j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 2 ( 2 0 1 4 ) 2 4 2 e2 4 9
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Association for Academic Surgery
“Open lung ventilation optimizes pulmonary function during lung surgery” John B. Downs, MD,a Lary A. Robinson, MD,b,* Michael L. Steighner, CRNA,a David Thrush, MD,a Richard R. Reich, PhD,c,d and Jukka O. Ra¨sa¨nen, MDa a
Department of Anesthesiology, Moffitt Cancer Center, Tampa, Florida Department of Thoracic Oncology (Surgery), Moffitt Cancer Center, Tampa, Florida c College of Arts and Sciences, University of South Florida Sarasota-Manatee, Florida d Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida b
article info
abstract
Article history:
Background: We evaluated an “open lung” ventilation (OV) strategy using low tidal volumes,
Received 27 February 2014
low respiratory rate, low FiO2, and high continuous positive airway pressure in patients
Received in revised form
undergoing major lung resections.
7 June 2014
Materials and methods: In this phase I pilot study, twelve consecutive patients were anes-
Accepted 17 June 2014
thetized using conventional ventilator settings (CV) and then OV strategy during which
Available online 20 June 2014
oxygenation and lung compliance were noted. Subsequently, a lung resection was performed. Data were collected during both modes of ventilation in each patient, with each patient acting
Keywords:
as his own control. The postoperative course was monitored for complications.
Anesthesia ventilation
Results: Twelve patients underwent open thoracotomies for seven lobectomies and five
Protective ventilation
segmentectomies. The OV strategy provided consistent one-lung anesthesia and improved
Lung resection
static compliance (40 7 versus 25 4 mL/cm H2O, P ¼ 0.002) with airway pressures similar
Thoracic surgery
to CV. Postresection oxygenation (SpO2/FiO2) was better during OV (433 11 versus
Postoperative pulmonary
386 15, P ¼ 0.008). All postoperative chest x-rays were free of atelectasis or infiltrates. No
complications
patient required supplemental oxygen at any time postoperatively or on discharge. The
Airway pressure release ventilation
mean hospital stay was 4 1 d. There were no complications or mortality.
Pulmonary atelectasis
Conclusions: The OV strategy, previously shown to have benefits during mechanical venti-
Lung surgery
lation of patients with respiratory failure, proved safe and effective in lung resection patients. Because postoperative pulmonary complications may be directly attributable to the anesthetic management, adopting an OV strategy that optimizes lung mechanics and gas exchange may help reduce postoperative problems and improve overall surgical results. A randomized trial is planned to ascertain whether this technique will reduce postoperative pulmonary complications. ª 2014 Elsevier Inc. All rights reserved.
Presented at the Academic Surgical Congress, San Diego, CA, February 4e6, 2014. * Corresponding author. Department of Thoracic Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. Tel.: þ1 813 745 6895; fax: þ1 813 745 3027. E-mail address: [email protected] (L.A. Robinson). 0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.06.029
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 2 ( 2 0 1 4 ) 2 4 2 e2 4 9
1.
Introduction
Postoperative pulmonary complications (PPC) are a major cause of morbidity, mortality, and health-care costs [1,2]. As many as 33% of patients undergoing upper abdominal surgery and up to 56% of lung resection patients will develop PPC’s [1,3]. Two of every three in-hospital postoperative deaths are caused by pulmonary complications [4]. The economic impact of PPC is estimated at $11.9 billion annually [1,4]. Cigarette smoking, upper abdominal or thoracic surgery, age >70, chronic obstructive pulmonary disease, obesity (body mass index 30 kg/m2), anesthetic times >180 min, renal failure, poor nutritional status, and significant blood loss are felt to be preoperative risk factors [5]. However, early postoperative atelectasis is considered to be the common pathway to PPC’s [1,3,5]. Patients undergoing general anesthesia for lung resections are particularly prone to PPC and additionally are often difficult to ventilate and oxygenate [6]. General anesthesia, muscle relaxation, high levels of inspired oxygen, supine, lateral, and lithotomy positions all have been shown to promote atelectasis, which in some individuals may persist for >24 h postoperatively [7]. Almost all patients receive elevated concentrations of oxygen intraoperatively and postoperatively, sometimes for days, in an attempt to alleviate the arterial hypoxemia resulting from atelectasis. Most investigators feel that postoperative atelectasis likely leads to retained secretions and subsequent pneumonia, which may progress under some circumstances to acute respiratory failure and even acute respiratory distress syndrome (ARDS) [1,6]. Conceivably, some of these complications may be attributable directly to atelectasis due to anesthetic management, yet there is no consensus regarding the optimal intraoperative ventilatory strategy during one-lung ventilation for noncardiac thoracic surgery [8] or abdominal surgery [2]. Most recommendations revolve around attempts to prevent arterial hypoxemia, with little regard for optimization of lung function [9]. In spite of the overwhelming evidence that anesthetic management may play a significant role in the occurrence of PPC, little or no attention has been given to intraoperative maneuvers to optimize lung function [1]. Nevertheless, one recently published clinical trial by Severgnini et al. [10] in 2013 focusing on using protective ventilation during anesthesia for abdominal surgery demonstrated improved postoperative lung function and decreased clinical signs of infection.
243
Remarkably, in this randomized trial, postoperative lung function abnormalities persisted as long as 5 d after surgery in the control ventilation group. We hypothesized that an open lung ventilation (OV) strategy, using low (physiologic) tidal volume (Vt), low respiratory rate (RR), low concentration of inspired oxygen (FiO2), and a high level of continuous positive airway pressure (CPAP) all with proven benefits during mechanical ventilation of patients with respiratory failure, would allow us to optimize intraoperative lung mechanics and gas exchange. In essence, the open lung ventilation strategy is designed to maintain alveoli open and functional throughout the ventilatory cycle. This pilot study was designed to evaluate the safety and efficacy of an open lung ventilation strategy in the challenging group of surgical patients undergoing an open thoracotomy for major lung resection. The open thoracotomy lung resection method was chosen for this pilot study because it is the most common lung surgery approach currently used in the United States, and this method is perceived to be the most difficult postoperatively for patients to ventilate and avoid postoperative complications. In fact, most of the lobectomies and segmentectomies in the United States are still performed by open thoracotomy (57% open, 40% Video-assisted thoracic surgery (VATS), and 3.4% robotic) [11], so this surgical approach is also quite appropriate to study. Finally, because the conventional and test anesthesia ventilation techniques were used and data were obtained sequentially in all surgical procedures, patients acted as their own controls for this phase I study.
