Lung-protective perioperative mechanical ventilation

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

Hemmes, S.N.T.

Publication date

2015

Document Version

Final published version

Link to publication

Citation for published version (APA):

Hemmes, S. N. T. (2015). Lung-protective perioperative mechanical ventilation.

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Lung-protective perioperative

mechanical ventilation

Beyond the dangers of high tidals,

on the perils of PEEP

Sabrine N.T. Hemmes

U I T N O D I G I N G

voor het bijwonen van de openbare verdediging van het proefschrift LUNG-PROTECTIVE PERIOPERATIVE MECHANICAL VENTILATION van Sabrine Hemmes Op vrijdag 11 december 2015 om 13.00 uur

De Aula van de UvA

Oude Lutherse kerk Singel 411, Amsterdam

Aansluitend bent u van harte uitgenodigd voor

de receptie ter plaatse

Paranimfen:

Jet Heering hdheering@hotmail.com

06 - 14 77 53 37 Pieter Roel Tuinman prtuinman@hotmail.com 06 - 21 24 52 00 Sabrine Hemmes Vrolikstraat 232-1 1092TW Amsterdam s.hemmes@amc.nl

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mechanical ventilation

Beyond the dangers of high tidals,

on the perils of PEEP

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COLOFON

Lung-protective perioperative mechanical ventilation

Academic thesis, University of Amsterdam, Amsterdam, The Netherlands ISBN: 978-94-6233-149-5

Author: Sabrine N.T. Hemmes Lay-out: Barbara ten Brink

Cover: Image by Heng Swee Lim - Website: http://www.ilovedoodle.com Print: Gildeprint, Enschede, The Netherlands

Financial support for the publication of this thesis was kindly provided by: Universiteit van Amsterdam, Abbvie, Edwards Lifesciences, Chipsoft

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ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit

op vrijdag 11 december 2015, te 13.00 uur door Sabrine Nienke Tallechina Hemmes

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PROMOTIECOMMISSIE

Promotores: prof. dr. M.J. Schultz Universiteit van Amsterdam

prof. dr. dr. M.W. Hollmann Universiteit van Amsterdam

Overige leden: prof. dr. L.P.H.J. Aarts Universiteit van Leiden

prof. dr. C. Boer Vrije Universiteit Amsterdam prof. dr. M.A. Boermeester Universiteit van Amsterdam prof. dr. G. Cinnella University of Foggia, Italy prof. dr. M.M. Levi Universiteit van Amsterdam prof. dr. W.S. Schlack Universiteit van Amsterdam prof. dr. M.B. Vroom Universiteit van Amsterdam Faculteit der Geneeskunde

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Appendices

Nederlandse samenvatting

Contributing authors and affiliations Publications PhD Portfolio Curriculum Vitae Acknowledgements 215 223 251 267 284 296 302 304 308 310

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General introduction and

outline of the thesis

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Prevention of postoperative pulmonary complications

Mechanical ventilation is frequently considered a simple but foremost harmless intervention in patients under general anaesthesia for surgery. Recent investigations, however, suggest that intraoperative ventilation has a strong potential to cause so called ventilator-associated lung injury.1_{Of all patients undergoing ventilation during general anaesthesia for surgery, 5%}

will develop one or more postoperative pulmonary complications, that are associated with high morbidity and mortality.2, 3_{There are several mechanisms through which intraoperative}

ventilation could cause ventilator–associated lung injury, as such contributing to development of postoperative pulmonary complications (fig. 1). First, positive pressure ventilation can overstretch patent alveoli causing damage in those parts of the lung that are aerated during the whole breath cycle (fig. 1A & 1C).4, 5_{Second, repeated opening and closing of alveoli that collapse}

at the end of expiration is associated with increased shear stress, known to cause epithelial destruction (fig. 1B & 1D).6-8_{Third, hyperoxia can result in absorption atelectasis, and cause injury}

of cellular structures through increased production of reactive oxygen species (ROS) (fig. 1E).9

All these harmful effects are suggested to be preventable through the use of lung–protective ventilator settings, using low tidal volumes for prevention of overdistension,10,11_{use of positive}

end–expiratory pressure (PEEP)12, 13_{with or without so–called recruitment manoeuvres to prevent}

repeated opening and closing,14, 15_{and low oxygen fractions (FiO}

2) preventing atelectasis and

ROS production.16_{These insights have led to a paradigm shift from supranormal intraoperative}

ventilation, with large tidal volumes to prevent atelectasis and high levels of FiO2 to maximize

oxygenation, to safer ventilation, using lower levels of tidal volumes, higher levels of PEEP and lower arterial oxygen thresholds.

Tidal volumes

Low tidal volumes in animal studies

The harmful effects of high tidal volumes were first recognized in animal studies of ventilation.17

In these preclinical studies lungs of animals were either challenged with injurious ventilation strategies using different tidal volumes alone, or in combination with other challenges such as intratracheal instillation of lipopolysaccharide or live bacteria.18_{More or less they all showed}

that the extent of alveolar damage and pulmonary oedema depends on the size of tidal volumes used.17, 18

Low tidal volumes in patients with ARDS

Traditionally patients were ventilated with large tidal volumes of 10 to 15 mL/kg predicted body weight (PBW). These volumes far exceeded the range of normal tidal volumes in healthy subjects in rest (7 to 8 mL/kg PBW). The rationale was to prevent atelectasis, as such optimizing oxygenation and ventilation.19_{Randomized controlled clinical trials in critically ill patients with}

the acute respiratory distress syndrome (ARDS), however, showed large tidal volumes to be harmful.20-24_{Two metaanalyses convincingly confirmed that ventilation with low tidal volumes in}

patients with ARDS is associated with improved survival.25, 26_{Consequently, nowadays ventilation}

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Low tidal volumes in critically ill patients without ARDS

The finding that ventilation with low tidal volumes benefits patients with ARDS evoked interest in lung–protective ventilation in critically ill patients who need ventilation for other reasons than ARDS, for example comatose patients with neurologic damage and patients after major cardiac surgery. One randomized controlled trial comparing ventilation with low tidal volumes (6 mL/kg PBW) to ventilation with high tidal volumes (10 mL/kg PBW) indeed suggested benefit from low tidal volumes, as it seemed to reduce the incidence of ARDS.29 These findings were confirmed in a series of metaanalyses.18, 30, 31 In addition, these analyses revealed that ventilation with low tidal volumes was associated with earlier liberation from the ventilator. Even though a substantial reduction in tidal volume size is seen in recent years,27, 28 lung–protective ventilation using low tidal volumes is not yet considered standard of care for critically ill patients who need ventilatory support for reasons other than ARDS.

