Does a Protective Ventilation Strategy Reduce the Risk of Pulmonary Complications After Lung Cancer Surgery?

: A Randomized Controlled Trial

Mikyung Yang, Hyun Joo Ahn, Kwhanmien Kim, Jie Ae Kim, Chin A Yi, Myung Joo Kim and Hyo Jin Kim Chest 2011;139;530-537; Prepublished online September 9, 2010; DOI 10.1378/chest.09-2293 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/139/3/530.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2011by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

CHEST

Original Research
CRITICAL CARE

Does a Protective Ventilation Strategy Reduce the Risk of Pulmonary Complications After Lung Cancer Surgery?
A Randomized Controlled Trial
Mikyung Yang, MD, PhD; Hyun Joo Ahn, MD, PhD; Kwhanmien Kim, MD, PhD; Jie Ae Kim, MD, PhD; Chin A Yi, MD, PhD; Myung Joo Kim, MD; and Hyo Jin Kim, MD

Background: Protective ventilation strategy has been shown to reduce ventilator-induced lung injury in patients with ARDS. In this study, we questioned whether protective ventilatory settings would attenuate lung impairment during one-lung ventilation (OLV) compared with conventional ventilation in patients undergoing lung resection surgery. Methods: One hundred patients with American Society of Anesthesiology physical status 1 to 2 who were scheduled for an elective lobectomy were enrolled in the study. During OLV, two different ventilation strategies were compared. The conventional strategy (CV group, n 5 50) consisted of FIO2 1.0, tidal volume (VT) 10 mL/kg, zero end-expiratory pressure, and volume-controlled ventilation, whereas the protective strategy (PV group, n 5 50) consisted of FIO2 0.5, VT 6 mL/kg, positive end-expiratory pressure 5 cm H2O, and pressure-controlled ventilation. The composite primary end point included PaO2/FIO2 , 300 mm Hg and /or the presence of newly developed lung lesions (lung inltration and atelectasis) within 72 h of the operation. To monitor safety during OLV, oxygen saturation by pulse oximeter (SpO2), PaCO2, and peak inspiratory pressure (PIP) were repeatedly measured. Results: During OLV, although 58% of the PV group needed elevated FIO2 to maintain an SpO2 . 95%, PIP was signicantly lower than in the CV group, whereas the mean PaCO2 values remained at 35 to 40 mm Hg in both groups. Importantly, in the PV group, the incidence of the primary end point of pulmonary dysfunction was signicantly lower than in the CV group (incidence of PaO2/FIO2 , 300 mm Hg, lung inltration, or atelectasis: 4% vs 22%, P , .05). Conclusion: Compared with the traditional large VT and volume-controlled ventilation, the application of small VT and PEEP through pressure-controlled ventilation was associated with a lower incidence of postoperative lung dysfunction and satisfactory gas exchange. Trial registry: Australian New Zealand Clinical Trials Registry; No.: ACTRN12609000861257; URL: www.anzctr.org.au CHEST 2011; 139(3):530537
Abbreviations: ALI 5 acute lung injury; CV 5 conventional strategy group; OLV 5 one-lung ventilation; PEEP 5 positive end-expiratory pressure; PIP 5 peak inspiratory pressure; PV 5 protective strategy group; Spo2 5 oxygen saturation by pulse oximeter; VILI 5 ventilator-induced lung injury; Vt 5 tidal volume; ZEEP 5 zero end-expiratory pressure

aspects of ventilator-induced lung The important are volutrauma, barotrauma, atelecinjury (VILI)

trauma, and oxygen toxicity. The protective ventilation strategy, which addresses these issues by using a small Vt with positive end-expiratory pressure (PEEP), limited airway pressure, and low Fio2, has gained wide acceptance as a ventilation strategy and has been shown to reduce VILI in patients with ARDS.1-3 It is uncertain whether the instigation of mechanical ventilation can induce some degree of structural
530

injury to normal lungs.4-6 Recently, the safety issue of conventional methods for one-lung ventilation (OLV) has been raised because of the possibility for VILI using a large tidal volume (Vt) in lung resection surgery. Conventional methods for OLV often use a Vt of 8 to 12 mL/kg (the same Vt for two-lung ventilation) to prevent atelectasis,7,8 and systemic oxygenation is optimized by increasing Fio2 to 1.0 to create a buffer should ventilation and oxygenation become difcult. PEEP is usually not applied because it can
Original Research