2.
Methods
After obtaining informed consent, adult patients electively scheduled to undergo an open thoracotomy for lung resection were enrolled. The investigation was approved by the Institutional Review Boards of the Moffitt Cancer Center (protocol #MCC17297) and the University of South Florida College of Medicine. Procedures followed were in accordance with the ethical standards of The Committee on Human Experimentation at the Moffitt Cancer Center. All patient information was collected in compliance with Health Insurance Portability and Accountability Act regulations. Patients were excluded from the study if they had a prior operative procedure in the ipsilateral pleural cavity, or if the
Table 1 e Anesthesia techniques. Ventilator settings Vt RR I:E Inspired oxygen (FiO2) Positive end-expiratory pressure (PEEP) or CPAP RP
Conventional (CV)
Open lung (OV)
6 mL/kg Amount needed to keep exhaled CO2 (PetCO2) 40e45 mm Hg 1:2 Usually 0.21 or amount needed to maintain oxygen saturation (SpO2) >88% 3 cm H2O
6 mL/kg (maintained by adjusting CPAP and RP) Amount needed to keep exhaled CO2 (PetCO2) 40e45 mm Hg 2:1, 3:1, or 4:1 Usually 0.21 or amount needed to maintain oxygen saturation (SpO2) >88% 30 cm H2O initially, then the amount needed to maximize compliance
None
Level required for Vt of 6 mL/kg
244
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Fig. 1 e Research protocol.
expected duration of the procedure was 88%. After 10 min, plateau airway pressure (Paw), RR, PEEP, Vt, FiO2, PetCO2, and SpO2 were recorded. Respiratory system static compliance was calculated as Vt/ (Paw-PEEP). To implement the research protocol for an “open lung” ventilation strategy, the I:E ratio was changed to 2:1, 3:1, or 4:1 so that each mechanical breath began just as expiratory flow of the previous breath approached 0 L/min. Paw was initially set to 30 cm H20, a value arbitrarily selected for lung recruitment, and expiratory pressure setting of the machine, henceforth referred to as the release pressure (RP), was adjusted to maintain a Vt of 5e6 mL/kg. After 2 min, Paw was
reduced in 2 cm H20 decrements and RP was adjusted at each level to maintain a Vt 5e6 mL/kg. At each pressure level, respiratory system static compliance was calculated as Vt/ (PaweRP). The Paw and RP were left at levels that produced the highest respiratory system compliance. The Paw was recorded at a “0” flow state, that is, it was a prolonged “plateau” pressure. After a 10-min stabilization period, data collection was repeated. The patient was positioned in a lateral decubitus position for the operative procedure. One-lung ventilation was established using CV as described previously. Following the thoracotomy and equilibration of all values, data were collected and OV was then instituted, as described previously. After a period of stabilization, the data collection was repeated for the OV technique. Open lung ventilation was maintained for the remainder of the operative procedure, until chest wall closure. After lung resection and before chest closure, a continuous Paw of 30 cm H2O was applied momentarily to the operated lung with the chest cavity filled with saline to ensure there was no bronchial stump air leak. A tunneled extrapleural catheter (On-Q, I-Flow, LLC, Lake Forest, CA) was inserted percutaneously for postoperative pain management, the operative lung was reexpanded, and two-lung ventilation was instituted using CV settings. After stabilization, data collection was repeated in the lateral position using CV and OV in
Table 2 e Patient demographics. Value (n ¼ 12; M:F 6:6) Age (y) Weight (kg) BMI (kg/m2) Smoking (pack-years) FEV1.0 (% of predicted) DLCO (% of predicted) Preoperative PaO2 Preoperative PaCO2 Preoperative pH
Mean
Standard deviation
Range
67.9 82.1 29.2 43.1 80.0 74.8 77.1 39.5 7.40
7.8 6.7 7.3 3.0 4.7 3.9 3.9 1.0 0.01
55e80 48e140 17e43 30e60 50e106 52e95 61e108 36e48 7.38e7.45
BMI ¼ body mass index; DLCO ¼ diffusing capacity for carbon monoxide; FEV1 ¼ forced expiratory volume at 1 second.