Low tidal volumes during intraoperative ventilation

Several small clinical trials of intraoperative ventilation suggested that tidal volume reduction could reduce local production of inflammatory mediators and possibly improve pulmonary mechanics.32-34_{A large retrospective trial showed that pressure- and volume–limited ventilation}

during general surgery decreases the development of postoperative respiratory complications.35

Recently, three randomized controlled trials provided more robust evidence for benefit from this ventilation strategy.36-38_{An Italian single–centre trial showed that a ventilation strategy using tidal}

volumes of 7 mL/kg PBW compared to ventilation with tidal volumes of 9 mL/kg PBW during abdominal surgery was associated with superior postoperative pulmonary function.36_{A French}

multicentre trial found that in patients undergoing abdominal surgery a ventilation strategy with reduced tidal volumes of 6 mL/kg PBW compared to tidal volumes of 12 mL/kg PBW was associated with a decreased incidence of postoperative complications by almost 65%.37_One

Chinese trial in patients undergoing spinal fusion reported an even more impressive benefit of tidal volume reduction from 12 to 6 mL/kg PBW on postoperative pulmonary complications.38

Contrasting to these results, one retrospective study showed that use of low tidal volume ventilation (6 to 8 mL/kg PBW) is associated with increased postoperative mortality, though the authors claim this to be caused by insufficient levels of PEEP.39_{Despite the suggestion that}

low tidal volume ventilation in surgery patients is increasingly accepted,40, 41_{recent studies show}

imperfect implementation of this strategy in the operation room.42-45

Positive end–expiratory pressure

Positive end–expiratory pressure in animal studies

Several studies in animals with lung injury have shown that ventilation with PEEP compared to ventilation without PEEP improves oxygenation and lung mechanics, and prevents formation of lung edema.5, 17, 46_{Similar results came from studies in animals without lung injury. Ventilation}

with PEEP in combination with low tidal volumes attenuated local production of inflammatory mediators,47-52_{lung edema,}48, 51_{and cell injury.}47-52_{One important shortcoming of PEEP, however,}

is that it could cause overdistension of the lung parts that remain aerated during the complete breath cycle.53_{In addition, use of higher levels of PEEP could compromise the circulation.}54

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Figure 1. Mechanisms through which intraoperative ventilation could cause ventilator– associated lung injury

A) Ventilation at high lung volumes result in overdistention of the lung and hyperinflation may cause gross barotrauma (air leaks), but can also cause an increase in pulmonary oedema; B) ventilation at low lung volumes causes repeated opening and closing of alveoli that collapse at the end of expiration, resulting in increased shear stress and lung injury (atelectrauma). Collapse of large regions of the lung during ventilation at low lung volumes cause lung inhomogeneity; C) ventilation at too high levels of PEEP can aggravate overdistention of lung tissue at end-expiration; D) ventilation at low levels of PEEP increases formation of atelectasis and lung inhomogeneity; E) high levels of fractional inspired oxygen (FiO2) can increase

the production of reactive oxygen species (ROS), which have a direct toxic effect on lung cells. Too high levels of FiO2 also

increases the risk of resorption atelectasis; F) these mechanical and chemical stressors cause structural and biological changes in the alveoli. Inflammatory mediators are released in the lung and recruit neutrophils. They also cause changes that promote pulmonary fibrosis. The increase in alveolar-capillary permeability causes an increase in pulmonary oedema, but also facilitate translocation of mediators and bacteria to the systemic circulation; G) these structural and biological changes result in lung injury, which can cause an increase in postoperative pulmonary complications and worse clinical outcome with increased length of hospital stay and higher incidence of mortality (H)

Positive end–expiratory pressure in patients with ARDS

Three randomized controlled trials in patients with ARDS failed to show an effect of higher levels of PEEP on survival.55-57_{One metaanalysis using the individual patient data of these three trials,}

however, showed survival benefit in patients with more severe ARDS.58_{Consequently, nowadays}

most clinicians use higher levels of PEEP (10 cm H2O and higher) in patients with moderate or

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Positive end–expiratory pressure in critically ill patients without ARDS

In critical care patients without ARDS, there is limited evidence for benefit of PEEP.59, 60_One

randomized controlled trial in patients at risk for ARDS showed no difference between a strategy using PEEP (5 to 8 cm H2O) and a strategy using a minimal levels of PEEP for adequate oxygenation

with regard to later development of ARDS or mortality.59_{This was confirmed in another trial in}

patients without ARDS, but in this trial use of higher levels of PEEP was associated with a lower incidence of ventilator–associated pneumonia.60_{In the randomized controlled trial comparing low}

and high tidal volumes (6 ml/kg PBW versus 10 ml/kg PBW) in patients without ARDS mentioned above,29_{an independent association between higher levels of PEEP and development of ARDS}

was found. In the postoperative phase there is also no clear evidence for benefit from PEEP. Indeed, while PEEP improves pulmonary compliance and arterial oxygenation, these effects only last in the first hours after surgery.61_{This is also true for the prevention of atelectasis.}62_{In one}

trial in patients after cardiac surgery in which PEEP was titrated on the best achievable PaO2

level no sustained benefit was found.63_{In general, intensive care unit clinicians now use PEEP}

levels between 4 and 7 cm H2O in critically ill patients who need ventilation for other reasons

than ARDS,28_{though the best level of PEEP for these patients remains unclear.}

Positive end–expiratory pressure during intraoperative ventilation

Induction of anaesthesia induces atelectasis,64_{increasing ventilation–perfusion mismatch and}

suboptimal oxygenation.65_{Intraoperative use of PEEP, with or without recruitment manoeuvres,}

is suggested to prevent atelectasis and repeated opening and closing of lung tissue.6514_Indeed,

use of higher levels of PEEP seems to improve oxygenation and respiratory mechanics in a wide range of patient populations and surgical settings.15, 66-74_{However, in most trials of intraoperative}

