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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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Intraoperative Protective Mechanical
Ventilation for Prevention of Postoperative
Pulmonary Complications
A Comprehensive Review of the Role of
Tidal Volume, Positive End-Expiratory
Pressure and Lung Recruitment
Manoeuvres
Güldner A, Kiss T, Serpa Neto A, Hemmes SNT, Canet J, Spieth PM, Rocco PRM, Schultz MJ, Pelosi P, Gama de Abreu M.
40
Abstract
Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality following major surgery. Intraoperative lung-protective mechanical ventilation has the potential to reduce the incidence of postoperative pulmonary complications. This review discusses the relevant literature on definition of and methods to predict occurrence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis to the non-injured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure and recruitment manoeuvres. The authors propose an algorithm for protective intraoperative mechanical ventilation based upon evidence from recent randomized clinical trials.
Ch apt er 3 41
Introduction
Postoperative pulmonary complications (PPCs) can have an important impact on the morbidity and mortality of patients who need major surgery.1 Approximately 5% of patients undergoing
general surgery will develop a PPC and one of five patients who developed a PPC die within 30 days of surgery.1 Furthermore, the number of PPCs is strongly associated with postoperative
length of stay and short-term and long-term mortality.1,2
There is growing evidence that intraoperative lung-protective mechanical ventilation using low tidal volumes, with or without high levels of positive end–expiratory pressure (PEEP) and recruitment manoeuvres, prevents PPCs compared to mechanical ventilation with high tidal volumes and low levels of PEEP without recruitment maneuvers.3-6
In the present article, we review the definition of and methods to predict PPCs, the patho-physiology of ventilator-induced lung injury (VILI) with emphasis on the non-injured lung, and ventilation strategies to minimize PPCs. To identify the most recent evidence from the literature on randomized clinical trials (RCTs) addressing intraoperative mechanical ventilation and non-clinical as well as non-clinical postoperative outcome measures, we conducted a MEDLINE review using the following search terms: (‘lower tidal volume’ OR ‘low tidal volume’ OR ‘protective ventilation’ OR ‘recruitment manoeuvres’ OR ‘PEEP’ OR ‘positive end expiratory pressure’). Retrieved articles, and cross–referenced studies from those articles, were screened for pertinent information.
Definition and prediction of postoperative pulmonary
complications
Summary of current definitions
PPCs are usually presented as a composite, which then includes possible fatal and non-fatal respiratory events of new onset occurring in the postoperative period. Currently, there is no agreement about which of these events should be considered as PPC, for example respiratory failure, lung injury, pneumonia, prolonged or unplanned mechanical ventilation or intubation, hypoxemia, atelectasis, bronchospasm, pleural effusion, pneumothorax, ventilatory depression, and aspiration pneumonitis.7,8 From a clinical standpoint, it is worthwhile to present PPCs as a
composite, because any of these events alone or their associations has a significant impact on the postoperative outcome,1 using different definitions. However, it is clear that these events
can have different pathophysiologic mechanisms. For this reason, some studies have focused on single events, mainly respiratory failure9 and pneumonia.10
PPCs, to be considered as such, must be related to anesthesia and/or surgery. Furthermore, the time frame must be well defined. Usually, an event is only considered as PPC if it develops within 5 to 7 days after surgery.8,11
42
Prediction of Postoperative Pulmonary Complications
Prediction of PPCs, or any of the single postoperative respiratory events that is part of that composite, can be useful to plan perioperative strategies aiming at their prevention, and also to reduce health system costs.12 First, the risk factors associated with the development of PPCs must
be identified. In 2006, the American College of Physicians published a systematic review of the literature listing a number of risk factors for PPCs according to their respective levels of evidence.13
In recent years, that list has been expanded to include other factors found to increase the risk of PPCs. Table 1 depicts risk factors associated with PPCs according to the current literature. Approximately 50% of the risk for PPCs are attributable to the patient’s health conditions, while the other 50% are related to the surgical procedure and the anaesthetic management itself.1
Table 1. Risk factors for postoperative pulmonary complications
Patient characteristics Preoperative testing Surgery Anaesthetic management
Age Low albumin Open thoracic surgery General anesthesia Male sex Low SpO2 (≤ 95%) Cardiac surgery High respiratory driving pressure (≥ 13 cmH
2O)
ASA class ≥ 3 Anaemia (Hb < 10 g/dL) Open upper abdominal surgery High inspiratory oxygen fraction Previous respiratory
infection Major vascular surgery High volume of crystalloid administration Functional dependency Neurosurgery Red blood cell transfusion Congestive heart failure Urology Residual neuromuscular blockade COPD Duration of surgery > 2h Nasogastric tube use
Smoking Emergent surgery
Renal failure
Gastroesophageal reflux disease
Weight loss
ASA, American Society of Anesthesiologists; COPD, chronic obstructive pulmonary disease; Hb, haemoglobin concentration; PPCs, postoperative pulmonary complications; SpO2, oxygensaturation as measured by pulse oximetry. Respiratory driving
pressure, defined as inspiratory plateau airway pressure minus positive end-expiratory pressure
Based on risk factors, different scores have been developed that have the potential to predict the occurrence of PPCs,6,14-16 as shown in table 2. However, their applicability may be limited
since they were derived from restricted settings,16 retrospective databases,15 or only validated
for specific PPCs.6,14 The Assess Respiratory RIsk in Surgical Patients in CATalonia (ARISCAT) study
was conducted in a general surgical population of Catalonia, Spain.1 After a multivariate analysis,
Ch
apt
er
3
43
a clinically relevant predictive capability (c-statistic, 0.90). Recently, the ARISCAT score was externally validated in a large European surgical sample (the Prospective Evaluation of a RIsk Score for Postoperative Pulmonary COmPlications in Europe, PERISCOPE study).2 Although differences
in the performance of the ARISCAT score have been observed between European geographic areas, the score was able to discriminate three levels of PPCs risk (low, intermediate and high). Thus, at present, the ARISCAT score may represent the most valuable tool for predicting PPCs across different countries and surgical populations.