245
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Statistical comparison of results obtained during OV and CV was conducted using the Wilcoxon signed rank test. Differences with P 90% before transport to the postanesthesia care unit (PACU). In the PACU, if the SpO2 was 25 cm H2O in any patient during either ventilation modality. During one-lung ventilation, Paw during OV did not increase significantly. At the end of surgery, when both lungs were ventilated in the lateral position, compliance during CV was similar to that observed after induction in the supine position (Fig. 2). However, during OV under these conditions, compliance did not reach the level observed before thoracotomy (P ¼ 0.008). Still, compliance during OV was higher than that calculated during CV (P ¼ 0.02). Postoperatively, all patients maintained spontaneous ventilation without difficulty. One morbidly obese patient (body mass index 43) with obstructive sleep apnea required face-mask BiPAP with room air for 2 h until he was fully awake. Intraoperatively, one patient had persistent SpO2 6 mL/kg is necessary to prevent atelectasis, hypoxemia, and hypoventilation [15]. For instance, many anesthesiologists use a Vt of 10 mL/kg and a RR of 10 per minute initially; then, during one-lung ventilation they decrease Vt, increase RR by 50%, and increase inspired oxygen to 100%. Because of the atelectasis that generally ensues, FiO2 is frequently maintained at high levels, which may exacerbate the atelectasis [16]. Our results do not support the need for increased Vt and indeed reveal that a Vt of 6 mL/kg and a low RR are capable of providing adequate oxygenation even with room air, and adequate ventilation, as long as the Paw is sufficiently high to prevent atelectasis and maintain the alveoli “open.” This patient population was chosen for investigation because one-lung ventilation in the lateral decubitus position during lung resection provides the greatest challenge to anesthesiologists to prevent intraoperative arterial hypoxemia and adequate ventilation [6]. We used static compliance as an indirect reflection of relative lung volume with regard to lung collapse, atelectasis, and hyperinflation. The reduction in compliance that almost always occurs during lung resections is due in a large part to microatelectasis developing in the dependent ventilated lung. However, during surgery, atelectasis in the nonoperative lung is never directly visualized so compliance provides an indirect but reliable indication of atelectasis. Also at the end of the surgical case, the operative lung is reexpanded under direct vision, but still enough time passes before the patient is extubated to allow the occurrence of significant atelectasis in the operative lung, especially if the FiO2 is elevated with the usual accompanying absorption atelectasis. The increase in compliance we observed with the OV technique was most likely due to less atelectasis. If atelectasis is reduced intraoperatively, it is reasonable to anticipate fewer PPC, and this is what we plan to explore in a future much larger randomized trial. The fact that no patient required any supplemental O2 in the recovery room is a reflection that
247
pulmonary gas exchange approximated preoperative levels. The ratio of SpO2/FiO2 is regarded to be a reflection of the gas exchange efficiency of the lung [17]. If hypoxemia occurs during one-lung ventilation with OV strategy, it most likely will be due to right-to-left shunting of blood or mismatching of ventilation and pulmonary perfusion. An increase in FiO2 will have minimal effect on hypoxemia secondary to right-to-left shunting of blood. Therefore, if an increase in inspired oxygen does increase SpO2 significantly, it indicates a mismatching of V/Q and the possibility that Paw is not sufficiently elevated, inspite of optimal compliance [18,19]. In the single patient in our study who developed right-to-left intrapulmonary shunting of blood, increasing FiO2 was minimally effective in increasing SpO2. It is likely that “shunted” blood flow from the operated, nondependant lung contributed to the relative hypoxemia. We were able to maintain adequate SpO2 with increased FiO2 indicating that some V/Q mismatch was present as well. Application of CPAP to the operative lung might have improved oxygenation but was not used because it would have reexpanded the lung and interrupted the operative procedure. The “open lung” strategy applied in our investigation is similar to that described by Bratzke et al. [20]. However, that study used an anesthesia ventilator (bird Corp, Palm Springs, CA) designed to provide airway pressure release ventilation (APRV), which would allow spontaneous breathing with CPAP, as well as mechanical ventilation with APRV. A recent animal study by Roy et al. [21,22] using APRV in an anesthetized pig model of acute lung injury demonstrated striking protection against ARDS by using this ventilation technique immediately after the lung injury compared with conventional low Vt conventional ventilation. Their results suggested that APRV protected the lungs by attenuating lung permeability, inflammation, edema, and surfactant degradation. Current anesthesia ventilators are not capable of providing APRV, or intermittent CPAP, as described by Bratzke et al. [20]. Therefore, we attempted to closely mimic Bratzke’s methodology using pressure-controlled ventilation with an I:E ratio of 2:1e4:1. The “release” pressure was obtained by using the anesthesia machine “PEEP” setting. The difference between the “pressure control” setting and the “PEEP” setting determined the ventilating pressure or “release” pressure. The “Paw” was the pressure control setting. Regardless of the technique used, we used consistently lower FiO2 levels than commonly recommended or necessary for these procedures, both in the operating room and PACU. Yet, significant arterial hypoxemia was never a problem in any patient at any time. This finding has several implications. Even during induction of general anesthesia and just before tracheal extubation by maintaining exhaled oxygen at only 80%, we avoided total denitrogenation of the lungs to minimize absorption atelectasis [23]. The use of low FiO2 (room air) allowed us to use the pulse oximeter as a monitor of adequacy of both ventilation and gas exchange [24]. It reassured us that intrapulmonary shunting of blood was minimal, even with one-lung completely unventilated. Interestingly, this may mean that optimal inflation of the dependent lung causes less perfusion of the collapsed, operated lung. We selected 30 cm H2O as the Paw level to recruit the atelectatic lung, although a recruitment maneuver usually entails a higher-suggested airway pressure. In every
248
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patient, we observed an increase in respiratory system compliance as we decreased the Paw level, indicating that at Paw ¼ 30 cm H2O we not only recruited all possible atelectatic lung but hyperinflated some lung regions, making them less compliant. However, as we decreased the Paw, at a critical point, compliance again decreased, indicating that we had passed the inflection point on the pressure:volume curve. We set the Paw level to 4 cm H2O above that point and determined that to be the level to produce optimal compliance. The level of Paw required to maximize compliance was higher than the airway pressure used to ventilate patients with CV. Therefore, the airway pressure applied during CV was inadequate to open some atelectatic lung areas in the dependent lung, even transiently. Such areas likely would remain collapsed throughout the entire operative procedure. Furthermore, it is likely that many areas of the lung collapse during exhalation, open during the positive pressure breath, and collapse again during exhalation. This repeated alveolar collapse and expansion (RACE) has been shown to be injurious in experimental lung injury models [14]. The first study designed to test intraoperative protective anesthesia ventilation techniques was a small randomized trial in open abdominal surgery patients published by Severgnini et al. [10] in 2013. Their protective ventilation strategy used lower Vts (7 mL/kg), 10 cm H20 PEEP, and various recruitment maneuvers. They documented improved postoperative pulmonary function compared with control ventilation techniques but the study was underpowered to determine whether protective ventilation may decrease pulmonary complications. Of particular note, they did document that there were depressed pulmonary function and oxygenation postoperatively as well as increasing atelectasis in the control patients (low Vt and no PEEP) for long as 5 d but not in the protective ventilation group. Recent studies in open-chest rabbits ventilated with Vts of 8e12 mL/kg and no PEEP revealed histologic damage to peripheral airways, and inflammation likely related to repeated alveolar collapse and reexpansion (RACE) [25]. This phenomenon may be an unrecognized complication in patients undergoing general anesthesia [26]. Our phase I pilot study in lung resection patients was designed to test the feasibility and safety of the use of a protective open lung ventilation strategy and consisted of only 12 patients. We now plan to follow this study with a much larger randomized trial of lobectomies by minimally invasive (VATS and robotic-assisted) and open thoracotomy techniques that is powered to provide more definitive data about the potential for reduction of PPC using OV.