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

direct more blood ow to the nonventilated lung and cause shunt aggravation.7-9 However, this approach to OLV is not an evidence-based guideline and has a potential for volutrauma, barotrauma, atelectrauma, and oxygen toxicity. Several studies have shown some correlations between OLV and cumulative oxidative stress,10 proinammatory cytokine release,11 and tissue damage on histologic analysis.12 Furthermore, a retrospective analysis of contributing factors for acute lung injury (ALI) after lung resections has identied the increased duration of OLV as one of the main risk factors.13 With the signicant contributions of standardization of surgical techniques and advances in anesthetic management, lung resection surgery is now considered as a relatively safe procedure; however, various degrees of postoperative pulmonary complications still remain a matter of great concern.14 We, therefore, reasoned that because VILI could contribute to postoperative respiratory complications, a lung-protective ventilatory strategy during OLV might reduce these complications. To date, several observational studies have identied duration of OLV, Vt, and the level of inspiratory airway pressure as risk factors for postresection ALI-ARDS in thoracic surgery.13,15,16 From these reports, recent recommendations have suggested using smaller Vt and PEEP during OLV.17 However, there have been no prospective randomized trials assessing the impact of a standardized protective ventilatory regimen on intraoperative safety and on the occurrence of lung complications. Therefore, this study was performed to test the hypothesis that protective ventilation strategies can more effectively reduce postoperative pulmonary complications compared with conventional strategies, while providing safe OLV in patients undergoing lung resection surgery. Materials and Methods
Study Population Approval for the study was obtained from our institutional review board. Written informed consent for enrollment in the trial was obtained from each patient. Manuscript received October 7, 2009; revision accepted August 1, 2010. Afliations: From the Department of Anesthesiology and Pain Medicine (Drs Yang, Ahn, J. A. Kim, M. J. Kim, and H. J. Kim), the Department of Thoracic and Cardiovascular Surgery (Dr K. Kim), and the Department of Radiology (Dr Yi), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Correspondence to: Hyun Joo Ahn, MD, PhD, Department of Anesthesiology and Pain Medicine, Samsung Medical Center, 50 Ilwon-Dong, Kangnam-Gu, Seoul, Korea, 135-710; e-mail: hyunjooahn@skku.edu 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.09-2293
www.chestpubs.org

From January to May 2009, all patients with American Society of Anesthesiology physical status 1 to 2 and scheduled for an elective lobectomy in our hospital were subjected to the study. An exclusion criterion consisted of the patients refusal to take part in the study. As a result, a total of 122 patients were initially enrolled in the study. Patients were randomized into the conventional ventilation group (the CV group) or the protective ventilation group (the PV group) via a computer-generated random number table using a sealed envelope assignment. Anesthesia and Surgery Before anesthesia, a thoracic epidural catheter was inserted at the level of the thoracic segment from T4-5 to T6-7. Continuous infusion was started 15 min after OLV at a rate of 4 mL /h through the thoracic epidural catheter and was maintained for 2 to 3 days by patient-controlled epidural analgesia (hydromorphone 8 mg 1 0.2% ropivacaine 375 mL 1 normal saline 121 mL; bolus 1.5 mL, lockout time 15 min, basal infusion 4 mL/h). Patients who refused or failed to control epidural analgesia received IV patientcontrolled analgesia (fentanyl 1,500 mg 1 ketorolac 180 mg 1 normal saline 64 mL; bolus 1 mL, lockout time 15 min, basal infusion 1 mL /h). Intraoperative monitoring included a three-lead ECG, BP cuff, and measurements of oral temperature, oxygen saturation by pulse oximetry (Spo2), expired CO2, arterial pressure, and urine output. The trachea was intubated after administering propofol (2 mg/kg), rocuronium (0.6 mg/kg), and fentanyl (2 mg/kg). Anesthesia was maintained with inhaled sevourane in a 1:1 mixture of oxygen and air. After anesthesia induction, all patients received an arterial catheterization for continuous arterial BP measurement and arterial blood gas sampling. Blood gas tension analysis was performed immediately with standard blood gas electrodes (Rapidlab 1265; Bayer Healthcare; Leverkusen, Germany). Four surgeons experienced in major lung resections, each of whom performs more than 100 major lung resection surgeries per year, conducted each operation and were unaware of the strategy used. Lobectomies were performed through a standard posterolateral or anterolateral muscle-sparing thoracotomy or videoassisted thoracic surgery. Standardized uid replacement consisted of 10 mL /kg lactated Ringer solution preoperatively, followed by 6 mL /kg/h perioperatively. If mean arterial pressure was , 70 mm Hg for . 5 min, an additional uid challenge was achieved with 10 mL /kg hydroxyethyl starch. After surgery, all patients were extubated, admitted to the ICU, and monitored for at least 24 h. After extubation, patients were observed with supplemental oxygen for 30 min followed by return to room air. Supplemental oxygen was continued if patients showed an Spo2 value , 95%. Postoperative uid management for 24 h was 1 mL /kg/h. Bedside mobilization was tried at postoperative 6 h and continued if patients did not show decrease of Spo2 to , 90% and increase of heart rate . 20-30/min. Nothing by mouth was discontinued usually 6 to12 h after operation. Patients were cared for by attending physicians in the ICU not involved in the protocol and blinded to the allocated group. Study Protocol of Each Ventilator Strategy After tracheal intubation with a left- or right-sided standard double-lumen tube (Broncho-Cath 35F or 37F; Mallinckrodt Medical, Ltd; Athlone, Ireland) under beroptic bronchoscopy, mechanical ventilation was initiated with an anesthesia ventilator (Aestiva/5; Datex-Ohmeda, GE Healthcare; Helsinki, Finland) connected to a circle system. Gas ow and airway pressure were measured at the proximal end of the endotracheal tube with a standard monitor for ventilatory measurement (Datex-Ohmeda, GE Healthcare).
CHEST / 139 / 3 / MARCH, 2011