Putative mechanisms of ventilator-induced lung injury
The coexistence of closed, recruitable and already overdistended alveolar regions makes the lung vulnerable to detrimental effects of mechanical stress and strain induced by mechanical ventilation.17,18 The physical forces in some alveolar regions may exceed the elastic properties
of the lungs although gross measurements of airway pressures or lung mechanics as usually monitored under anesthesia still suggest mechanical ventilation is in a “safe” zone.19,20 Several
mechanisms have been postulated to describe the development of VILI.21 Increased airway
pressure (barotrauma) or the application of high tidal volumes (volutrauma) may cause damage or disruption of alveolar epithelial cells, by generating transpulmonary pressures (stress) that exceed the elastic properties of the lung parenchyma above its resting volume (strain).22,23 It has been
demonstrated that the duration of mechanical stress defined as the stress versus time product affects the development of pulmonary inflammatory response.24 While high stress versus time
product increased the gene expression of biological markers associated with inflammation and alveolar epithelial cell injury and low stress versus time product increased the molecular markers of endothelial cell damage, balanced stress versus time product as defined by an inspiratory to expiratory time ratio of 1:1 was associated with attenuated lung damage.24 Especially in the
presence of atelectasis, mechanical ventilation may cause damage by repetitive collapse and reopening of alveolar units, a phenomenon known as atelectrauma.25 All three mechanisms,
namely barotrauma, volutrauma and atelectrauma may affect alveolar as well as vascular epithelial and endothelial cells26,27 as well as promote extracellular matrix fragmentation.28,29
The extracellular matrix of the lung parenchyma seems to be particularly sensitive to stress from mechanical ventilation, as illustrated in figure 1. Initially, the proteoglycans on the endothelial side and between the endothelial and epithelial lines undergo damage dependent on tidal volume,28 as well as breathing pattern.29 The mechanical fragmentation of the extracellular
matrix promotes interstitial oedema and activation of metalloproteinases, further damaging the extracellular matrix itself. In a second step, fragments of the extracellular matrix can promote activation of inflammatory mediators.30,31 Furthermore, the damage of the extracellular matrix
induced by mechanical ventilation might be exacerbated by fluid load,32 which is not uncommon
during general anesthesia. However, fluid overload seems to minimize the inflammatory response, likely by dilution of extracellular matrix fragments or changes in their structure, thereby down regulating the local inflammatory response.32 This suggests that: 1) injurious mechanical
ventilation makes the lung more susceptible to further insults; 2) in previously healthy lungs, VILI can be induced without early increase in inflammatory mediators.
44 Ta bl e 2 . S co res fo r p red ictio n o f p os to per ativ e p ul mo na ry c omp lic atio ns Re fer en ce/ Yea r pu bl is hed St ud y d es ign Pa tien t p op ul atio n N umb er o f pa tien ts Sc or e a cr on ym Sc ori ng s ys tem Cu t-o ff Qu al ity o f pr ed ictio n Pr ed ictio n o f g en er al p os to per ativ e p ul mo na ry c omp lic atio ns Ca ne t e t. a l., 20 10 1 Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s unde rg oing nonob st et ric sur gic al pr oc edur es unde r g ene ra l, ne ur axia l, or re gional ane st he sia 2, 46 4 o ve ra ll 1, 62 4 de riv ation 83 7 va lida tion 3 pa tie nt s w ith m issing da ta for tw o pa ra m et er s re le va nt for the sc or e (SpO 2 +r espir at or y in fe ction dur ing la st m on th) AR IS CA T Asse ss Re spir at or y Risk in Sur gic al Pa tie nt s in Ca talonia Age 51–8 0 >8 0 SpO 2 % 91 –9 5 <9 0 Re spir at or y in fe ction <3 0 da ys Pr eope ra tiv e anae m ia (Hb <1 0 g/dl) Sur gic al inc ision: Pe riphe ra l U ppe r a bdom ina l In tr at hor ac ic Dur ation of sur ge ry : ≤2 h >2 -3 >3 Em er ge nc y pr oc edur e 3 16 8 24 17 11 1 15 24 1 16 23 8 Le vel /P oi nt /R at e o f PPC lo w /< 26 /1 .6 % ; m edium /2 6-4 4/ 13 .3 % hig h/≥4 5/4 2.1 % (v alida tion sub sa m ple ) PP C: Re spir at or y in fe ction, re spir at or y f ailur e, ple ur al effusion, a te le ct asis, pne um ot hor ax, br onc hospa sm , a spir ation pne um onitis De riv ation cohor t AU C: 0 .8 9 Va lida tion cohor t AU C: 0 .8 4 M az o e t. a l. 20 14 2 (V alida tion of A RI SCA T sc or e fr om Ca ne t e t. al., 2 01 0 1 in a lar ge r, in te rna tiona l, m ultic en te r cohor t) Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s unde rg oing nonob st et ric sur gic al pr oc edur es unde r g ene ra l, ne ur axia l, or ple xus bloc k ane st he sia 5, 09 9 AR IS CA T Asse ss Re spir at or y Risk in Sur gic al Pa tie nt s in Ca ta lonia se e a bo ve Le vel /P oi nt /Pr ed ict ed / Ob ser ved R at e o f PPC lo w /< 26 /0 .8 7% / 3 .3 9% m edium /2 6-4 4/ 7.8 2% /1 2.9 6% hig h/≥4 5/3 8.1 3% / 3 8.0 1% AU C: 0 .8 0