5.
Conclusions
Patients undergoing one-lung ventilation for elective lung resection with currently recommended ventilation techniques develop significant intraoperative atelectasis. However, using an open lung ventilation strategy during elective lung resection surgery appears to be safe and effective, will correct and prevent intraoperative atelectasis, and potentially may have a beneficial effect on the postoperative course of these patients who are at high risk for pulmonary complications.
Acknowledgment Authors’ contributions: J.B.D., L.A.R., M.L.S., D.T., R.R.R., and J.O.R. were involved in the conception and design of the study. J.B.D., L.A.R., M.L.S., and D.T. did collection of data. J.B.D., L.A.R., R.R.R., and J.O.R. did the analysis and interpretation of data. J.B.D., L.A.R., and R.R.R. did the writing of the article. J.B.D., L.A.R., M.L.S., D.T., R.R.R., and J.O.R. did the revision of the article with approval of the final version of the article. Financial support for study: Department of Anesthesiology unrestricted research funds and the Hoenle Foundation, Sarasota, FL thoracic surgery research funds.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. None of the authors have received any personal or financial support, nor are they involved with an organization that has financial interest in the subject matter.
references
[1] Shander A, Fleisher L, Barie P, Bigatello L, Sladen R, Watson C. Clinical and economic burden of postoperative pulmonary complications: patient safety summit on definition, risk-reducing interventions and preventative strategies. Crit Care Med 2011;39:2163. [2] Futier E, Constantin J, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med 2013;369:428. [3] Smetana GW. Preoperative pulmonary evaluation. N Engl J Med 1999;340:937. [4] Linde-Zwirble WL, Bloom JD, Mecca RS, Hansell DM. Postoperative pulmonary complications in adult elective surgery patients in the US: severity, outcomes, and resource use. Crit Care 2010;14(Suppl 1):P210. [5] Rock P, Rich PR. Postoperative pulmonary complications. Curr Opin Anesthesiol 2003;16:123. [6] Agostini P, Cieslik H, Rathinam S, et al. Postoperative pulmonary complications following thoracic surgery: are there any modifiable factors? Thorax 2010;65:815. [7] Strandberg A, Tokics L, Brismar B. Atelectasis during anaesthesia and in the postoperative period. Acta Anesthesiol Scand 1986;30:154. [8] Maslow A, Stafford T, Davignon K, Ng T. A randomized comparison of different ventilator strategies during thoracotomy for pulmonary resection. J Thorac Cardiovasc Surg 2013;146:38. [9] Roze H, Lafargue M, Outtara A. Case scenario: management of intraoperative hypoxemia during one-lung ventilation. Anesthesiology 2011;114:167. [10] Severgnini P, Selmo G, Lanza C, et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology 2013;118:1307. [11] Kent M, Wang T, Whyte R, Curran T, Flores R, Gangadharan S. Open, video-assisted thoracic surgery and robotic lobectomy: review of a national database. Ann Thorac Surg 2014;97:236.
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 2 ( 2 0 1 4 ) 2 4 2 e2 4 9
[12] Ashizawa K, Hayashi K, Aso N, Minami K. Lobar atalectasis: diagnostic pitfalls on chest radiography. Br J Radiol 2001;74: 89. [13] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301. [14] Schiller H, McCann UG 2nd, Carney D, Gatto L, Steinberg J, Nieman G. Altered alveolar mechanics in the acutely injured lung. Crit Care Med 2001;29:1049. [15] Bendixen HH, Hedley-Whyte J, Laver MB. Impaired oxygenation in surgical patients during general anesthesia with controlled ventilationda concept of atelectasis. N Engl J Med 1963;269:991. [16] Magnusson L, Spahn DR. New concepts of atelectasis during general anaesthesia. Br J Anaesth 2003;91:61. [17] Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB. National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/ FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007;132:410. [18] Douglas ME, Downs JB, Dannemiller FJ, Hodges MR, Munson ES. Change in pulmonary venous admixture with varying inspired oxygen. Anesth Analg 1976; 55:688.
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[19] Downs J. Has oxygen administration delayed appropriate respiratory care? fallacies regarding oxygen therapy. Respir Care 2003;48:611. [20] Bratzke E, Downs JB, Smith RA. Intermittent CPAP: a new mode of ventilation during general anesthesia. Anesthesiology 1998;89:334. [21] Roy S, Sadowitz B, Andrews P, et al. Early stabilizing alveolar ventilation prevents acute respiratory distress syndrome: a novel timing-based ventilatory intervention to avert lung injury. J Trauma Acute Care Surg 2012;73:391. [22] Roy S, Habashi N, Sadowitz B, et al. Early airway pressure release ventilation prevents ARDSda novel preventive approach to lung injury. Shock 2013;39:28. [23] Benoit Z, Wicky S, Fischer JF, et al. Effects of increased FiO2 before tracheal extubation on postoperative atelectasis. Anesth Analg 2002;95:1777. [24] Fu ES, Downs JB, Schweiger JW, Miguel RV, Smith RA. Supplemental oxygen impairs detection of hypoventilation by pulse oximetry. Chest 2004;126:1552. [25] D’Angelo E, Peccharia M, Gentile G. Dependence of lung injury on surface tension during low-volume ventilation in normal open-chest rabbits. J Appl Physiol 2007;102:174. [26] Hedenstierna G. Alveolar collapse and closure of airways: regular effects of anesthesia. Clin Physiol Funct Imaging 2003;23:123.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Association for Academic Surgery
“Open lung ventilation optimizes pulmonary function during lung surgery” John B. Downs, MD,a Lary A. Robinson, MD,b,* Michael L. Steighner, CRNA,a David Thrush, MD,a Richard R. Reich, PhD,c,d and Jukka O. Ra¨sa¨nen, MDa a
Department of Anesthesiology, Moffitt Cancer Center, Tampa, Florida Department of Thoracic Oncology (Surgery), Moffitt Cancer Center, Tampa, Florida c College of Arts and Sciences, University of South Florida Sarasota-Manatee, Florida d Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida b
article info
abstract
Article history:
Background: We evaluated an “open lung” ventilation (OV) strategy using low tidal volumes,
Received 27 February 2014
low respiratory rate, low FiO2, and high continuous positive airway pressure in patients
Received in revised form
undergoing major lung resections.