PEEP, recruitment of lung tissue was not maintained in the postoperative period at the post anaesthesia care unit (PACU).72, 73

Benefit of higher levels of PEEP on postoperative outcome was suggested in the three randomized controlled trials of lung–protective intraoperative ventilation mentioned above, where use of low tidal volumes was actually combined with higher levels of PEEP with recruitment maneuvers.36-38

It is difficult, if not impossible to conclude what prevented postoperative complications: the use of low tidal volumes or the high levels of PEEP, or recruitment manoeuvres, or altogether. Despite this, both low tidal volumes and high levels of PEEP with recruitment manoeuvres are suggested to be beneficial.75_{A recent large retrospective study confirms this suggestion, showing}

that both low tidal volumes (< 10 mL/kg) and higher PEEP levels (≥ 5 cmH2O) are independently

associated with a decreased risk of postoperative respiratory complications.35

The lack of sufficient evidence for benefit of higher levels of PEEP during surgery is mirrored in the remarkable variation in use of intraoperative PEEP varying from 17% to as high as 82% of recently reported series.40-42, 44, 45

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Oxygen fractions

Oxygen fractions in animal studies

The potentially toxic effects of high fractions of inspired oxygen (FiO2) have long been known

from animal studies. Mice exposed to hyperoxia develop a condition similar to ARDS, which is at least in part dependent on an increased production of reactive oxygen species (ROS) by mitochondria.76, 77_{Hyperoxia could further cause atelectasis, tracheobronchitis, interstitial fibrosis,}

protein leakage and neutrophil infiltration.78-80_{In spontaneous breathing rodents with pneumonia,}

hyperoxia has been shown to contribute to bacterial spread beyond the lungs,81_{lung injury and}

even lethality.82_{More cytokine production and increased lung injury was found in experiments}

in ventilated rodents with hyperoxia during injurious ventilation (tidal volume > 20 mL/kg).83-85

Oxygen fractions in patients with ARDS

In human lungs high FiO2 can also accelerate the production of ROS, which overwhelms natural

anti–oxidant defences and injures cellular structures in the lung.9,16,86,87_{Furthermore, hyperoxia}

can cause derecruitment of lung tissue by resorption atelectasis.88_{Critically ill patients with lung}

injury are possibly more prone to the harmful pulmonary effects of oxygen toxicity, which can coincide with the primary pulmonary injury (e.g., ARDS, pneumonia) and ventilator–associated lung injury.77,89,90_{One small trial found that 100% compared to 60% FiO}

2 increased development of

atelectasis in patients with ARDS, which was prevented by application of higher levels of PEEP.91

However, clinical trials examining the effect of hyperoxia on the development of lung injury in patients with ARDS are lacking.

Oxygen fractions in critically ill patients without ARDS

In critical care patients who need ventilatory support for reasons other than ARDS, an association between hyperoxia and mortality was found in ventilated patients,89_{patients after cardiac arrest,}92

and patients with traumatic brain injury,93_{or stroke.}94_{However, other studies did not reveal such}

associations.90, 95-97_{For example, two recent metaanalyses investigating the effect of high FiO}

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in critical care patients on survival showed mixed results.98, 99_{One metaanalysis did not find a}

significant association in the general ICU,98_{while another metaanalysis of pooled data from all}

critically ill patients suggested arterial hyperoxia to increase the risk of mortality.99_{In subset}

analyses, hyperoxia was associated with decreased survival in patients after cardiac arrest, traumatic brain injury, and stroke.98 _{In patients after cardiac arrest a dose–dependent association}

between hyperoxia and patient outcome was found.99,100_{Notably, arterial hyperoxia decreases}

coronary blood flow and cardiac output, increases systemic vascular resistance, and contributes to reperfusion injury in patients with myocardial infarction.101-104_{A recent randomized controlled}

trial in patients with myocardial infarction indeed clearly showed that supplemental oxygen increased myocardial injury.105_{Research on the effect of FiO}

2 on the development of lung injury

in patients ventilated for other reasons than ARDS, however, is currently unavailable. Despite the lack of evidence, current guidelines in critically ill patients aim at PaO2 levels around 55–80

mm Hg.55,106

Oxygen fractions during intraoperative ventilation

Anaesthesiologists use high FiO2 during pre–oxygenation and denitrogenation to prolong the

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induced by ventilation–perfusion mismatches caused by alveolar collapse.64_{High FiO}

2 (> 80%)

increases the incidence of resorption atelectasis, which not only augments atelectasis formation after induction,107,108_{but also directly before emergence from anaesthesia in the post–oxygenation}

phase, annulling the open lung created during intraoperative ventilation.109_{At the same time,}

there is a risk of hyperoxia–induced injury to the lungs. The available trials and metaanalyses on perioperative hyperoxia focused on the beneficial effect of high FiO2 on postoperative nausea

and vomiting110-112_{and postoperative wound infections.}113-118_{A large trial on postoperative}

wound infections investigated the effect of 80% compared to 30% oxygen during surgery on development of postoperative pulmonary complications as secondary endpoint and found no difference in incidence of atelectasis, pneumonia, and respiratory failure.117_{A clinical trial in}

obese patients showed worse postoperative lung function in patients receiving FiO2 during

ventilation.119_{One metaanalysis found no difference in presence or absence of atelectasis or}

postoperative gas exchange during intraoperative ventilation with either high or low FiO2.120 A

large recent metaanalysis, however, suggested that hyperoxia was not associated with increased 30–day mortality.121_{Sufficiently powered clinical trials on lung injury and postoperative pulmonary}

complications due to high FiO2 are lacking.