Ch apt er 3 45 Ta bl e 2 . S co res fo r p red ictio n o f p os to per ativ e p ul mo na ry c omp lic atio ns Re fer en ce/ Yea r pu bl is hed St ud y d es ign Pa tien t p op ul atio n N umb er o f pa tien ts Sc or e a cr on ym Sc ori ng s ys tem Cu t-o ff Qu al ity o f pr ed ictio n Pr ed ictio n o f g en er al p os to per ativ e p ul mo na ry c omp lic atio ns Ca ne t e t. a l., 20 10 1 Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s unde rg oing nonob st et ric sur gic al pr oc edur es unde r g ene ra l, ne ur axia l, or re gional ane st he sia 2, 46 4 o ve ra ll 1, 62 4 de riv ation 83 7 va lida tion 3 pa tie nt s w ith m issing da ta for tw o pa ra m et er s re le va nt for the sc or e (SpO 2 +r espir at or y in fe ction dur ing la st m on th) AR IS CA T Asse ss Re spir at or y Risk in Sur gic al Pa tie nt s in Ca talonia Age 51–8 0 >8 0 SpO 2 % 91 –9 5 <9 0 Re spir at or y in fe ction <3 0 da ys Pr eope ra tiv e anae m ia (Hb <1 0 g/dl) Sur gic al inc ision: Pe riphe ra l U ppe r a bdom ina l In tr at hor ac ic Dur ation of sur ge ry : ≤2 h >2 -3 >3 Em er ge nc y pr oc edur e 3 16 8 24 17 11 1 15 24 1 16 23 8 Le vel /P oi nt /R at e o f PPC lo w /< 26 /1 .6 % ; m edium /2 6-4 4/ 13 .3 % hig h/≥4 5/4 2.1 % (v alida tion sub sa m ple ) PP C: Re spir at or y in fe ction, re spir at or y f ailur e, ple ur al effusion, a te le ct asis, pne um ot hor ax, br onc hospa sm , a spir ation pne um onitis De riv ation cohor t AU C: 0 .8 9 Va lida tion cohor t AU C: 0 .8 4 M az o e t. a l. 20 14 2 (V alida tion of A RI SCA T sc or e fr om Ca ne t e t. al., 2 01 0 1 in a lar ge r, in te rna tiona l, m ultic en te r cohor t) Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s unde rg oing nonob st et ric sur gic al pr oc edur es unde r g ene ra l, ne ur axia l, or ple xus bloc k ane st he sia 5, 09 9 AR IS CA T Asse ss Re spir at or y Risk in Sur gic al Pa tie nt s in Ca ta lonia se e a bo ve Le vel /P oi nt /Pr ed ict ed / Ob ser ved R at e o f PPC lo w /< 26 /0 .8 7% / 3 .3 9% m edium /2 6-4 4/ 7.8 2% /1 2.9 6% hig h/≥4 5/3 8.1 3% / 3 8.0 1% AU C: 0 .8 0 Pr ed ictio n o f s el ect ed p os to per ativ e p ul mo na ry c omp lic atio ns Johnson e t. al. 2 00 7 14 (R ee va lua te d in a br oade r cohor t fr om Ar oz ulla h et . al. 2 00 0 9) Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s unde rg oing m ajor ge ne ra l or v asc ula r pr oc edur es pe rf or m ed unde r ge ne ra l, spina l, or epidur al a ne st he sia 90 ,0 55 de riv ation 89 ,9 48 v alida tion RR I Re spir at or y fa ilur e R isk Inde x Ty pe of sur ge ry In te gum en ta ry Re spir at or y a nd he m ic He ar t Ane ur ysm M out h, pa la te St om ac h, in te stine s Endoc rine Pr edisposing fa ct or s M ale se x Ag e 4 0-6 5 Ag e >6 5 AS A c la ss 3 AS A c la ss 4 -5 W or k R VU 1 0-1 7 W or k R VU >1 7 Em er ge nc y Se psis His tor y of se ve re COP D Asc ite s Dy spnoe a Im pa ire d se nsor ium >2 a lc oholic dr ink s/d in 2 w k Ble eding disor de rs W eig ht loss > 10 % Ac ut e r ena l f ailur e Cong es tiv e he ar t fa ilur e Sm ok er St rok e W ound class ot he r tha n c le an Pr eope ra tiv e album in <3 .5 Cr ea tinine >1 .5 Pr eope ra tiv e 1 3 2 2 7 2 2 1 2 2 3 5 2 4 2 2 2 2 2 1 1 1 1 1 2 1 1 1 1 1 1 2 Le vel /P oi nt /Pr ed ict ed / Ob ser ved o f Pr ob ab ili ty of PR F lo w /< 8/0 .2 % /0 .0 8% m edium /8 -1 2/1 .0 % /0 .8 4% hig h/ > 12 /6 .6 % /6 .7 5% PR F: M ec hanic al v en tila tion for >4 8h or unpla nne d re in tuba tion De riv ation cohor t AU C: 0 .8 56 Va lida tion cohor t AU C: 0 .8 63