531

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

During two-lung ventilation, all patients received the same ventilation protocol consisting of Fio2 0.5, Vt of 10 mL /kg predicted body weight, zero end-expiratory pressure (ZEEP), and volume-controlled ventilation with an inspiratory pause of 30% and inspiration to expiration ratio of 1:2. During OLV, the CV group received the same ventilation protocol except the Fio2 value, which was elevated to 1.0. The PV group received an Fio2 0.5, PEEP 5 cm H2O, and pressure-controlled ventilation. Pressure was adjusted to achieve a Vt reading of 6 mL/kg predicted body weight. Peak pressure and plateau pressure were the same in the PV group. Respiratory frequencies were adjusted to achieve a Paco2 measurement between 35 and 45 mm Hg throughout anesthesia. The maximal allowable peak inspiratory pressure (PIP) on volume-controlled ventilation was set at 30 cm H2O and, in the case that this value was exceeded, volume-controlled ventilation was changed to pressure-controlled ventilation. If it was not possible to reduce PIP with this method or if the patient was already in pressure-controlled ventilation, Vt was reduced by 1 mL/kg. The minimum Spo2 allowed during the operation was 95%. In cases of Spo 2 being , 95%, Fio2 was increased by 0.2 at 3-min intervals until Fio2 reached 1.0 in the PV group. If Spo2 fell below 95% with Fio 2 at 1.0 in both groups, continuous positive airway pressure on the excluded lung or intermittent two-lung ventilation was applied. The anesthesiologists were not blinded to the strategy used, but they were not involved in the collection of arterial blood gas analysis, parameters of ventilation, or ICU data. Measurements The composite primary end point included Pao2/Fio2 , 300 mm Hg and/or the presence of newly developed lung lesions (lung inltration and atelectasis) within 72 h of the operation.13 Postoperative pulmonary complications were observed in the ICU and the ward for 1 week. Pao2/Fio2 readings were measured 2 h after ICU arrival and at 3:00 am during the ICU stay. Chest radiographs were taken every morning. A single radiologist blinded to the treatment group, as well as the clinical condition of each subject, evaluated each radiograph. The radiographs were divided into four quadrants (right upper, right lower, left upper, and left lower), and each quadrant was scored based on the intensity of inltrates, as follows: no inltrate 5 0, less than one-third of the quadrant opacied 5 1; one-third to two-thirds of the quadrant opacied 5 2; more than two-thirds of the quadrant opacied 5 3. The sum of the quadrant scores was converted into a chest radiographic assessment score.18 ALI was diagnosed by (1) sudden onset of respiratory distress; (2) diffuse pulmonary inltrates on the chest radiograph consistent with alveolar edema; (3) impaired oxygenation with a Pao2/Fio2 ratio of , 300 mm Hg; (4) absence of hydrostatic pulmonary edema due to cardiac insufciency or uid overload, on the basis of pulmonary arterial catheterization, ECG, laboratory data (creatine kinase-MB fraction level, troponin level), clinical evaluation, or a combination of these.13,19 Intercurrent complications, such as bronchopneumonia, aspiration, thromboembolism, cardiac origin pulmonary edema, or postoperative bleeding, were not included as VILI complications. For the second end point involving the intraoperative safety of the two ventilation strategies, four sets of measurements were successively obtained during the operation: Spo2, Pao2, Paco2, and PIP values were measured at the baseline time in the lateral decubitus position before ventilation strategy application, 15 min and 60 min after initiation of OLV, and 15 min after the end of OLV. The ventilatory regimen was considered inappropriate or unsafe when the inspiratory airway pressure was . 30 cm H2O or Spo2 was , 95%.
532

Power and Statistical Analysis Because there have been no reports comparing the incidences of Pao2/Fio2 values being , 300 mm Hg and pulmonary complications between the two ventilation strategies, the sample size was calculated based on previous data, which showed a difference in postoperative Pao2/Fio2 readings between Vt of 9 mL/kg with a ZEEP group vs Vt of 5 mL /kg with a 5 cm H2O PEEP group.15 Forty-seven subjects in each group were required to detect a difference in mean Pao2/Fio2 values of 50 mm Hg, with an estimated SD of 85 mm Hg, a power of 80%, and a 5% risk of a type one error. Discrete data were presented as percentages, and continuous data were presented as mean 6 SD. The Student t test or MannWhitney test with Bonferroni correction was used for continuous variables. The Pearson x2 or Fisher exact test was applied for categorical variables. Changes from baseline in continuous variables were analyzed using analysis of variance. P value , 0.05 was considered statistically signicant. Statistical analysis was performed with the software program SAS 9.1.3 (SAS Institute, Inc; Cary, North Carolina).

Results Of the 122 patients, 11 in each group were excluded from the study because of incomplete data, changes of surgical plan, or excessive bleeding. Fifty patients in each group remained and were analyzed (Fig 1). There was no difference in demographic or operational data between the two groups (Tables 1, 2). Besides predetermined Fio2 and Vt measurements, the respiratory rate and respiratory system compliance were higher and the PIP and plateau pressure were lower in the PV group than in the CV group during OLV. PaO2 and pH levels were lower, and Paco2 was higher in the PV group than in the CV group during OLV (Table 3). During OLV, 58% of the patients in the PV group required elevated Fio2 because the Spo2 value was , 95%, leading to a mean Fio2 reading of 0.62 (15 min after initiation of OLV) to 0.67 (60 min after initiation of OLV). Thirty percent of patients in the CV group needed to change ventilation modes from volumecontrolled ventilation to pressure-controlled ventilation because of a PIP value . 30 cm H2O. After the change, the mean PIP value was reduced to 23 cm H2O, and the patients required no further assistance. One patient in the CV group and two in the PV group required rescue methods, such as continuous positive airway pressure on the operated lung or two-lung ventilation, because Spo2 dropped below 95% with Fio2 at 1.0 (Table 3). The PV group showed higher postoperative Pao2/Fio2 (Fig 2) as compared with the CV group. Comparatively, the PV group also presented fewer cases of Pao2/Fio2 , 300 mm Hg (1 vs 8, P 5 .03), with an OR of 9.3 (95% CI, 1.1-77.7), and a lesser incidence of lung inltration or atelectasis (2 vs 10, P 5 .03), with an OR of 6.0 (95% CI, 1.2-29.0). The total number of patients who exhibited Pao2/Fio2 , 300 mm Hg,
Original Research