Aims of this thesis

This thesis is a collection of investigations that focused on several aspects of perioperative ventilation, specifically ventilation practice and the associations between ventilator settings and the effects on postoperative pulmonary complications and outcome. The main interest was on PEEP. We hypothesized that the use of higher PEEP and recruitment manoeuvres would protect against development of postoperative pulmonary complications during intraoperative ventilation. The specific aims of this thesis were:

1. To investigate the effect of intraoperative use of PEEP and recruitment manoeuvres on occurrence of postoperative pulmonary complications during low tidal volume ventilation during open abdominal surgery.

2. To determine the association between intraoperative use of high tidal volumes, PEEP and recruitment manoeuvres, and the occurrence of postoperative pulmonary complications. 3. To investigate the effects of development of postoperative lung injury on postoperative

clinical course and mortality.

4. To examine the effects of different levels of PEEP during postoperative ventilation after coronary artery bypass grafting on the duration to extubation.

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Outline of this thesis

The following chapters in this thesis report on observational studies, clinical trials and metaanalyses that reported on several aspects of lung–protective perioperative ventilation, including effects of tidal volume size and level of PEEP.

Chapter 2 provides the results of a metaanalysis of eight clinical trials examining the effects of intraoperative ventilator settings on postoperative outcome of non–cardiac surgery patients. We hypothesized that use of low tidal volumes and/or PEEP with or without recruitment manoeuvres could prevent postoperative pulmonary complications, and as such improving postoperative outcome. In this metaanalysis we tried to separate the effects of tidal volume and PEEP manipulations.

Chapter 3 constitutes a comprehensive review of the literature on predictive models of postoperative pulmonary complications, the pathophysiology of ventilation–induced lung injury, and protective ventilation strategies, including the respective roles of tidal volume size, the level of PEEP and the use of recruitment manoeuvres. In this review we propose an algorithm for protective intraoperative mechanical ventilation.

In Chapter 4 and chapter 5 we describe the design and the results, respectively, of the ‘Local Assessment of Ventilatory Management during General Anaesthesia for Surgery’–study (LAS VEGAS), a prospective observational cohort study designed to assess intraoperative ventilation practice in Europe and the America’s, and to test the hypothesis that certain ventilator settings, especially high tidal volumes and low PEEP levels, are associated with the occurrence of postoperative pulmonary complications.

In Chapter 6 we show the results of a metaanalysis using individual patient data from 15 randomized controlled trials of intraoperative ventilation. We hypothesized that intraoperative ventilation with lower tidal volumes protects against postoperative pulmonary complications, and that use of higher levels of PEEP adds to the beneficial effects of lower tidal volumes. Chapter 7 and chapter 8 constitute the design and results of the PROVHILO trial (High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery), a randomized controlled trial of intraoperative ventilation for open abdominal surgery. In chapter 9 entails letters with comments on PROVHILO written by peers, as well as our Author’s reply. In this trial patients were randomized to ventilation with high levels of PEEP (12 cm H2O) with recruitment manoeuvres or low levels of PEEP (0 to 2 cm H2O) without recruitment

manoeuvres. We hypothesized that a ventilation strategy with high levels of PEEP and recruitment manoeuvres would protect against development of postoperative pulmonary complications. In Chapter 10 we describe the results of another metaanalysis, using individual patient data from 12 clinical investigations of intraoperative ventilation. We hypothesized that the occurrence of postoperative lung injury was associated with a worse outcome, and that postoperative outcome would depend on intraoperative ventilation settings.

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In Chapter 11 we present the results of a secondary analysis of two randomized controlled trials of postoperative ventilation in patients undergoing cardiac surgery, in which we determined the effects of PEEP manipulations on pulmonary compliance and gas exchange in the first hours of weaning from mechanical ventilation and time on the ventilator.122, 123_{We hypothesized that}

higher levels of PEEP would improve pulmonary function, but not to be associated with a shorter duration of postoperative ventilation.

This thesis ends with a summary of the abovementioned studies and a general discussion in chapter 12, with Dutch translation in chapter 13.

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67. Valenza F, Vagginelli F, Tiby A, et al. Effects of the beach chair position, positive end-expiratory pressure, and pneumoperitoneum on respiratory function in morbidly obese patients during anesthesia and paralysis. Anesthesiology 2007; 107(5): 725-32

68. Hedenstierna G, Santesson J. Studies on intra-pulmonary gas distribution in the extremely obese. Influence of anaesthesia and artificial ventilation with and without positive end-expiratory pressure. Acta anaesthesiologica Scandinavica 1977; 21(4): 257-65

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70. Gander S, Frascarolo P, Suter M, Spahn DR, Magnusson L. Positive end-expiratory pressure during induction of general anesthesia increases duration of nonhypoxic apnea in morbidly obese patients. Anesthesia and Analgesia 2005; 100(2): 580-4

71. Coussa M, Proietti S, Schnyder P, et al. Prevention of atelectasis formation during the induction of general anesthesia in morbidly obese patients. Anesthesia and Analgesia 2004; 98(5): 1491-5

72. Wetterslev J, Hansen EG, Roikjaer O, Kanstrup IL, Heslet L. Optimizing peroperative compliance with PEEP during upper abdominal surgery: effects on perioperative oxygenation and complications in patients without preoperative cardiopulmonary dysfunction. European journal of anaesthesiology 2001; 18(6): 358-65

73. Weingarten TN, Whalen FX, Warner DO, et al. Comparison of two ventilatory strategies in elderly patients undergoing major abdominal surgery. British journal of anaesthesia 2010; 104(1): 16-22

74. Wirth S, Baur M, Spaeth J, Guttmann J, Schumann S. Intraoperative positive end-expiratory pressure evaluation using the intratidal compliance-volume profile. British journal of anaesthesia 2015; 114(3): 483-90

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76. Clark JM, Lambertsen CJ. Pulmonary oxygen toxicity: a review. Pharmacological reviews 1971; 23(2): 37-133 77. Morse D, Otterbein LE, Watkins S, et al. Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers

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80. Fracica PJ, Knapp MJ, Piantadosi CA, et al. Responses of baboons to prolonged hyperoxia: physiology and qualitative pathology. Journal of applied physiology 1991; 71(6): 2352-62

81. Kikuchi Y, Tateda K, Fuse ET, et al. Hyperoxia exaggerates bacterial dissemination and lethality in Pseudomonas aeruginosa pneumonia. Pulmonary pharmacology & therapeutics 2009; 22(4): 333-9

82. Tateda K, Deng JC, Moore TA, et al. Hyperoxia mediates acute lung injury and increased lethality in murine Legionella pneumonia: the role of apoptosis. Journal of immunology 2003; 170(8): 4209-16

83. Li LF, Liao SK, Ko YS, Lee CH, Quinn DA. Hyperoxia increases ventilator-induced lung injury via mitogen-activated protein kinases: a prospective, controlled animal experiment. Critical care 2007; 11(1): R25

84. Makena PS, Luellen CL, Balazs L, et al. Preexposure to hyperoxia causes increased lung injury and epithelial apoptosis in mice ventilated with high tidal volumes. American journal of physiology Lung cellular and molecular physiology 2010; 299(5): L711-9

85. Quinn DA, Moufarrej RK, Volokhov A, Hales CA. Interactions of lung stretch, hyperoxia, and MIP-2 production in ventilator-induced lung injury. Journal of applied physiology 2002; 93(2): 517-25.

86. Aggarwal NR, Brower RG. Targeting normoxemia in acute respiratory distress syndrome may cause worse short-term outcomes because of oxygen toxicity. Annals of the American Thoracic Society 2014; 11(9): 1449-53

87. Barazzone C, White CW. Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2 family proteins. American journal of respiratory cell and molecular biology 2000; 22(5): 517-9

88. Edmark L, Auner U, Enlund M, Ostberg E, Hedenstierna G. Oxygen concentration and characteristics of progressive atelectasis formation during anaesthesia. Acta Anaesthesiologica Scandinavica 2011; 55(1): 75-81

89. de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Critical Care 2008; 12(6): R156

90. Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in mechanically ventilated patients. Intensive Care Medicine 2012; 38(1): 91-8

91. Aboab J, Jonson B, Kouatchet A, Taille S, Niklason L, Brochard L. Effect of inspired oxygen fraction on alveolar derecruitment in acute respiratory distress syndrome. Intensive Care Medicine 2006; 32(12): 1979-86

92. Kilgannon JH, Jones AE, Shapiro NI, et al. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. Jama 2010; 303(21): 2165-71

93. Brenner M, Stein D, Hu P, Kufera J, Wooford M, Scalea T. Association between early hyperoxia and worse outcomes after traumatic brain injury. Archives of surgery 2012; 147(11): 1042-6

94. Rincon F, Kang J, Maltenfort M, et al. Association between hyperoxia and mortality after stroke: a multicenter cohort study. Critical Care Medicine 2014; 42(2): 387-96

95. Bellomo R, Bailey M, Eastwood GM, et al. Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. Critical care 2011; 15(2): R90

96. Young P, Beasley R, Bailey M, et al. The association between early arterial oxygenation and mortality in ventilated patients with acute ischaemic stroke. Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine 2012; 14(1): 14-9

97. Raj R, Bendel S, Reinikainen M, et al. Hyperoxemia and long-term outcome after traumatic brain injury. Critical Care 2013; 17(4): R177

98. Damiani E, Adrario E, Girardis M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and metaanalysis. Critical care 2014; 18(6): 711

99. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, de Jonge E. Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A Systematic Review, Metaanalysis, and Meta-Regression of Cohort Studies. Critical Care Medicine 2015

100. Wang CH, Chang WT, Huang CH, et al. The effect of hyperoxia on survival following adult cardiac arrest: a systematic review and metaanalysis of observational studies. Resuscitation 2014; 85(9): 1142-8

101. Farquhar H, Weatherall M, Wijesinghe M, et al. Systematic review of studies of the effect of hyperoxia on coronary blood flow. American heart journal 2009; 158(3): 371-7

102. Kenmure AC, Murdoch WR, Beattie AD, Marshall JC, Cameron AJ. Circulatory and metabolic effects of oxygen in myocardial infarction. British medical journal 1968; 4(5627): 360-4

103. McNulty PH, Robertson BJ, Tulli MA, et al. Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease. Journal of applied physiology 2007; 102(5): 2040-5

104. Mak S, Azevedo ER, Liu PP, Newton GE. Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure. Chest 2001; 120(2): 467-73

105. Stub D, Smith K, Bernard S, et al. Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. Circulation 2015; 131(24): 2143-50

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106. Patroniti N IG. Mechanical ventilation—Skills and techniques. Patient-centered Acute Care Training (PACT) Module— European Society of Intensive Care Medicine 2015

107. Edmark L, Kostova-Aherdan K, Enlund M, Hedenstierna G. Optimal oxygen concentration during induction of general anesthesia. Anesthesiology 2003; 98(1): 28-33

108. Hedenstierna G. Oxygen and anesthesia: what lung do we deliver to the post-operative ward? Acta Anaesthesiologica Scandinavica 2012; 56(6): 675-85

109. Benoit Z, Wicky S, Fischer JF, et al. The effect of increased FiO2 before tracheal extubation on postoperative atelectasis. Anesthesia and Analgesia 2002; 95(6): 1777-81, table of contents

110. Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999; 91(5): 1246-52

111. Orhan-Sungur M, Kranke P, Sessler D, Apfel CC. Does supplemental oxygen reduce postoperative nausea and vomiting? A metaanalysis of randomized controlled trials. Anesthesia and analgesia 2008; 106(6): 1733-8

112. Simurina T, Mraovic B, Mikulandra S, et al. Effects of high intraoperative inspired oxygen on postoperative nausea and vomiting in gynecologic laparoscopic surgery. Journal of clinical anesthesia 2010; 22(7): 492-8