46 Re fer en ce/ Yea r pu bl is hed St ud y d es ign Pa tien t p op ul atio n N umb er o f pa tien ts Sc or e a cr on ym Sc ori ng s ys tem Cu t-o ff Qu al ity o f pr ed ictio n bilir ubin >1 .0 W hit e blood c oun t <2 .5 / > 10 Pr eope ra tiv e se rum sodium > 14 5 Pla te le t c oun t <1 50 SG O T >4 0 Ha em at oc rit <3 8 1 1 2 1 1 Br ue ck m ann et . al. 2 01 3 15 Re tr ospe ctiv e sing le -c en tr e, ob se rv ationa l cohor t s tudy Ca se s w ith a sur gic al pr oc edur e if t he a dult pa tie nt w as in tuba te d at the be ginning and e xt uba te d at the e nd of t he pr oc edur e 33 ,7 69 o ve ra ll 16 ,8 85 de riv ation 16 ,8 84 v alida tion SPOR C Sc or e for Pr edic tion of Pos tope ra tiv e Re spir at or y Com plic ations AS A sc or e ≥3 Em er ge nc y pr oc edur e Hig h-r isk se rv ic e Cong es tiv e he ar t fa ilur e Chr onic pulm onar y dise ase 3 3 2 2 1 Sc or e V al ues /Pr ob ab ili ty o f Rei nt ub atio n 0/0 .1 2% 1–3 /0 .4 5% 4–6 /1 .6 4% 7–1 1/5 .8 6% (v alida tion sub sa m ple ) De riv ation cohor t AU C: 0 .8 1 Va lida tion cohor t AU C: 0 .8 1 Pr ed ictio n o f A LI /A RDS Ga jic e t. a l. 20 11 6 (sim ilar to Tr illo-A lv ar ez et . al. 2 01 1 12 6, but use d a la rg er , m ultic en te r cohor t) Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s w ith one or m or e ALI risk fa ct or s, inc luding se psis, shoc k, pa nc re atitis, pne um onia , aspir ation, hig h-r isk tr aum a, or hig h-r isk sur ge ry 5, 58 4 o ve ra ll 2, 50 0 de riv ation 3, 08 4 v alida tion LI PS Lung Injur y Pr edic tion Sc or e Pr edisposing Conditions Shoc k Aspir ation Se psis Pne um onia Hig h-r isk sur ge ry Or thopae dic spine Ac ut e a bdom en Ca rdiac Aor tic v asc ula r if e m er ge nc y sur ge ry Hig h r isk tr aum a Tr aum atic br ain injur y Sm ok e inha la tion N ea r dr ow ning Lung c on tusion M ultiple fr ac tur es Risk m odifie rs Alc ohol abuse Obe sit y (B M I >3 0) Hy poa lbum ine m ia Che m ot he ra py FI O2 >0 .3 5 (>4 L/m in) Ta ch ypne a (R R>3 0) SpO 2 <9 5% Ac idosis (pH <7 .3 5) Dia be te s m ellit us, if se ptic 2 2 1 1.5 1 2 2.5 3.5 +1.5 2 2 2 1.5 1.5 1 1 1 1 2 1.5 1 1.5 -1 >4 Cut -off f or de ve lopm en t of ALI / A RDS Com bine d AU C: 0 .8 0 Se nsitiv ity : 0.6 9 Spe cific ity : 0.7 8 Kor e t. a l. 20 14 16 (sim ilar to Kor e t. a l. 20 11 12 7, but use d a lar ge r, m ultic en te r cohor t; se conda ry analy sis of Ga jic e t. a l. 20 11 6) Se conda ry analy sis of a pr ospe ctiv e, m ultic en te r cohor t s tudy Adult pa tie nt s pr ese nting w ith one or m or e ALI risk fa ct or s, inc luding se psis, shoc k, pa nc re atitis, pne um onia , aspir ation, hig h-risk tr aum a, or hig h-r isk sur ge ry and unde rg oing a sur gic al pr oc edur e 1, 56 2 SL IP 2 Sur gic al Lung Injur y Pr edic tion 2 Sur gic al pr oc edur e Hig h-r isk c ar diac sur ge ry Hig h-r isk aor tic va sc ula r sur ge ry Em er ge nc y sur ge ry Ba se line he alt h st at us Se psis Cir rhosis Adm ission sour ce ot he r t han hom e Ph ysiolog ic m ar ke rs of ac ut e illne ss Re spir at or y r at e 20 –2 9 Re spir at or y r at e ≥ 30 FI O >32 5% SpO 2 <9 5% 7 11 10 10 20 9 7 14 13 5 ≥1 9 Cut -off f or de ve lopm en t of AR DS AU C: 0 .8 4 Se nsitiv ity : 0.8 2 Spe cific ity : 0.7 5 ALI , a cut e lung injur y; A RDS, a cut e re spir at or y dis tr ess sy ndr om e; A SA , A m er ic an Soc ie ty of Ane st he siolog ist s c lassific ation; A U C, a re a unde r t he c ur ve ; B M I, body m ass inde x; C OP D, chr onic ob st ruc tiv e pulm ona ry dise ase ; FI O2 , fr ac tion of inspir ed oxy ge n; H b, ha em og lobin; P PC , pos tope ra tiv e pulm ona ry c om plic ation; P RF , pos tope ra tiv e re spir at or y fa ilur e, R VU , re la tiv e v alue unit s (a m ea sur e of sur gic al c om ple xit y); SG O T, se rum g lut am ic -o xaloac etic tr ansa m ina se ; SpO 2 , o xy ge n sa tur ation a s m ea sur ed b y pulse o xim et ry
Ch apt er 3 47 Re fer en ce/ Yea r pu bl is hed St ud y d es ign Pa tien t p op ul atio n N umb er o f pa tien ts Sc or e a cr on ym Sc ori ng s ys tem Cu t-o ff Qu al ity o f pr ed ictio n bilir ubin >1 .0 W hit e blood c oun t <2 .5 / > 10 Pr eope ra tiv e se rum sodium > 14 5 Pla te le t c oun t <1 50 SG O T >4 0 Ha em at oc rit <3 8 1 1 2 1 1 Br ue ck m ann et . al. 2 01 3 15 Re tr ospe ctiv e sing le -c en tr e, ob se rv ationa l cohor t s tudy Ca se s w ith a sur gic al pr oc edur e if t he a dult pa tie nt w as in tuba te d at the be ginning and e xt uba te d at the e nd of t he pr oc edur e 33 ,7 69 o ve ra ll 16 ,8 85 de riv ation 16 ,8 84 v alida tion SPOR C Sc or e for Pr edic tion of Pos tope ra tiv e Re spir at or y Com plic ations AS A sc or e ≥3 Em er ge nc y pr oc edur e Hig h-r isk se rv ic e Cong es tiv e he ar t fa ilur e Chr onic pulm onar y dise ase 3 3 2 2 1 Sc or e V al ues /Pr ob ab ili ty o f Rei nt ub atio n 0/0 .1 2% 1–3 /0 .4 5% 4–6 /1 .6 4% 7–1 1/5 .8 6% (v alida tion sub sa m ple ) De riv ation cohor t AU C: 0 .8 1 Va lida tion cohor t AU C: 0 .8 1 Pr ed ictio n o f A LI /A RDS Ga jic e t. a l. 20 11 6 (sim ilar to Tr illo-A lv ar ez et . al. 2 01 1 12 6, but use d a la rg er , m ultic en te r cohor t) Pr ospe ctiv e, m