7 June 2014
Materials and methods: In this phase I pilot study, twelve consecutive patients were anes-
Accepted 17 June 2014
thetized using conventional ventilator settings (CV) and then OV strategy during which
Available online 20 June 2014
oxygenation and lung compliance were noted. Subsequently, a lung resection was performed. Data were collected during both modes of ventilation in each patient, with each patient acting
Keywords:
as his own control. The postoperative course was monitored for complications.
Anesthesia ventilation
Results: Twelve patients underwent open thoracotomies for seven lobectomies and five
Protective ventilation
segmentectomies. The OV strategy provided consistent one-lung anesthesia and improved
Lung resection
static compliance (40 7 versus 25 4 mL/cm H2O, P ¼ 0.002) with airway pressures similar
Thoracic surgery
to CV. Postresection oxygenation (SpO2/FiO2) was better during OV (433 11 versus
Postoperative pulmonary
386 15, P ¼ 0.008). All postoperative chest x-rays were free of atelectasis or infiltrates. No
complications
patient required supplemental oxygen at any time postoperatively or on discharge. The
Airway pressure release ventilation
mean hospital stay was 4 1 d. There were no complications or mortality.
Pulmonary atelectasis
Conclusions: The OV strategy, previously shown to have benefits during mechanical venti-
Lung surgery
lation of patients with respiratory failure, proved safe and effective in lung resection patients. Because postoperative pulmonary complications may be directly attributable to the anesthetic management, adopting an OV strategy that optimizes lung mechanics and gas exchange may help reduce postoperative problems and improve overall surgical results. A randomized trial is planned to ascertain whether this technique will reduce postoperative pulmonary complications. ª 2014 Elsevier Inc. All rights reserved.
Presented at the Academic Surgical Congress, San Diego, CA, February 4e6, 2014. * Corresponding author. Department of Thoracic Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. Tel.: þ1 813 745 6895; fax: þ1 813 745 3027. E-mail address: [email protected] (L.A. Robinson). 0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.06.029
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 2 ( 2 0 1 4 ) 2 4 2 e2 4 9
1.
Introduction
Postoperative pulmonary complications (PPC) are a major cause of morbidity, mortality, and health-care costs [1,2]. As many as 33% of patients undergoing upper abdominal surgery and up to 56% of lung resection patients will develop PPC’s [1,3]. Two of every three in-hospital postoperative deaths are caused by pulmonary complications [4]. The economic impact of PPC is estimated at $11.9 billion annually [1,4]. Cigarette smoking, upper abdominal or thoracic surgery, age >70, chronic obstructive pulmonary disease, obesity (body mass index 30 kg/m2), anesthetic times >180 min, renal failure, poor nutritional status, and significant blood loss are felt to be preoperative risk factors [5]. However, early postoperative atelectasis is considered to be the common pathway to PPC’s [1,3,5]. Patients undergoing general anesthesia for lung resections are particularly prone to PPC and additionally are often difficult to ventilate and oxygenate [6]. General anesthesia, muscle relaxation, high levels of inspired oxygen, supine, lateral, and lithotomy positions all have been shown to promote atelectasis, which in some individuals may persist for >24 h postoperatively [7]. Almost all patients receive elevated concentrations of oxygen intraoperatively and postoperatively, sometimes for days, in an attempt to alleviate the arterial hypoxemia resulting from atelectasis. Most investigators feel that postoperative atelectasis likely leads to retained secretions and subsequent pneumonia, which may progress under some circumstances to acute respiratory failure and even acute respiratory distress syndrome (ARDS) [1,6]. Conceivably, some of these complications may be attributable directly to atelectasis due to anesthetic management, yet there is no consensus regarding the optimal intraoperative ventilatory strategy during one-lung ventilation for noncardiac thoracic surgery [8] or abdominal surgery [2]. Most recommendations revolve around attempts to prevent arterial hypoxemia, with little regard for optimization of lung function [9]. In spite of the overwhelming evidence that anesthetic management may play a significant role in the occurrence of PPC, little or no attention has been given to intraoperative maneuvers to optimize lung function [1]. Nevertheless, one recently published clinical trial by Severgnini et al. [10] in 2013 focusing on using protective ventilation during anesthesia for abdominal surgery demonstrated improved postoperative lung function and decreased clinical signs of infection.
243
Remarkably, in this randomized trial, postoperative lung function abnormalities persisted as long as 5 d after surgery in the control ventilation group. We hypothesized that an open lung ventilation (OV) strategy, using low (physiologic) tidal volume (Vt), low respiratory rate (RR), low concentration of inspired oxygen (FiO2), and a high level of continuous positive airway pressure (CPAP) all with proven benefits during mechanical ventilation of patients with respiratory failure, would allow us to optimize intraoperative lung mechanics and gas exchange. In essence, the open lung ventilation strategy is designed to maintain alveoli open and functional throughout the ventilatory cycle. This pilot study was designed to evaluate the safety and efficacy of an open lung ventilation strategy in the challenging group of surgical patients undergoing an open thoracotomy for major lung resection. The open thoracotomy lung resection method was chosen for this pilot study because it is the most common lung surgery approach currently used in the United States, and this method is perceived to be the most difficult postoperatively for patients to ventilate and avoid postoperative complications. In fact, most of the lobectomies and segmentectomies in the United States are still performed by open thoracotomy (57% open, 40% Video-assisted thoracic surgery (VATS), and 3.4% robotic) [11], so this surgical approach is also quite appropriate to study. Finally, because the conventional and test anesthesia ventilation techniques were used and data were obtained sequentially in all surgical procedures, patients acted as their own controls for this phase I study.