113. Scifres CM, Leighton BL, Fogertey PJ, Macones GA, Stamilio DM. Supplemental oxygen for the prevention of postcesarean infectious morbidity: a randomized controlled trial. American journal of obstetrics and gynecology 2011; 205(3): 267 e1-9 114. Greif R, Akca O, Horn EP, Kurz A, Sessler DI. Supplemental perioperative oxygen to reduce the incidence of

surgical-wound infection. NEJM 2000; 342(3): 161-7

115. Qadan M, Akca O, Mahid SS, Hornung CA, Polk HC, Jr. Perioperative supplemental oxygen therapy and surgical site infection: a metaanalysis of randomized controlled trials. Archives of surgery 2009; 144(4): 359-66

116. Pryor KO, Fahey TJ, 3rd, Lien CA, Goldstein PA. Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial. JAMA 2004; 291(1): 79-87

117. Meyhoff CS, Wetterslev J, Jorgensen LN, et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI randomized clinical trial. JAMA 2009; 302(14): 1543-50 118. Bustamante J, Tamayo E, Alvarez FJ, et al. Intraoperative PaO2 is not related to the development of surgical site

infections after major cardiac surgery. Journal of cardiothoracic surgery 2011; 6: 4

119. Zoremba M, Dette F, Hunecke T, Braunecker S, Wulf H. The influence of perioperative oxygen concentration on postoperative lung function in moderately obese adults. European journal of anaesthesiology 2010; 27(6): 501-7 120. Hovaguimian F, Lysakowski C, Elia N, Tramer MR. Effect of intraoperative high inspired oxygen fraction on surgical

site infection, postoperative nausea and vomiting, and pulmonary function: systematic review and metaanalysis of randomized controlled trials. Anesthesiology 2013; 119(2): 303-16

121. Wetterslev J, Meyhoff CS, Jorgensen LN, Gluud C, Lindschou J, Rasmussen LS. The effects of high perioperative inspiratory oxygen fraction for adult surgical patients. The Cochrane Database of Systematic Reviews 2015; 6: CD008884 122. Dongelmans DA, Veelo DP, Paulus F, et al. Weaning automation with adaptive support ventilation: a randomized

controlled trial in cardiothoracic surgery patients. Anesthesia and Analgesia 2009; 108(2): 565-71

123. Dongelmans DA, Veelo DP, Binnekade JM, et al. Adaptive support ventilation with protocolized de-escalation and escalation does not accelerate tracheal extubation of patients after nonfast-track cardiothoracic surgery. Anesthesia and Analgesia 2010; 111(4): 961-7

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Intraoperative Ventilatory Strategies

to Prevent Postoperative Pulmonary

Complications – a Metaanalysis

Hemmes SNT, Serpa Neto A, Schultz MJ

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Abstract

Purpose. It is uncertain whether patients undergoing short–lasting mechanical ventilation for surgery benefit from lung–protective intraoperative ventilatory settings including the use of lower tidal volumes, higher levels of positive end–expiratory pressure (PEEP) and/or recruitment manoeuvres (RM). We meta–analysed trials testing the effect of lung–protective intraoperative ventilatory settings on the incidence of postoperative pulmonary complications.

Recent findings. Eight articles (1669 patients) were included. Metaanalysis showed a decrease in lung injury development (risk ratio [RR] 0.40; 95% CI 0.22–0.70; I2_{0%; number needed to}

treat [NNT] 37), pulmonary infection (RR 0.64; 95% CI 0.43–0.97; I2_{0%; NNT 27) and atelectasis}

(RR 0.67; 95% CI 0.47–0.96; I2_{48%; NNT 31) in patients receiving intraoperative MV with lower}

tidal volumes. Metaanalysis also showed a decrease in lung injury development (RR 0.29; 95% CI 0.14–0.60; I2_{0%; NNT 29), pulmonary infection (RR 0.62; 95% CI 0.40–0.96; I}2_{15%; NNT 33)}

and atelectasis (RR 0.61; 95% CI 0.41–0.91; I2_{0%; NNT 29) in patients ventilated with higher}

levels of PEEP, with or without RM.

Summary. Lung–protective intraoperative ventilatory settings may have the potential to protect against postoperative pulmonary complications.

Keywords. Mechanical ventilation, Intraoperative, Postoperative complications, Tidal volume, Positive end-expiratory pressure

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Introduction

Mechanical ventilation (MV) has the potential to cause so–called ventilator–associated lung injury (VALI). VALI results from overdistention of non–dependent lung tissue causing excessive cyclic strain of alveolar cells,1_{and repetitive opening and closing of dependent lung tissue}

resulting in cyclic cell stress due to the extreme forces exposed to lung cells at the interfaces between open and closed alveoli.2,3_{Lung–protective MV with use of lower tidal volumes, which}

is suggested to prevent alveolar overdistention, benefits critically ill patients suffering from acute respiratory distress syndrome (ARDS).4_{MV with higher levels of positive end–expiratory}

pressure (PEEP) with or without recruitment manoeuvres (RM), which is suggested to prevent repetitive opening and closing of alveoli, also seems beneficial at least in patients with severe ARDS.4_{Recent clinical studies suggest MV with lower tidal volumes even to benefit critically ill}

patients without ARDS.5-7

MV is an essential supportive strategy during general anaesthesia for surgery. It is uncertain whether short–lasting MV during surgery also has the potential to cause VALI.8_{However, both}

animal and human studies show VALI can develop shortly after initiation of MV.7,9,10_{In addition,}

general anaesthesia causes large atelectasis, especially when muscle relaxants are used.11_As

a consequence, there is an increased risk of overdistention of non–atelectatic lung tissue as well as repetitive opening and closing of partly atelectatic lung tissue. Thus, patients who need MV for surgery may also be vulnerable to the harmful effects of MV. Notably, surgical patients frequently suffer from postoperative pulmonary complications, with reported incidences of up to 5.0%.12,13_{It is tempting to speculate on a causal relation between these complications and}

intraoperative ventilatory settings.