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

Figure 1. The ow diagram of the study. CV 5 conventional strategy group; PV 5 protective strategy group.

lung inltration, or atelectasis was 11 and 2 in the CV and PV groups, respectively (P 5 .02), with an OR of 6.8 (95% CI, 1.4-32.4). Four patients in the CV group and one patient in the PV group met the ALI criteria (P 5 .362). One patient who met the ALI criteria in the CV group died of ARDS. The onset of lung lesions and chest radiographic assessment scores in patients with lung inltrates were not different between the two groups (Fig 3, Table 4). The duration of ICU stay (39 6 81 h vs 29 6 26 h for CV and PV, respectively) and hospital stay (7.7 6 3.5 days vs 7.8 6 3.1 days for CV and PV, respectively) did not differ between the two groups. However, the duration of ICU stay between those who developed pulmonary complications compared with those who did not was signicantly different (median value of 52 h [quartile 25%-75%, 24-88 h] vs 22 h [quartile 25%-75%, 19-26 h], P , .05, respectively). For other pulmonary complications, pneumothorax (CV group: 6%; PV group: 8%), pleural effusion (CV group: 6%; PV group: 6%), and chylothorax (CV group: 0%; PV group: 2%) were shown. Atrial brillation was shown in 12% and 8% of patients in the CV and PV groups, respectively. Transient ischemic attack (2%) and stroke (2%) were shown in the CV group only. Perioperative mortality was 2% and 0% in the CV and PV groups, respectively. Discussion A protective ventilation strategy consisting of Fio2 0.5, Vt 6 mL/kg, PEEP 5 cm H2O, and pressurecontrolled ventilation provided benecial effects in
www.chestpubs.org

terms of fewer pulmonary complications and improved oxygenation indices compared with the conventional ventilation strategy. There have been few studies comparing CV and PV strategies during OLV. In an animal study, OLV with 8 mL/kg of Vt with ZEEP was associated with an increase in surrogate markers of lung injury, lung weight gain, and inammatory cytokine levels, as compared with OLV with 4 mL /kg of Vt with PEEP 1 cm H2O.20 The only randomized controlled trial on humans was performed on patients undergoing OLV for esophagectomies.15 Their ndings included an attenuated systemic proinammatory response, reduced extravascular lung water index, and improved Pao2/Fio2 that allowed for earlier extubation in patients who received low Vt (5 mL/kg) with a PEEP level of 5 cm H2O, as compared with a Vt of 10 mL/kg with ZEEP. Recently, a retrospective cohort study that assessed the clinical impact of PV strategy in patients undergoing lung cancer resection has demonstrated that the small Vt levels (, 8 mL/kg), pressure-controlled ventilation, limitation of the inspiratory plateau pressure to 35 cm H2O, and the addition of PEEP (4 and 10 cm H2O) signicantly decreased the incidences of ALI (from 3.7% to 0.9%, P , .01) and atelectasis (from 8.8% to 5.0%, P 5 .018) compared with the data before the implementation of the PV strategy.21 Our study was the rst randomized controlled trial performed on patients undergoing lung resection surgery using all of the known protective measures during OLV. The study showed higher postoperative Pao2/Fio2 and fewer pulmonary complications in the PV strategy.
CHEST / 139 / 3 / MARCH, 2011

533

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

Table 1Characteristics of Patients

Characteristic Age, y Sex, M (F) Weight predicted, kg Height, cm BMI ASA physical status, 1 (2) Underlying disease Hypertension Diabetes mellitus COPD Heart disease Previous chemotherapy and radiotherapy Previous lung surgery Alcohol, no/social/heavy Smoking No Stop more than 6 mo Stop within 6 mo Current smoker Pack-years Echocardiography, LVEF, % PFT FEV1, % predicted FEV1/FVC, % predicted ppoFEV1, % Obstructive Restrictive Combined CV 60 6 10 31 (19) 59 6 15 162 6 8 23.8 6 2.9 29 (21) 13 6 2 2 5 2 32/13/5 25 13 7 5 34.9 64 6 5 104 6 17 74 6 9 80.3 6 15.1 10 2 0 PV 58 6 12 31 (19) 61 6 17 161 6 15 23.3 6 2.8 26 (24) 9 3 3 5 7 2 28/14/8 21 12 12 5 43 65 6 5 105 6 19 74 6 11 82.0 6 16.1 14 1 0