2.
Methods
After obtaining informed consent, adult patients electively scheduled to undergo an open thoracotomy for lung resection were enrolled. The investigation was approved by the Institutional Review Boards of the Moffitt Cancer Center (protocol #MCC17297) and the University of South Florida College of Medicine. Procedures followed were in accordance with the ethical standards of The Committee on Human Experimentation at the Moffitt Cancer Center. All patient information was collected in compliance with Health Insurance Portability and Accountability Act regulations. Patients were excluded from the study if they had a prior operative procedure in the ipsilateral pleural cavity, or if the
Table 1 e Anesthesia techniques. Ventilator settings Vt RR I:E Inspired oxygen (FiO2) Positive end-expiratory pressure (PEEP) or CPAP RP
Conventional (CV)
Open lung (OV)
6 mL/kg Amount needed to keep exhaled CO2 (PetCO2) 40e45 mm Hg 1:2 Usually 0.21 or amount needed to maintain oxygen saturation (SpO2) >88% 3 cm H2O
6 mL/kg (maintained by adjusting CPAP and RP) Amount needed to keep exhaled CO2 (PetCO2) 40e45 mm Hg 2:1, 3:1, or 4:1 Usually 0.21 or amount needed to maintain oxygen saturation (SpO2) >88% 30 cm H2O initially, then the amount needed to maximize compliance
None
Level required for Vt of 6 mL/kg
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Fig. 1 e Research protocol.
expected duration of the procedure was 88%. After 10 min, plateau airway pressure (Paw), RR, PEEP, Vt, FiO2, PetCO2, and SpO2 were recorded. Respiratory system static compliance was calculated as Vt/ (Paw-PEEP). To implement the research protocol for an “open lung” ventilation strategy, the I:E ratio was changed to 2:1, 3:1, or 4:1 so that each mechanical breath began just as expiratory flow of the previous breath approached 0 L/min. Paw was initially set to 30 cm H20, a value arbitrarily selected for lung recruitment, and expiratory pressure setting of the machine, henceforth referred to as the release pressure (RP), was adjusted to maintain a Vt of 5e6 mL/kg. After 2 min, Paw was
reduced in 2 cm H20 decrements and RP was adjusted at each level to maintain a Vt 5e6 mL/kg. At each pressure level, respiratory system static compliance was calculated as Vt/ (PaweRP). The Paw and RP were left at levels that produced the highest respiratory system compliance. The Paw was recorded at a “0” flow state, that is, it was a prolonged “plateau” pressure. After a 10-min stabilization period, data collection was repeated. The patient was positioned in a lateral decubitus position for the operative procedure. One-lung ventilation was established using CV as described previously. Following the thoracotomy and equilibration of all values, data were collected and OV was then instituted, as described previously. After a period of stabilization, the data collection was repeated for the OV technique. Open lung ventilation was maintained for the remainder of the operative procedure, until chest wall closure. After lung resection and before chest closure, a continuous Paw of 30 cm H2O was applied momentarily to the operated lung with the chest cavity filled with saline to ensure there was no bronchial stump air leak. A tunneled extrapleural catheter (On-Q, I-Flow, LLC, Lake Forest, CA) was inserted percutaneously for postoperative pain management, the operative lung was reexpanded, and two-lung ventilation was instituted using CV settings. After stabilization, data collection was repeated in the lateral position using CV and OV in
Table 2 e Patient demographics. Value (n ¼ 12; M:F 6:6) Age (y) Weight (kg) BMI (kg/m2) Smoking (pack-years) FEV1.0 (% of predicted) DLCO (% of predicted) Preoperative PaO2 Preoperative PaCO2 Preoperative pH
Mean
Standard deviation
Range
67.9 82.1 29.2 43.1 80.0 74.8 77.1 39.5 7.40
7.8 6.7 7.3 3.0 4.7 3.9 3.9 1.0 0.01
55e80 48e140 17e43 30e60 50e106 52e95 61e108 36e48 7.38e7.45
BMI ¼ body mass index; DLCO ¼ diffusing capacity for carbon monoxide; FEV1 ¼ forced expiratory volume at 1 second.
