applied, under pressure-controlled modes.25,26 Pilot studies at our institution had also suggested that the key elements for such good hemodynamic tolerance (eTable 2 in Supplement 2) were a negative leg-raising test and a high-enough mean arterial blood pressure beforehand. Both were strictly optimized before starting the maneuvers.

Although ICU and hospital costs have not been directly measured, differences in procedures or differences in resources utilization were not identified between groups during the mechanical ventilation period. The only observable difference was the settings on the mechanical ventilator, along with the 1-hour shorter (P = .15) mechanical ventilation period in the intensive recruitment strategy group. It is possible that the clinician’s awareness of better lung function was related to a faster sequence of weaning steps. In contrast, the utilization of resources after extubation was higher in the moderate recruitment strategy group, with more frequent use of supplemental oxygen (Figure 4B), noninvasive ventilation (Table 3), and modestly longer ICU and hospital length of stay.

Limitations

This study has several important limitations. The criteria for defining postoperative pulmonary complication may influence the results. This study used the definition elaborated by Kroenke et al,16 which was also used in some recent trials.4,13 To try to achieve unbiased application, objective definitions were further preestablished: hypoxemia, need of noninvasive ventilation, and radiographic abnormalities (requiring concordance of 2 independent observers). In addition, death was included as a maximum complication, increasing its reliance on clinical outcomes. Within this context, post hoc analysis demonstrated a higher rate of major pulmonary complications (pulmonary scores ≥3) was observed in the control (moderate) group (26%), compared with previous trials (≤22%4,13). Contributing to this difference, however, was the strict inclusion criteria (Pao2/Fio2 <250 at PEEP ≥5 cm H2O), which may have selected patients with higher probability of response to PEEP and recruitment maneuvers. This predictive enrichment27 was part of the study design, increasing the power of the study but decreasing generalizability. Also, because of the particular injury of cardiopulmonary bypass3,22 patients with more inflamed lungs were probably selected. Most patients in the present study developed at least some minor pulmonary complication, although at a systematically lower frequency in the intensive recruitment strategy group.

The single-center nature of this study limits the generalizability of findings to a broader population. The large population studied and the consistent physiologic analysis, add some robustness to results. In addition, other important factors, such as fluid balance and analgesia after ICU arrival, were not extensively measured. Counterbalancing this, the chances of systematic biases were low because the investigators were not responsible for daily prescriptions (eg, oxygen therapy, fluids, drugs) and, after extubation, the clinical staff was blinded to randomization and allocation, especially so in the ward.

Conclusions

Among patients with hypoxemia after cardiac surgery, the use of an intensive alveolar recruitment strategy compared with a moderate recruitment strategy resulted in less severe pulmonary complications during the hospital stay.

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Article Information

Corresponding Author: Marcelo Britto Passos Amato, MD, PhD, Cardio-Pulmonary Department, Pulmonary Division, Heart Institute (Incor), Hospital Das Clínicas da FMUSP, University of São Paulo, Avenue Dr Arnaldo 455, sala 2144 (Second Floor), São Paulo, SP, Brazil, CEP: 01246-903 (amato.marcelo.bp@gmail.com).

Published Online: March 21, 2017. doi:10.1001/jama.2017.2297

Author Contributions: Dr Amato had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Leme, Hajjar, Volpe, Fukushima, Feltrim, Nozawa, Coimbra, Kalil Filho, Auler, Jatene, Amato.

Acquisition, analysis, or interpretation of data: Leme, Hajjar, Volpe, De Santis Santiago, Osawa, Pinheiro de Almeida, Gerent, Franco, Ianotti, Hashizume, Gomes Galas, Amato.

Drafting of the manuscript: Leme, Hajjar, Volpe, Fukushima, Pinheiro de Almeida, Gerent, Franco, Feltrim, Nozawa, Coimbra, Ianotti, Hashizume, Amato.

Critical revision of the manuscript for important intellectual content: Hajjar, Volpe, De Santis Santiago, Osawa, Kalil Filho, Auler, Jatene, Gomes Galas, Amato.

Statistical analysis: Volpe, Fukushima, De Santis Santiago, Amato.

Obtained funding: Amato.

Administrative, technical, or material support: Leme, Osawa, Gerent, Franco, Feltrim, Coimbra, Hashizume, Kalil Filho, Amato.

Supervision: Leme, Hajjar, Pinheiro de Almeida, Nozawa, Auler, Jatene, Gomes Galas, Amato.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Amato reports that his research laboratory has received grants in the last 5 years from the following companies: Covidien/Medtronics, Dixtal Biomedica Ltd, and Timpel SA. No other disclosures were reported.

Funding/Support: This study was partially supported by FAPESP (Fundação de Amparo e Pesquisa do Estado de São Paulo) and FINEP (Financiadora de Estudos e Projetos).

Role of the Funder/Sponsor: FAPESP and FINEP had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Disclaimer: The content, findings, and conclusions of this report are solely the responsibility of the authors and do not necessarily represent the official views of FAPESP and FINEP.

Meeting Presentations: Selected data from this article were partially presented at the 33rd, 34th, and 37th International Symposium on Intensive Care and Emergency Medicine; Brussels, Belgium; 2013, 2014, and March 24, 2017, respectively.

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