Table 2Characteristics of Surgery

Characteristic Pathology, squamous/adeno/other, No. Stage, No. T, 1/2/3/4 N, 0/1/2 M, 0/1 Surgeon,a 1/2/3/4 Type of surgery Lobectomy, R/L Bilobectomy, R Sleeve, R/L Open PLMS PL Other VATS Duration of operation, min Duration of anesthesia, min Duration of OLV, min Amount of uid, mL Crystalloid Colloid Blood loss, mL Transfusions, events Transfusion, units Urine output, mL/kg/h Pain control, epidural/IV PCA CV 10/30/10 21/21/4/1 39/2/6 47/0 27/9/9/5 25/21 2 1/1 18 1 1 30 191 6 61 251 6 60 126 6 53 1,526 6 508 561 6 213 244 6 132 1 1 1.6 6 1.1 20/30 PV 12/29/9 24/20/1/0 38/1/6 45/0 13/14/12/11 31/15 2 1/1 17 5 1 27 177 6 61 233 6 60 120 6 41 1,526 6 471 575 6 184 384 6 471 3 1.7 1.5 6 0.9 30/20

Data are expressed as mean 6 SD or No. of patients. There were no differences between the groups. Heart disease: one patient had pacemaker insertion because of complete AV block in the PV group, and the remaining patients had previous coronary stent; all these patients showed no abnormal symptoms or echocardiographies before surgery. Previous lung surgery: one patient had ipsilateral wedge resection, one had lung biopsy in the CV group; one patient had contralateral lung lobectomy, one had ipsilateral wedge resection in the PV group. ASA 5 American Society of Anesthesiologists; CV 5 conventional strategy group; F 5 female; LVEF 5 left ventricular ejection fraction; M 5 male; PFT 5 pulmonary function test; ppoFEV1 5 postoperative predicted FEV1; PV 5 protective strategy group.

Data are expressed as mean 6 SD or No. of patients. Adeno 5 adenocarcinoma; epidural 5 epidural patient-controlled analgesia; L 5 left; OLV 5 one-lung ventilation; PCA 5 patient-controlled analgesia; PL 5 posterolateral muscle-cutting thoracotomy; PLMS 5 posterolateral muscle-sparing thoracotomy; R 5 right; squamous 5 squamous cell carcinoma; VATS 5 video-assisted thoracic surgery. See Table 1 for expansion of other abbreviations. aFour surgeons were labeled from 1 to 4.

This result can possibly be attributed to the net effect of all of these protective measures. Small Vt ventilation reduced volutrauma, barotrauma, and ALI in ICU patients.22 In thoracic surgery, Schilling et al16 discovered reduced alveolar concentrations of tumor necrosis factor-a and soluble intercellular adhesion molecules in patients ventilated with small Vt as compared with large Vt (5 vs 10 mL/kg). Small Vt ventilation was usually accompanied with PEEP in most studies,6,15,20 and the lack of PEEP would worsen oxygenation and shunt fractions during small Vt ventilation.23 The application of PEEP minimized alveolar collapse and atelectrauma during mechanical ventilation.23 Atelectrauma resulted from a high shear force on collapsed alveolar walls and through the repeated collapse and reexpansion of the walls with each respiratory cycle is known to cause injury
534

not only to the alveoli that are being recruited but also to adjacent non-atelectatic alveoli.24,25 High ventilating pressures are signicantly associated with lung injury.13 In our study, the upper limit of PIP was set at 30 cm H2O. This was accomplished through small Vt, but pressure-controlled ventilation also reduced PIP and plateau pressure effectively in the PV group. The pressure-controlled mode of ventilation has been recently adopted in ventilators in the operating room. The conventional volume-controlled mode uses a constant inspired ow (square wave), creating a progressive increase of airway pressure toward the PIP, which is reached as the full Vt has been delivered. On the contrary, the pressurecontrolled mode uses a decelerating ow pattern, with maximal ow at the beginning of inspiration until the set pressure is reached, after which ow rapidly decreases. This balances the decreasing compliance of the expanding lung.26 The pressure-controlled mode was associated with statistically signicant decreases in peak and plateau airway pressures and improved oxygenation and shunt fraction in thoracotomies.27 The pressure-controlled mode also showed
Original Research

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

Table 3Characteristics of Ventilator Parameters and Intraoperative Arterial Blood Gas Analysis
CV Characteristic Vt, mL RR, bpm PIP, cm H2O Pplateau, cm H2O Compliance, mL/cm H2O PEEP, cm H2O Fio2 Pao2, mm Hg Paco2, mm Hg pH Hematocrit, % Spo2 , 95% PIP . 30 cm H2O Tbaseline 551 6 85 9.4 6 0.9 18 6 2 15 6 2 31.9 6 4.5 0.7 6 0.9 0.58 6 0.12 290 6 79 34.8 6 5.3 7.46 6 0.03 35.4 6 3.9 TOLV15 542 6 101 9.1 6 1.4 23 6 3b 19 6 3b 24.7 6 4.3b 0.8 6 1.1 0.95 6 0.02b 240 6 102 36.0 6 4.5 7.46 6 0.04 35.3 6 3.7 1 15 TOLV60 543 6 97 9.4 6 1.5 23 6 2b 19 6 3b 24.4 6 3.9b 1.0 6 1.2 0.96 6 0.01b 249 6 107 35.4 6 4.0 7.45 6 0.03 35.0 6 3.7 TTLV15 522 6 127 9.6 6 3.0 19 6 4 16 6 4 30.4 6 7.9 1.0 6 1.3 0.64 6 0.18 301 6 109 38.9 6 5.7c 7.41 6 0.05c 33.7 6 3.9 Tbaseline 562 6 80 9.7 6 0.9 18 6 2 15 6 3 32.6 6 6.1 0.7 6 0.9 0.56 6 0.07 291 6 60 36.4 6 4.4d 7.45 6 0.04e 35.5 6 3.4 TOLV15 369 6 62 12.0 6 2.1a,b 18 6 4a 18 6 4a,b 28.9 6 7.4a 4.6 6 1.4a,b 0.62 6 0.12a 118 6 42a,b 39.1 6 4.9a 7.42 6 0.04a 35.2 6 3.6
a,b