ultic en te r, ob se rv ationa l cohor t s tudy Adult pa tie nt s w ith one or m or e ALI risk fa ct or s, inc luding se psis, shoc k, pa nc re atitis, pne um onia , aspir ation, hig h-r isk tr aum a, or hig h-r isk sur ge ry 5, 58 4 o ve ra ll 2, 50 0 de riv ation 3, 08 4 v alida tion LI PS Lung Injur y Pr edic tion Sc or e Pr edisposing Conditions Shoc k Aspir ation Se psis Pne um onia Hig h-r isk sur ge ry Or thopae dic spine Ac ut e a bdom en Ca rdiac Aor tic v asc ula r if e m er ge nc y sur ge ry Hig h r isk tr aum a Tr aum atic br ain injur y Sm ok e inha la tion N ea r dr ow ning Lung c on tusion M ultiple fr ac tur es Risk m odifie rs Alc ohol abuse Obe sit y (B M I >3 0) Hy poa lbum ine m ia Che m ot he ra py FI O2 >0 .3 5 (>4 L/m in) Ta ch ypne a (R R>3 0) SpO 2 <9 5% Ac idosis (pH <7 .3 5) Dia be te s m ellit us, if se ptic 2 2 1 1.5 1 2 2.5 3.5 +1.5 2 2 2 1.5 1.5 1 1 1 1 2 1.5 1 1.5 -1 >4 Cut -off f or de ve lopm en t of ALI / A RDS Com bine d AU C: 0 .8 0 Se nsitiv ity : 0.6 9 Spe cific ity : 0.7 8 Kor e t. a l. 20 14 16 (sim ilar to Kor e t. a l. 20 11 12 7, but use d a lar ge r, m ultic en te r cohor t; se conda ry analy sis of Ga jic e t. a l. 20 11 6) Se conda ry analy sis of a pr ospe ctiv e, m ultic en te r cohor t s tudy Adult pa tie nt s pr ese nting w ith one or m or e ALI risk fa ct or s, inc luding se psis, shoc k, pa nc re atitis, pne um onia , aspir ation, hig h-risk tr aum a, or hig h-r isk sur ge ry and unde rg oing a sur gic al pr oc edur e 1, 56 2 SL IP 2 Sur gic al Lung Injur y Pr edic tion 2 Sur gic al pr oc edur e Hig h-r isk c ar diac sur ge ry Hig h-r isk aor tic va sc ula r sur ge ry Em er ge nc y sur ge ry Ba se line he alt h st at us Se psis Cir rhosis Adm ission sour ce ot he r t han hom e Ph ysiolog ic m ar ke rs of ac ut e illne ss Re spir at or y r at e 20 –2 9 Re spir at or y r at e ≥ 30 FI O2 >3 5% SpO 2 <9 5% 7 11 10 10 20 9 7 14 13 5 ≥1 9 Cut -off f or de ve lopm en t of AR DS AU C: 0 .8 4 Se nsitiv ity : 0.8 2 Spe cific ity : 0.7 5 ALI , a cut e lung injur y; A RDS, a cut e re spir at or y dis tr ess sy ndr om e; A SA , A m er ic an Soc ie ty of Ane st he siolog ist s c lassific ation; A U C, a re a unde r t he c ur ve ; B M I, body m ass inde x; C OP D, chr onic ob st ruc tiv e pulm ona ry dise ase ; FI O2 , fr ac tion of inspir ed oxy ge n; H b, ha em og lobin; P PC , pos tope ra tiv e pulm ona ry c om plic ation; P RF , pos tope ra tiv e re spir at or y fa ilur e, R VU , re la tiv e v alue unit s (a m ea sur e of sur gic al c om ple xit y); SG O T, se rum g lut am ic -o xaloac etic tr ansa m ina se ; SpO 2 , o xy ge n sa tur ation a s m ea sur ed b y pulse o xim et ry
48
At the cellular level, physical stimuli are transformed into chemical signals, e.g. pro- and anti-inflammatory mediators by means of direct cell injury or indirect activation of cellular signalling pathways. This process is known as “mechanotransduction”.33 Some mediators may promote local
effects such as pro-apoptotic or pro-fibrotic actions, while others act as homing molecules recruiting local and remote immune cell populations (e.g. neutrophils and macrophages).34 These local effects
as well as their immunological consequences are summarized by the term “biotrauma”.35
Besides the extracellular matrix, both the endothelial and the epithelial compartment of the alveolar-capillary unit are affected by stress and strain originating from mechanical ventilation. In the endothelium, high stress can lead to direct cell breaks, resulting in capillary stress failure.36,37 Furthermore, mechanical stress as well as inflammatory stimuli (i.e. TNF alpha)
may trigger contractions of the cytoskeleton 38 resulting in disruption of adherence junctions,39
which increase endothelial permeability and contribute to oedema formation. Similar to the pulmonary endothelium, mechanical stress and strain increase the permeability of the alveolar epithelium,40 a phenomenon found during ventilation at high,41 as well as low42 lung volumes.
Additionally, low lung volume ventilation can lead to repetitive collapse and reopening of lung, affecting the epithelium of small airways, yielding plasma membrane disruption,43 as well as
epithelial necrosis and sloughing.44
Figure 1. Alterations of the extracellular matrix in lungs during mechanical ventilation and fluid administration
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Alveolar fluid clearance is essential to maintain intra-alveolar fluid homeostasis, which is usually compromised during VILI. Whereas ventilation with high tidal volumes directly decreases Na,K-adenosintriphosphatase activity,45 ventilation at low lung volumes may indirectly impair fluid