We hypothesize use of intraoperative lung–protective ventilatory settings to lower the incidence of postoperative pulmonary complications, and consequently on the postoperative clinical course and length of hospital stay. To test this hypothesis, we meta–analysed clinical trials of MV for surgery, focusing on the use of lower tidal volumes and/or higher levels of PEEP and RM. This is a secondary metaanalysis of a previously published metaanalysis of clinical trials testing lung–protective MV in patients who received short–term MV (i.e., in the operation room for surgery) or long–term MV (i.e., in the intensive care unit because of critical illness).14_{The present}

metaanalysis is restricted to the clinical trials in the operation room.

Methods

We searched Medline (1966–2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL). All reviewed articles and cross–referenced studies from retrieved articles were screened for pertinent information. Articles were selected for inclusion in the metaanalysis if they evaluated two types of MV in patients with uninjured lungs undergoing surgery. In one arm of the trial, MV should be protective (lower tidal volumes, and/or higher levels of PEEP with or without use of RMs). Then, this protective strategy should be compared with conventional methods

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(higher tidal volumes, and no or lower levels of PEEP and no use of RMs) in the other arm of the trial. We excluded trials of patients undergoing cardiac surgery. We also excluded revisions and trials that did not report the outcomes of interest (defined below). When we found duplicate articles of the same trial in preliminary abstracts and articles, we analysed data from the most complete data set.

Data were extracted from each article using a data recording form developed for the previously published metaanalysis.14_{After extraction, data were reviewed and compared by the second}

author. Whenever needed, we obtained additional information about a specific study by directly questioning the principal investigator of the specific trial.

The primary endpoint was the incidence of lung injury in each arm of the trial. Secondary endpoints included incidence of pulmonary infection (using the authors’ definition) or atelectasis. Statistical analysis was performed as described in the original metaanalysis.14

Results

The initial search yielded 2.123 articles (459 from MEDLINE, 141 from CENTRAL, 885 from CINAHL, and 638 from Web of Science) (figure 1). After removing 711 duplicate articles, we evaluated the abstracts of 1.412 articles. After evaluating them, 1.364 articles were excluded because they did not meet inclusion criteria. Another five articles were excluded because MV was applied for other reasons than surgery, no data on outcome of interest was reported in 28, and same cohort previously analysed in seven. Finally, eight articles were included in the final analysis.15-22

Tidal volume reduction

Our search of the literature revealed eight articles (1669 patients) reporting on trials comparing lower with conventional tidal volumes during surgery (table 1 and table 2). Metaanalysis of these trials showed that 17 of 858 patients (2.0%) ventilated with lower tidal volumes and 36 of 755 patients (4.7%) ventilated with conventional tidal volumes developed lung injury during follow-up (risk ratio [RR] 0.40; 95% confidence interval [CI] 0.22–0.70; number needed to treat [NNT] 37) (figure 2). The analysis displayed no signs of heterogeneity (I2_{= 0%). Pulmonary infection}

and atelectasis showed lower incidence in patients receiving lower tidal volume ventilation (RR 0.64; 95% CI 0.43–0.97; NNT 27 and RR 0.67; 95% CI 0.47–0.96; NNT 31, respectively). The I2_test

indicated no heterogeneity in the analysis of pulmonary infection, but moderate heterogeneity in the analysis of atelectasis (0% and 48% respectively).

Higher levels of PEEP and RMs

Our search of the literature revealed five articles (1323 patients) reporting on trials comparing no or lower levels of PEEP (up to 3 cmH2O) with higher levels of PEEP (from 3 to 12 cmH2O)

during surgery (table 1).

Metaanalysis of these trials shows that 9 of 654 patients (1.4%) ventilated with higher levels of PEEP developed postoperative lung injury compared to 31 of 629 patients (4.9%) receiving

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lower levels of PEEP (RR 0.29; 95% CI 0.14–0.60; NNT 29) (figure 3), without any signs for heterogeneity within the analysis (I2 _{= 0%). A beneficial effect of higher levels of intraoperative}

PEEP on postoperative pulmonary infection and atelectasis was also found (RR 0.62; 95% CI 0.40– 0.96; NNT 33 and RR 0.61; 95% CI 0.41–0.91; NNT 29, respectively). The I2_{test indicated moderate}

heterogeneity in the analysis of pulmonary infection, but not in the analysis of atelectasis (15% and 0% respectively). We did not find trials specifically investigating exclusively the effects of intraoperative RM.

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30 Ta bl e 1 . Ch ar act eri stics o f t he i ncl ud ed st ud ies a nd su mma ry o f c on tin uo us v ari ab les Pr ot ectiv e Co ns er va tiv e Pr ot ectiv e Co ns er va tiv e St ud y N VT PE EP RM N VT PE EP RM N Se tti ng Des ign FU Ti me o f M V Pri ma ry Ou tc ome M ic he le t 15 52 5 5 N 26 9 0 N 26 OS RC T 18 7. 06 ± 1 .8 1 7. 76 ± 1 .8 5 Cy to ki ne s i n bl oo d Ca i 16 16 6 0 N 8 10 0 N 8 N eur o RC T 7. 15 6. 90 ± 2 .2 0 7. 4 ± 3. 10 CT A te le ct as is Lin 7 40 5 3-5 N 20 9 0 N 20 OS RC T 24 4. 33 ± 0 .9 0 4. 23 ± 0 .7 1 Cy to ki ne s i n bl oo d Lic ke r 18 10 91 6 3 Y 55 8 9 3 N 53 3 OS CO H ---2.9 3 ± 1 .2 0 2.7 6 ± 1 .0 LI W eing ar te n 19 40 6 12 Y 20 10 0 N 20 Sur gic al RC T Disc ha rg e 5.1 3 ± 1 .8 6 5.7 3 ± 1 .7 1 O xy ge na tion Bus tam an te 20 22 9 8 4 N 15 4 10 4 N 75 Sur gic al CR O ---N S N S TM V; ICU LS; M or ta lit y Ya ng 21 10 0 6 5 N 50 10 0 N 50 OS RC T 16 8 2. 00 ± 0 .6 8 2. 11 ± 0 .8 0 LI Tr esc han 22 10 1 6 5 Y 50 12 5 Y 51 Sur gic al RC T 12 0 8.7 0 ± 5 .2 0 8.7 0 ± 5 .9 0 Spir om et ry Tot al 1, 66 9 6.1 4 ± 0.8 6 4.5 0 (3 .0 -5 .0 ) ---88 6 10 .3 5 ± 1.1 5 0 (0 - 3.7 5) ---78 3 ---6.5 7 (4 .5 0 – 1 9.5 0) 6.9 0 (3 .6 3 – 8.7 0) 7.4 0 (3 .4 9 – 10 .3 5) ---Mean ± st andar d de vi ation; Medi an (in ter quartil e rang e); VT : Ti dal v ol ume (in mL/kg); FU: Fol lo w -up; OS : Onc ol ogy sur ger y; RC T: Randomi zed con tr ol led tri al; COH: Cohort; CR O: Cr oss-se ctional; C T: Com put ed t om og ra ph y; N S: N ot spe cifie d; LI : Lung injur y; TM V: Tim e of m ec ha nic al v en tila tion; ICU LS: ICU le ng th of s ta y