PV TOLV60 361 6 53 12.8 6 1.9a,b 18 6 3a 18 6 3a,b 27.7 6 6.5a,b 4.8 6 1.0a,b 0.67 6 0.16a,b 135 6 55a,b 39.0 6 3.6a 7.42 6 0.04a 34.3 6 3.8
a,b

TTLV15 518 6 96 9.7 6 1.2 19 6 4 16 6 4 32.1 6 10.4 1.6 6 1.9 0.58 6 0.13a 273 6 75 38.1 6 4.5 7.41 6 0.04 33.4 6 3.8f

2 0

Data are expressed as mean 6 SD. Between groups, t test for all continuous variables. Within groups, one-way analysis of variance and Tukey honestly signcant different test as post hoc. Compliance is respiratory system compliance, Vt/PIP. PEEP 5 peak end-expiratory pressure; PIP 5 peak airway pressure; Pplateau 5 plateau airway pressure; RR 5 respiratory rate; Spo2 5 oxygen saturation by pulse oximetry; Tbaseline 5 baseline time after anesthetic induction and before ventilation strategy application; TOLV15 5 15 min after initiation of OLV; TOLV60 5 60 min after initiation of OLV; TTLV15 5 15 min after the end of OLV; Vt 5 tidal volume. See Table 1 and 2 legends for expansion of other abbreviations. aP , .05 compared with the counterpart of the CV group. bP , .05 compared with the Tbaseline and TTLV . 15 cP , .05 compared with the Tbaseline, TOLV , and TOLV 15 60. dP , .05 compared with the TOLV , TOLV 15 60. eP , .05 compared with the TOLV , TOLV , and TTLV . 15 60 15 fP , .05 compared with the Tbaseline.

homogeneous gas distribution and avoidance of regional overdistension, as seen through CT scans,28 as compared with the volume-controlled mode. Exposure to 100% oxygen can lead to absorption atelectasis24 and signicantly increased pulmonary capillary permeability, with consequent increases in lymphatic ow.29 Furthermore, the collapse of the

operative lung and surgical manipulation during OLV result in relative organ ischemia and tissue damage. Higher Fio2 during OLV can, therefore, lead to an increased production of radical oxygen species, proinammatory cytokines, and subsequent lung injury on reventilation-induced reperfusion.11,30,31 In this regard, Douzinas et al32 recommended that reperfusion should occur at a lower Fio2 because hypoxemic reperfusion has been shown to attenuate the reperfusion syndrome. In our study, Paco2 was higher in the PV group during OLV. However, mean Paco2 values remained

Figure 2. Postoperative Pao2/Fio2 values between the CV and PV groups. Pao2/Fio2 measurements at 2 h after the ICU arrival (POD0) and at 3:00 am on postoperative day 1 (POD1) are shown. Data are expressed as mean 6 SD with a Mann-Whitney rank sum test for POD0 and t test for POD1. POD0 5 Pao2/Fio2 measurements at 2 h after the ICU arrival; POD1 5 Pao2/Fio2 measurements at 3:00 am on postoperative day 1. *P , .05. See Figure 1 legend for expansion of abbreviations.
www.chestpubs.org

Figure 3. Pulmonary complications between the CV and PV groups. Pao2/Fio2 measurements , 300 mm Hg and/or newly developed lung lesions (lung inltration and atelectasis) within 72 h of the operation were counted as pulmonary complication. The numbers of patients are represented as values. *P , .05 by Fisher exact test; P , .05 by x2 test. ALI 5 acute lung injury; P/F , 300 5 Pao2/Fio2 values , 300 mm Hg. See Figure 1 legend for expansion of other abbreviations.
CHEST / 139 / 3 / MARCH, 2011

535

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

Table 4Lung Lesions

CV Lesion Atelectasis Lung inltration Radiologic score Onset time (POD) Ipsilateral 0 2 3.3 6 1.8 0.9 6 1.1 Contralateral 3 4 Bilateral 0 1 Ipsilateral 1 1 4.5 6 0.7 1.5 6 2.1 PV Contralateral 0 0 Bilateral 0 0

Data are expressed as the number of patients, scores, or days. Radiologic score is the chest radiographic assessment score (0-3 points in each quadrant of the lung, normal 5 0 to most severe 5 12). Onset time is the onset time of lung lesion. Contralateral 5 nonoperated lung; ipsilateral 5 operated lung; POD 5 postoperative day. See Table 1 for expansion of other abbreviations.