clearance due to hypoxia following increased alveolar collapse.46
Impairment of barrier function of the endothelium and epithelium, as well as of fluid clearance leads to the development of interstitial and alveolar oedema, which subsequently causes surfactant dysfunction, and impairs lungs elastic and resistive properties.47 Dysfunction of the
surfactant system makes the lung susceptible to alveolar collapse contributing to deterioration of lung mechanics and impairing pulmonary host defense.48
Although most evidence of gross structural alterations of endothelium and epithelium induced by mechanical ventilation originates from in vitro investigations of cultured cells or in vivo investigations in acute lung injury models,49 ventilation applying clinically relevant settings in
non-injured lungs can affect the alveolar-capillary barrier function, especially in the presence of independent inflammatory triggers, making mechanical ventilation a powerful hit in presence of systemic inflammation.27
Due to the disturbed integrity of the alveolar-capillary barrier function and consecutive systemic translocation of pathogens or inflammatory mediators, VILI may lead to a systemic inflammatory response affecting not only the lungs, but distal organs as well.50
Lung inhomogeneity, e.g. due to atelectasis formation, is a major contributing factor to the development of VILI. However, most experimental evidence is derived from acute lung injury models. Although their basic pathogenic mechanisms may be similar, the magnitude and time course of atelectasis formation in acute lung injury may be very different from those of atelectasis occurring during anesthesia and relatively short-term intraoperative mechanical ventilation. Resorption of alveolar gas51,52 and compression of lung structures53-56 may lead to atelectasis during
short-term mechanical ventilation in non-injured lungs, whereby the former might play a more important role.
In a porcine model of experimental pneumonia, both exogenous surfactant administration and ventilation according to the open lung approach attenuated bacterial growth and systemic translocation by minimizing alveolar collapse and atelectasis formation.57 In a similar model of
experimental pneumonia in mechanically ventilated piglets, bacterial translocation was lowest with individually tailored PEEP levels, whereas low and high PEEP promoted bacterial translocation.58
In isolated non-perfused mouse lungs, both an “open lung approach” (tidal volume 6 mL/kg, recruitment manoeuvres and PEEP of 14 - 16 cmH2O) as well as a “lung rest strategy” (tidal
volume of 6 ml/kg, PEEP of 8 - 10 cmH2O, no recruitment manoeuvres) were associated with
reduced pulmonary inflammatory response and improved respiratory mechanics compared to injurious mechanical ventilation (tidal volume of 20 ml/kg, PEEP of 0 cmH2O).59 Interestingly, the
“lung rest strategy” was associated with less apoptosis but more ultrastructural cell damage, most likely due to increased activation of mitogen-activated protein kinase pathways as compared to the “open lung strategy”.59
50
In healthy mice, mechanical ventilation with a tidal volume of 8 ml/kg and PEEP of 4 cmH2O induced
a reversible increase in plasma and lung tissue cytokines as well as increased leukocyte influx, but the integrity of the lung tissue was preserved.60 In another investigation, even least-injurious
ventilator settings were able to induce VILI in the absence of a previous pulmonary insult in mice.61
Of note, the deleterious effects of mechanical ventilation in non-injured lungs are partly dependent on its duration.62 However, an experimental study demonstrated that large tidal volumes had only
minor if any deleterious effects on lungs, despite prolonged mechanical ventilation.23 Possibly, this
is explained by the lack of a previous inflammatory insult, as for example surgery. In fact, systemic inflammation may prime the lungs to injury by mechanical ventilation.63
Mechanical ventilation strategies to protect lungs during
surgery
Atelectasis and intraoperative mechanical ventilation
Atelectasis develops in as much as 90% of patients undergoing general anesthesia,64 and
can persist to different degrees after surgery, also surrounding pleura effusion, as illustrated in figure 2. The area of non-aerated lung tissue near to the diaphragm varies depending on the surgical procedure and patient characteristics, but has been estimated in the range of 3-6 %65-67
to 20-25%,64 and even higher if calculated as amount of tissue.