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Table 2. Synthesis of demographic, ventilatory and laboratorial characteristics of the patients in the final follow-up

Protective Ventilation

(n = 886) Conventional Ventilation (n = 73) p-value

Age, years 60.27 ± 8.31 60.33 ± 8.06 0.910

Weight, kg 73.04 ± 13.04 73.01 ± 12.56 0.965

Tidal volume, ml/kg IBWa _{6.14 ± 0.86} _{10.35 ± 1.15} _{< 0.0001}

PEEP, cmH2Oa 6.62 ± 2.65 2.74 ± 2.82 0.001

Plateau pressure, cmH2Oa 16.62 ± 2.76 20.45 ± 2.54 0.021

Respiratory rate, beats per minutea _{16.62 ± 2.72} _{10.78 ± 2.67} _0.007

Minute-ventilation, litres/minutea _{7.76 ± 2.61} _{8.56 ± 2.58} _0.917

PaO2 / FiO2a 332.86 ± 61.48 339.68 ± 67.70 0.797

PaCO2, mmHga 41.86 ± 3.32 39.05 ± 3.42 0.052

pHa _{7.35 ± 0.03} _{7.39 ± 0.03} _0.073

Mean ± standard deviation; IBW: ideal body weight; PEEP: positive end expiratory pressure; a_{: in the final of the follow-up}

Discussion

This metaanalysis suggests that intraoperative MV with lower tidal volumes may protect surgical patients from development of postoperative lung injury, pulmonary infections and atelectasis. This metaanalysis also suggests that intraoperative use of higher levels of PEEP during MV attenuates development of lung injury, pulmonary infection and atelectasis.

Implementation of lung–protective MV for surgery has the potential to significantly reduce postoperative pulmonary complications. Considering the high number of surgical procedures performed worldwide daily,23_{reduction of postoperative pulmonary complications could be}

of great importance. Notably, a recent international prospective trial shows the incidence of postoperative mortality to be as high as 4%, much higher than previously assumed.24_{A large}

international observational study is underway to address the effect of intraoperative ventilatory settings on postoperative complications.25

Prescription of MV in critically ill patients has definitely changed over the last decades. There has been progressive reduction of tidal volume size, from > 12 ml/kg in the 1970s 26,27_{to < 9 ml/}

kg in more recent epidemiologic studies of MV practice in Europe and the Americas.28-31_This

change was largely stimulated by results from animal studies, which clearly show injurious tidal volume settings to aggravate pre–existing pulmonary injury.9_{Several clinical trials confirm the}

existence of VALI by showing reduced morbidity and mortality in patients with ARDS ventilated with lower tidal volumes.4_{While initially intensive care unit physicians have been reluctant to}

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of lower tidal volumes in patients with ARDS, e.g., in patients with sepsis.32_{Critically ill patients}

without ARDS also seem to benefit from ventilation with lower tidal volumes.5,6_{One recent}

randomized controlled trial shows a lower tidal volume strategy to protect against lung injury in patients without ARDS at onset of MV in the intensive care unit.7

Notably, a recent observational study in patients undergoing short–term postoperative MV after cardiac surgery shows MV with tidal volumes > 10 ml/kg to be associated with prolonged MV, hemodynamic instability, multiple organ failure, and prolonged stay in the ICU, compared to MV with lower tidal volumes. In this study women and obese patients are found to be particularly at risk of receiving ventilation with too large tidal volumes.33_{These results confirm, at least in part}

findings from another recent study that identifies female gender, overweight and underweight as independent factors for MV with too large tidal volumes.34

MV with lower tidal volumes may not come without challenges. Use of lower tidal volumes could increase cyclic alveolar collapse of dependent lung regions, raising the risk of atelectrauma. Application of PEEP is an easy intervention that may counteract this side–effect of lower tidal volume ventilation. Lower tidal volume ventilation could also lead to hypercapnia and hypercapnic acidosis. Notably, so-called permissive hypercapnia is thought to have lung–protective qualities, Figure 3. Effect of intraoperative ventilation with higher levels of PEEP

Lung-protective perioperative mechanical ventilation - Thesis (complete)

Lung-protective perioperative mechanical ventilation

Hemmes, S.N.T.

Publication date

2015

Document Version

Final published version

Link to publication

Citation for published version (APA):

Hemmes, S. N. T. (2015). Lung-protective perioperative mechanical ventilation.

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Lung-protective perioperative

mechanical ventilation

Beyond the dangers of high tidals,

on the perils of PEEP

Sabrine N.T. Hemmes

U I T N O D I G I N G

mechanical ventilation

Beyond the dangers of high tidals,

on the perils of PEEP

CONTENTS

Appendices

General introduction and

outline of the thesis

Prevention of postoperative pulmonary complications

Tidal volumes

Positive end–expiratory pressure

Oxygen fractions

Aims of this thesis

Outline of this thesis

References

Intraoperative Ventilatory Strategies

to Prevent Postoperative Pulmonary

Complications – a Metaanalysis

Abstract

Introduction

Methods

Results

Discussion