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Statistical comparison of results obtained during OV and CV was conducted using the Wilcoxon signed rank test. Differences with P 90% before transport to the postanesthesia care unit (PACU). In the PACU, if the SpO2 was 25 cm H2O in any patient during either ventilation modality. During one-lung ventilation, Paw during OV did not increase significantly. At the end of surgery, when both lungs were ventilated in the lateral position, compliance during CV was similar to that observed after induction in the supine position (Fig. 2). However, during OV under these conditions, compliance did not reach the level observed before thoracotomy (P ¼ 0.008). Still, compliance during OV was higher than that calculated during CV (P ¼ 0.02). Postoperatively, all patients maintained spontaneous ventilation without difficulty. One morbidly obese patient (body mass index 43) with obstructive sleep apnea required face-mask BiPAP with room air for 2 h until he was fully awake. Intraoperatively, one patient had persistent SpO2 6 mL/kg is necessary to prevent atelectasis, hypoxemia, and hypoventilation [15]. For instance, many anesthesiologists use a Vt of 10 mL/kg and a RR of 10 per minute initially; then, during one-lung ventilation they decrease Vt, increase RR by 50%, and increase inspired oxygen to 100%. Because of the atelectasis that generally ensues, FiO2 is frequently maintained at high levels, which may exacerbate the atelectasis [16]. Our results do not support the need for increased Vt and indeed reveal that a Vt of 6 mL/kg and a low RR are capable of providing adequate oxygenation even with room air, and adequate ventilation, as long as the Paw is sufficiently high to prevent atelectasis and maintain the alveoli “open.” This patient population was chosen for investigation because one-lung ventilation in the lateral decubitus position during lung resection provides the greatest challenge to anesthesiologists to prevent intraoperative arterial hypoxemia and adequate ventilation [6]. We used static compliance as an indirect reflection of relative lung volume with regard to lung collapse, atelectasis, and hyperinflation. The reduction in compliance that almost always occurs during lung resections is due in a large part to microatelectasis developing in the dependent ventilated lung. However, during surgery, atelectasis in the nonoperative lung is never directly visualized so compliance provides an indirect but reliable indication of atelectasis. Also at the end of the surgical case, the operative lung is reexpanded under direct vision, but still enough time passes before the patient is extubated to allow the occurrence of significant atelectasis in the operative lung, especially if the FiO2 is elevated with the usual accompanying absorption atelectasis. The increase in compliance we observed with the OV technique was most likely due to less atelectasis. If atelectasis is reduced intraoperatively, it is reasonable to anticipate fewer PPC, and this is what we plan to explore in a future much larger randomized trial. The fact that no patient required any supplemental O2 in the recovery room is a reflection that
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pulmonary gas exchange approximated preoperative levels. The ratio of SpO2/FiO2 is regarded to be a reflection of the gas exchange efficiency of the lung [17]. If hypoxemia occurs during one-lung ventilation with OV strategy, it most likely will be due to right-to-left shunting of blood or mismatching of ventilation and pulmonary perfusion. An increase in FiO2 will have minimal effect on hypoxemia secondary to right-to-left shunting of blood. Therefore, if an increase in inspired oxygen does increase SpO2 significantly, it indicates a mismatching of V/Q and the possibility that Paw is not sufficiently elevated, inspite of optimal compliance [18,19]. In the single patient in our study who developed right-to-left intrapulmonary shunting of blood, increasing FiO2 was minimally effective in increasing SpO2. It is likely that “shunted” blood flow from the operated, nondependant lung contributed to the relative hypoxemia. We were able to maintain adequate SpO2 with increased FiO2 indicating that some V/Q mismatch was present as well. Application of CPAP to the operative lung might have improved oxygenation but was not used because it would have reexpanded the lung and interrupted the operative procedure. The “open lung” strategy applied in our investigation is similar to that described by Bratzke et al. [20]. However, that study used an anesthesia ventilator (bird Corp, Palm Springs, CA) designed to provide airway pressure release ventilation (APRV), which would allow spontaneous breathing with CPAP, as well as mechanical ventilation with APRV. A recent animal study by Roy et al. [21,22] using APRV in an anesthetized pig model of acute lung injury demonstrated striking protection against ARDS by using this ventilation technique immediately after the lung injury compared with conventional low Vt conventional ventilation. Their results suggested that APRV protected the lungs by attenuating lung permeability, inflammation, edema, and surfactant degradation. Current anesthesia ventilators are not capable of providing APRV, or intermittent CPAP, as described by Bratzke et al. [20]. Therefore, we attempted to closely mimic Bratzke’s methodology using pressure-controlled ventilation with an I:E ratio of 2:1e4:1. The “release” pressure was obtained by using the anesthesia machine “PEEP” setting. The difference between the “pressure control” setting and the “PEEP” setting determined the ventilating pressure or “release” pressure. The “Paw” was the pressure control setting. Regardless of the technique used, we used consistently lower FiO2 levels than commonly recommended or necessary for these procedures, both in the operating room and PACU. Yet, significant arterial hypoxemia was never a problem in any patient at any time. This finding has several implications. Even during induction of general anesthesia and just before tracheal extubation by maintaining exhaled oxygen at only 80%, we avoided total denitrogenation of the lungs to minimize absorption atelectasis [23]. The use of low FiO2 (room air) allowed us to use the pulse oximeter as a monitor of adequacy of both ventilation and gas exchange [24]. It reassured us that intrapulmonary shunting of blood was minimal, even with one-lung completely unventilated. Interestingly, this may mean that optimal inflation of the dependent lung causes less perfusion of the collapsed, operated lung. We selected 30 cm H2O as the Paw level to recruit the atelectatic lung, although a recruitment maneuver usually entails a higher-suggested airway pressure. In every
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patient, we observed an increase in respiratory system compliance as we decreased the Paw level, indicating that at Paw ¼ 30 cm H2O we not only recruited all possible atelectatic lung but hyperinflated some lung regions, making them less compliant. However, as we decreased the Paw, at a critical point, compliance again decreased, indicating that we had passed the inflection point on the pressure:volume curve. We set the Paw level to 4 cm H2O above that point and determined that to be the level to produce optimal compliance. The level of Paw required to maximize compliance was higher than the airway pressure used to ventilate patients with CV. Therefore, the airway pressure applied during CV was inadequate to open some atelectatic lung areas in the dependent lung, even transiently. Such areas likely would remain collapsed throughout the entire operative procedure. Furthermore, it is likely that many areas of the lung collapse during exhalation, open during the positive pressure breath, and collapse again during exhalation. This repeated alveolar collapse and expansion (RACE) has been shown to be injurious in experimental lung injury models [14]. The first study designed to test intraoperative protective anesthesia ventilation techniques was a small randomized trial in open abdominal surgery patients published by Severgnini et al. [10] in 2013. Their protective ventilation strategy used lower Vts (7 mL/kg), 10 cm H20 PEEP, and various recruitment maneuvers. They documented improved postoperative pulmonary function compared with control ventilation techniques but the study was underpowered to determine whether protective ventilation may decrease pulmonary complications. Of particular note, they did document that there were depressed pulmonary function and oxygenation postoperatively as well as increasing atelectasis in the control patients (low Vt and no PEEP) for long as 5 d but not in the protective ventilation group. Recent studies in open-chest rabbits ventilated with Vts of 8e12 mL/kg and no PEEP revealed histologic damage to peripheral airways, and inflammation likely related to repeated alveolar collapse and reexpansion (RACE) [25]. This phenomenon may be an unrecognized complication in patients undergoing general anesthesia [26]. Our phase I pilot study in lung resection patients was designed to test the feasibility and safety of the use of a protective open lung ventilation strategy and consisted of only 12 patients. We now plan to follow this study with a much larger randomized trial of lobectomies by minimally invasive (VATS and robotic-assisted) and open thoracotomy techniques that is powered to provide more definitive data about the potential for reduction of PPC using OV.