Different mechanisms have been postulated to favour atelectasis formation during anesthesia, including: 1) collapse of small airways;68-70 2) compression of lung structures;53-56 3) absorption
Figure 2. Magnetic resonance imaging (MRI) scans of lungs of three patients before and on the first day after open abdominal surgery
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of intra-alveolar gas content;51,52 and 4) impairment of lung surfactant function.71 Mechanical
ventilation strategies for general anesthesia have been importantly influenced by the progressive decrease in oxygenation and compliance.72 Tidal volumes up to 15 mL/kg of predicted body
weight were advocated to increase the end-expiratory lung volume (EELV) and counteract atelectasis in the intraoperative period.72 Provided there is no contraindication, PEEP and lung
recruitment manoeuvres may also contribute to revert or prevent the loss of EELV and closure of small airways during anesthesia.
Tidal volumes for intraoperative protective ventilation
Driven by clinical and experimental studies, tidal volumes during mechanical ventilation have been importantly reduced in patients suffering from the acute respiratory distress syndrome (ARDS) in order to limit lung overdistension.73 Influenced by this practice in intensive care
unit patients, a similar trend was observed in the operation room. As reported by different investigators,74,75 average tidal volumes in the range of 6 to 9 mL/kg of predicted body weight have
gained broad acceptance for non-injured lungs, in spite of experimental23,76 and clinical data 77-79 suggest that higher values are not associated with increased lung damage or inflammation.
Furthermore, anaesthesiologists have consistently reduced tidal volumes also during one-lung ventilation. Whereas values as high as 10 mL/kg have been used in the past, experimental80,81
and clinical82-85 studies have suggested that tidal volumes of approximately 4 to 5 mL/kg may be
more appropriate for lung protection, while still allowing adequate gas exchange. Furthermore, a small RCT showed that atelectasis did not increase significantly with low tidal volume without PEEP from induction of anesthesia until the end of surgery.65 This is also supported by the fact
that mechanical ventilation with low tidal volume and PEEP did not result in a progressive deterioration of the respiratory system compliance and gas exchange during open abdominal surgery in a larger RCT.86 It must be kept in mind that “set” and “actual” (i.e. delivered) tidal
volumes can differ substantially,87 and that settings should be adjusted judiciously.
Positive end-expiratory pressure for intraoperative protective ventilation
Clinical studies have shown that a PEEP of 10 cmH2O is required to reduce or eliminate
atelectasis,67,88,89 improve compliance without increasing deadspace,90,91 and maintain end-expiratory
lung volume during general anesthesia in both non-obese and obese patients.92 Another study in
normal subjects showed that PEEP of 10 cmH2O increased lung volume, but did not improve the
respiratory function compared to PEEP of 0 cmH2O.54 Certainly, the level of PEEP should be chosen
according to the patient’s particular characteristics, the particularities of the surgical approach, and patient positioning. Several targets have been proposed for a more individual titration of PEEP during general anesthesia, including the following: 1) oxygenation,93 also combined with
dead space,90 or EELV91 ; 2) mechanical properties of the respiratory system94 ; and 3) distribution
of ventilation using electric impedance tomography.95,96 However, none of these has been shown
to improve patient outcome.
Although controversial, an alternative approach for PEEP during general anesthesia is the so-called “intraoperative permissive atelectasis”, when PEEP is kept relatively low and recruitment manoeuvres are waived. This concept aims at reducing the static stress in lungs, which is closely related to the mean airway pressure, assuming that collapsed lung tissue is protected against injury from mechanical ventilation (figure 3). Intraoperative permissive atelectasis may be limited
52
Figure 3. Effects of high and low tidal volumes (VT) at end-inspiration and end-expiration
with low and high PEEP during general anesthesia
by deterioration in oxygenation, which could require higher inspiratory oxygen fractions. Also, shear stress may occur at the interface between collapsed and open tissue,18 likely resulting
in lung damage and inflammation, even in presence of low global stress.97 Theoretically,
intraoperative low PEEP could increase the incidence and the amount of atelectasis even in the postoperative period, resulting in further PPCs. A recent large retrospective study investigating the association between intraoperative mechanical ventilator settings and outcomes suggested that the use of “minimal” PEEP (2.2 to 5 cmH2O) combined with low tidal volumes (6 to 8
mL/kg) is associated with increased risk of 30-day mortality.77 However, a large international
multicenter RCT challenged the concept that “minimal” PEEP combined with low tidal volumes in the intraoperative period is harmful.86 Also in elderly patients undergoing major open abdominal
surgery, a strategy consisting of low tidal volume, PEEP 12 cmH2O and recruitment manoeuvres
increased the PaO2 intraoperatively compared to a strategy with high tidal volume without PEEP,
but this effect was not maintained in the postoperative period.98 Even without recruitment
manoeuvres PEEP improved oxygenation during upper abdominal surgery compared to zero end-expiratory pressure, but again such effects were limited to the intraoperative period and did not prevent postoperative complications.99
Lung recruitment manoeuvres for intraoperative protective ventilation
PEEP is most effective for preserving respiratory function if preceded by a recruitment manoeuvre, which must overcome the opening pressures of up to 40 cmH2O in non-obese,100
and 40-50 cmH2O in obese patients,101 in the absence of lung injury. Recruitment manoeuvres
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Most commonly, such manoeuvres are performed by “bag squeezing” using the airway pressure-limiting valve of the anesthesia machine (figure 4A). However, recruitment manoeuvres are better controlled if performed during tidal ventilation, for example using a stepwise increase of PEEP, tidal volumes, or a combination of these (figure 4B). Provided there are no contraindications, the inspiratory plateau pressure as high as 40 cmH2O, are more likely to result in full recruitment.102
In anesthesia devices that allow pressure-controlled ventilation, recruitment manoeuvres can be conducted with a constant driving pressure of 15-20 cmH2O, and by increasing PEEP up to
20 cmH2O in steps of 5 cmH2O (30 to 60 s per step). After three to five breaths at a PEEP level
that allows achieving the target inspiratory pressure, PEEP and tidal volume are adjusted to the respective desired levels (figure 4C).