between 35 and 40 mm Hg in both groups, indicating adequate alveolar ventilation. Moderate hypercapnia potentiates the hypoxic pulmonary vasoconstriction response and is therefore unlikely to adversely affect oxygenation.33 Hypercapnia also appears to attenuate the cytokine response.34 Therefore, the moderate retention of CO2, as the result of small Vt, would be considered acceptable. In terms of the safety of OLV, the Spo2 value of all patients stayed . 95% during OLV except for one patient in the CV group and two patients in the PV group. These patients showed Spo2 levels , 95% despite Fio2 being at 1.0 and required rescue methods. Signicant desaturation was known to occur in 1% to 15% of the surgical population in spite of a high Fio2 during OLV.35,36 From these results, we concluded that the PV strategy was comparable to the CV strategy for safe oxygenation and alveolar ventilation during OLV, despite the smaller Vt and lower Fio2 values. However, 58% of the patients required elevated Fio2 levels to 0.67. As a result, initiating OLV with an Fio2 of 0.7 and altering its level with the guidance of Spo2 or Pao2 seems to be a reasonable approach. Limitations of this study include the short duration of the clinical follow-up period (1 week) and the inability to assess differences in the extravascular lung water index between the two groups through quantitative techniques, such as the single-indicator thermal dilution method.37 Further studies to acquire longterm results between the two ventilation strategies are necessary to determine if these short-term effects translate into long-term impairments. Second, using the PV strategy during the whole surgical period instead of during OLV might result in additional benets. Third, consensus on standard PEEP and Fio2 levels needs to be established. Fio2 levels of 0.7 at the beginning of OLV and 0.2 before reperfusion or setting individually different PEEP values using various recent techniques38 might bring further benets. Fourth, performing lung recruitment maneuvers as an additional PV strategy would be another valuable protective intervention that should be studied. In conclusion, the PV strategy showed higher postoperative Pao2/Fio2 values and fewer immediate
536

pulmonary complications than the CV strategy, while providing adequate oxygenation and ventilation during OLV. Therefore, performing OLV with an initial Fio2 value of 0.7 and Vt value of 6 mL/kg with PEEP at 5 cm H2O by the pressure-controlled mode appears to be the better approach for lung resection surgery. Acknowledgments
Author contributions: Dr Ahn had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including any adverse effects. Dr Yang: contributed to protocol design, data collection, analysis, writing the manuscript, and editing the manuscript. Dr Ahn: contributed to protocol design, data collection, analysis, writing the manuscript, and editing the manuscript. Dr K. Kim: contributed to data collection, analysis, and editing the manuscript. Dr J. A. Kim: contributed to data collection, analysis, and editing the manuscript. Dr Yi: contributed to data analysis and editing the manuscript. Dr M. J. Kim: contributed to data collection, analysis, and editing the manuscript. Dr H. J. Kim: contributed to data collection, analysis, and editing the manuscript. Financial/nonnancial disclosures: The authors have reported to CHEST that no potential conicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

References
1. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med. 1998;157(1):294-323. 2. American Thoracic Society TESoICM, The Societe de Reanimation de Langue Francaise. International consensus conferences in intensive care medicine: Ventilator-associated lung injury in ARDS. Am J Respir Crit Care Med. 1999;160(6): 2118-2124. 3. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med. 2006;32(1): 24-33. 4. Meier T, Lange A, Papenberg H, et al. Pulmonary cytokine responses during mechanical ventilation of noninjured lungs with and without end-expiratory pressure. Anesth Analg. 2008; 107(4):1265-1275. 5. Schultz MJ, Haitsma JJ, Slutsky AS, Gajic O. What tidal volumes should be used in patients without acute lung injury? Anesthesiology. 2007;106(6):1226-1231. 6. Wolthuis EK, Choi G, Dessing MC, et al. Mechanical ventilation with lower tidal volumes and positive end-expiratory
Original Research

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

7. 8. 9. 10.

11.

12. 13. 14.

15.

16. 17. 18.

19. 20.

21. 22.