5.
Conclusions
Patients undergoing one-lung ventilation for elective lung resection with currently recommended ventilation techniques develop significant intraoperative atelectasis. However, using an open lung ventilation strategy during elective lung resection surgery appears to be safe and effective, will correct and prevent intraoperative atelectasis, and potentially may have a beneficial effect on the postoperative course of these patients who are at high risk for pulmonary complications.
Acknowledgment Authors’ contributions: J.B.D., L.A.R., M.L.S., D.T., R.R.R., and J.O.R. were involved in the conception and design of the study. J.B.D., L.A.R., M.L.S., and D.T. did collection of data. J.B.D., L.A.R., R.R.R., and J.O.R. did the analysis and interpretation of data. J.B.D., L.A.R., and R.R.R. did the writing of the article. J.B.D., L.A.R., M.L.S., D.T., R.R.R., and J.O.R. did the revision of the article with approval of the final version of the article. Financial support for study: Department of Anesthesiology unrestricted research funds and the Hoenle Foundation, Sarasota, FL thoracic surgery research funds.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. None of the authors have received any personal or financial support, nor are they involved with an organization that has financial interest in the subject matter.
references
[1] Shander A, Fleisher L, Barie P, Bigatello L, Sladen R, Watson C. Clinical and economic burden of postoperative pulmonary complications: patient safety summit on definition, risk-reducing interventions and preventative strategies. Crit Care Med 2011;39:2163. [2] Futier E, Constantin J, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med 2013;369:428. [3] Smetana GW. Preoperative pulmonary evaluation. N Engl J Med 1999;340:937. [4] Linde-Zwirble WL, Bloom JD, Mecca RS, Hansell DM. Postoperative pulmonary complications in adult elective surgery patients in the US: severity, outcomes, and resource use. Crit Care 2010;14(Suppl 1):P210. [5] Rock P, Rich PR. Postoperative pulmonary complications. Curr Opin Anesthesiol 2003;16:123. [6] Agostini P, Cieslik H, Rathinam S, et al. Postoperative pulmonary complications following thoracic surgery: are there any modifiable factors? Thorax 2010;65:815. [7] Strandberg A, Tokics L, Brismar B. Atelectasis during anaesthesia and in the postoperative period. Acta Anesthesiol Scand 1986;30:154. [8] Maslow A, Stafford T, Davignon K, Ng T. A randomized comparison of different ventilator strategies during thoracotomy for pulmonary resection. J Thorac Cardiovasc Surg 2013;146:38. [9] Roze H, Lafargue M, Outtara A. Case scenario: management of intraoperative hypoxemia during one-lung ventilation. Anesthesiology 2011;114:167. [10] Severgnini P, Selmo G, Lanza C, et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology 2013;118:1307. [11] Kent M, Wang T, Whyte R, Curran T, Flores R, Gangadharan S. Open, video-assisted thoracic surgery and robotic lobectomy: review of a national database. Ann Thorac Surg 2014;97:236.
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 2 ( 2 0 1 4 ) 2 4 2 e2 4 9
[12] Ashizawa K, Hayashi K, Aso N, Minami K. Lobar atalectasis: diagnostic pitfalls on chest radiography. Br J Radiol 2001;74: 89. [13] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301. [14] Schiller H, McCann UG 2nd, Carney D, Gatto L, Steinberg J, Nieman G. Altered alveolar mechanics in the acutely injured lung. Crit Care Med 2001;29:1049. [15] Bendixen HH, Hedley-Whyte J, Laver MB. Impaired oxygenation in surgical patients during general anesthesia with controlled ventilationda concept of atelectasis. N Engl J Med 1963;269:991. [16] Magnusson L, Spahn DR. New concepts of atelectasis during general anaesthesia. Br J Anaesth 2003;91:61. [17] Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB. National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/ FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007;132:410. [18] Douglas ME, Downs JB, Dannemiller FJ, Hodges MR, Munson ES. Change in pulmonary venous admixture with varying inspired oxygen. Anesth Analg 1976; 55:688.
249
[19] Downs J. Has oxygen administration delayed appropriate respiratory care? fallacies regarding oxygen therapy. Respir Care 2003;48:611. [20] Bratzke E, Downs JB, Smith RA. Intermittent CPAP: a new mode of ventilation during general anesthesia. Anesthesiology 1998;89:334. [21] Roy S, Sadowitz B, Andrews P, et al. Early stabilizing alveolar ventilation prevents acute respiratory distress syndrome: a novel timing-based ventilatory intervention to avert lung injury. J Trauma Acute Care Surg 2012;73:391. [22] Roy S, Habashi N, Sadowitz B, et al. Early airway pressure release ventilation prevents ARDSda novel preventive approach to lung injury. Shock 2013;39:28. [23] Benoit Z, Wicky S, Fischer JF, et al. Effects of increased FiO2 before tracheal extubation on postoperative atelectasis. Anesth Analg 2002;95:1777. [24] Fu ES, Downs JB, Schweiger JW, Miguel RV, Smith RA. Supplemental oxygen impairs detection of hypoventilation by pulse oximetry. Chest 2004;126:1552. [25] D’Angelo E, Peccharia M, Gentile G. Dependence of lung injury on surface tension during low-volume ventilation in normal open-chest rabbits. J Appl Physiol 2007;102:174. [26] Hedenstierna G. Alveolar collapse and closure of airways: regular effects of anesthesia. Clin Physiol Funct Imaging 2003;23:123.