pressure prevents pulmonary inammation in patients without preexisting lung injury. Anesthesiology. 2008;108(1): 46-54. Wilson WC, Benumof JL. Anesthesia for thoracic surgery. In: Miller RD, ed. Millers Anesthesia. 6th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005:1894-1895. Cohen E. Management of one-lung ventilation. Anesthesiol Clin North America. 2001;19(3):475-495. Brodsky JB, Fitzmaurice B. Modern anesthetic techniques for thoracic operations. World J Surg. 2001;25(2):162-166. Misthos P, Katsaragakis S, Theodorou D, Milingos N, Skottis I. The degree of oxidative stress is associated with major adverse effects after lung resection: a prospective study. Eur J Cardiothorac Surg. 2006;29(4):591-595. Funakoshi T, Ishibe Y, Okazaki N, et al. Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inammatory cytokine gene expression in isolated rabbit lungs. Br J Anaesth. 2004;92(4):558-563. Yin K, Gribbin E, Emanuel S, et al. Histochemical alterations in one lung ventilation. J Surg Res. 2007;137(1):16-20. Licker M, de Perrot M, Spiliopoulos A, et al. Risk factors for acute lung injury after thoracic surgery for lung cancer. Anesth Analg. 2003;97(6):1558-1565. Licker MJ, Widikker I, Robert J, et al. Operative mortality and respiratory complications after lung resection for cancer: impact of chronic obstructive pulmonary disease and time trends. Ann Thorac Surg. 2006;81(5):1830-1837. Michelet P, DJourno XB, Roch A, et al. Protective ventilation inuences systemic inammation after esophagectomy: a randomized controlled study. Anesthesiology. 2006;105(5): 911-919. Schilling T, Kozian A, Huth C, et al. The pulmonary immune effects of mechanical ventilation in patients undergoing thoracic surgery. Anesth Analg. 2005;101(4):957-965. Sentrk M. New concepts of the management of one-lung ventilation. Curr Opin Anaesthesiol. 2006;19(1):1-4. Kerr KM, Auger WR, Marsh JJ, et al. The use of cylexin (CY-1503) in prevention of reperfusion lung injury in patients undergoing pulmonary thromboendarterectomy. Am J Respir Crit Care Med. 2000;162(1):14-20. Matthay MA. Conference summary: acute lung injury. Chest. 1999;116(1 suppl):119S-126S. Gama de Abreu M, Heintz M, Heller A, Szchnyi R, Albrecht DM, Koch T. One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure is injurious in the isolated rabbit lung model. Anesth Analg. 2003;96(1): 220-228. Licker M, Diaper J, Villiger Y, et al. Impact of intraoperative lung-protective interventions in patients undergoing lung cancer surgery. Crit Care. 2009;13(2):R41. Yilmaz M, Keegan MT, Iscimen R, et al. Toward the prevention of acute lung injury: protocol-guided limitation of large tidal volume ventilation and inappropriate transfusion. Crit Care Med. 2007;35(7):1660-1666.

23. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med. 1994;149(5):1327-1334. 24. Duggan M, Kavanagh BP. Atelectasis in the perioperative patient. Curr Opin Anaesthesiol. 2007;20(1):37-42. 25. Duggan M, McCaul CL, McNamara PJ, Engelberts D, Ackerley C, Kavanagh BP. Atelectasis causes vascular leak and lethal right ventricular failure in uninjured rat lungs. Am J Respir Crit Care Med. 2003;167(12):1633-1640. 26. Nichols D, Haranath S. Pressure control ventilation. Crit Care Clin. 2007;23(2):183-199. 27. Turul M, Camci E, Karadeniz H, Sentrk M, Pembeci K, Akpir K. Comparison of volume controlled with pressure controlled ventilation during one-lung anaesthesia. Br J Anaesth. 1997;79(3):306-310. 28. Prella M, Feihl F, Domenighetti G. Effects of short-term pressure-controlled ventilation on gas exchange, airway pressures, and gas distribution in patients with acute lung injury/ARDS: comparison with volume-controlled ventilation. Chest. 2002;122(4):1382-1388. 29. Royer F, Martin DJ, Benchetrit G, Grimbert FA. Increase in pulmonary capillary permeability in dogs exposed to 100% O2. J Appl Physiol. 1988;65(3):1140-1146. 30. Lases EC, Duurkens VA, Gerritsen WB, Haas FJ. Oxidative stress after lung resection therapy: A pilot study. Chest. 2000;117(4):999-1003. 31. Williams EA, Quinlan GJ, Goldstraw P, Gothard JW, Evans TW. Postoperative lung injury and oxidative damage in patients undergoing pulmonary resection. Eur Respir J. 1998;11(5): 1028-1034. 32. Douzinas EE, Kollias S, Tiniakos D, et al. Hypoxemic reperfusion after 120 mins of intestinal ischemia attenuates the histopathologic and inammatory response. Crit Care Med. 2004;32(11):2279-2283. 33. Balanos GM, Talbot NP, Dorrington KL, Robbins PA. Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography. J Appl Physiol. 2003;94(4):1543-1551. 34. Lang CJ, Barnett EK, Doyle IR. Stretch and CO2 modulate the inammatory response of alveolar macrophages through independent changes in metabolic activity. Cytokine. 2006; 33(6):346-351. 35. Brodsky JB, Lemmens HJ. Left double-lumen tubes: clinical experience with 1,170 patients. J Cardiothorac Vasc Anesth. 2003;17(3):289-298. 36. Slinger P, Suissa S, Triolet W. Predicting arterial oxygenation during one-lung anaesthesia. Can J Anaesth. 1992;39(10): 1030-1035. 37. Katzenelson R, Perel A, Berkenstadt H, et al. Accuracy of transpulmonary thermodilution versus gravimetric measurement of extravascular lung water. Crit Care Med. 2004;32(7):1550-1554. 38. Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med. 2008;359(20):2095-2104.

www.chestpubs.org

CHEST / 139 / 3 / MARCH, 2011

537

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians

Does a Protective Ventilation Strategy Reduce the Risk of Pulmonary Complications After Lung Cancer Surgery? : A Randomized Controlled Trial Mikyung Yang, Hyun Joo Ahn, Kwhanmien Kim, Jie Ae Kim, Chin A Yi, Myung Joo Kim and Hyo Jin Kim Chest 2011;139; 530-537; Prepublished online September 9, 2010; DOI 10.1378/chest.09-2293 This information is current as of March 25, 2011
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/139/3/530.full.html References This article cites 37 articles, 18 of which can be accessed free at: http://chestjournal.chestpubs.org/content/139/3/530.full.html#ref-list-1 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

Downloaded from chestjournal.chestpubs.org at McMaster University on March 25, 2011 2011 American College of Chest Physicians