A
B
C
Figure 4. Illustrative fluctuation of airway pressure during three types of lung recruitment manoeuvres for intraoperative mechanical ventilation
54 Ta bl e 3 . R an do mi zed c on tr ol led tri al s u si ng n on cl in ic al p rima ry o ut co mes Re fer en ce/ Yea r pu bl is hed St ud y d es ign Pati ent po pu la tio n/ N umb er In ter ven tio n gr ou p( s) Co nt ro l gr ou p N on cl in ic al p rima ry o ut co mes Sec on da ry o ut co mes Th or aci c s ur ger y W rig ge e t a l. 20 04 78 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing m ajor thor ac ic sur ge ry n=3 4 (2 ex clude d) PV V: 6T m L/k g PEEP : 1 0 c m H2 O Paw Lim it 3 5 cm H2 O dur ing TL V a nd OL V n=1 5 CV V: 1T 2-1 5 m L/k g ZEEP P Limaw it 3 5 cm H2 O dur ing TL V a nd OL V n=1 7 In flam m at or y m edia tor s in pla sm a: no diff er enc es be tw ee n g roup s f or TN Fα, IL-1 , IL-6 , I L-8 , I L-1 0, IL-1 2 Ga s e xc ha ng e: no diff er enc es be tw ee n gr oup s Sc hilling e t a l. 20 05 82 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing ele ctiv e ope n thor ac ic sur ge ry n=3 2 PV V: 5T m L/k g dur ing TL V a nd OL V PEEP : 3 c m H2 O , TL V PEEP : 0 -2 c m H2 O , OL V Paw Lim it 3 0 cm H2 O n=1 6 CV V: 1T 0 m L/k g dur ing TL V a nd OL V PEEP : 3 c m H2 O , TL V PEEP : 0 -2 c m H2 O , OL V Paw Lim it 3 0 cm H2 O n=1 6 In flam m at or y m edia tor s in BA L: TN Fα and sI CA M lo w er dur ing PV No diff er enc es be tw ee n g roup s for c ell c oun t, P M N e las ta se , tot al pr ot ein, a lbum in, IL-8 , IL-1 0 Pa O2 /FI O2 : no diff er enc es be tw ee n gr oup s Pa CO2 : hig he r dur ing P V M ic he le t e t a l. 20 06 83 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing pla nne d esopha ge ct om y n=5 2 PV V: 9T m L/k g, TL V VT : 5 m L/k g OL V PEEP : 5 c m H2 O , TL V and OL V n=2 6 CV V: 9T m L/k g, TL V a nd OL V ZEEP , TL V a nd OL V n=2 6 In flam m at or y m edia tor s in pla sm a: IL-1 ß, IL-6 , I L-8 lo w er dur ing P V N o diff er enc es be tw ee n g roup s for TN Fα Pa O2 /FI O2 and Pa CO2 : hig he r dur ing P V EVL W I: lo w er dur ing P V Tim e t o e xt uba tion: shor te r dur ing P V Lin et a l. 2 00 8 10 3 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing esopha ge ct om y n=4 0 PV V: 1T 0 m L/k g, TL V VT : 5 -6 m L/k g OL V PEEP : 3 -5 c m H2 O , OL V n=2 0 CV V: 1T 0 m L/k g, TL V and OL V ZEEP , TL V a nd OL V n=2 0 In flam m at or y m edia tor s in pla sm a: IL-6 , I L-8 , lo w er dur ing PV Ppeak , Ppla t , a nd Raw : lo w er dur ing P V
Ch apt er 3 55 U nz ue ta e t al. 20 12 10 4 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing ele ctiv e ope n thor ac ot om y n=4 0 PV V: 8T m L/k g, TL V VT : 6 m L/k g OL V PEEP : 8 c m H2 O , TL V and OL V RM w ith s te pw ise PEEP / Paw inc re ase un til 2 0/4 0 c m H2 O be for e s ta rt of OL V n=2 0 CV V: 8T m L/k g, TL V VT : 6 m L/k g OL V PEEP : 8 c m H2 O , TL V a nd O LV no RM be for e s ta rt of OL V n=2 0 De ad spa ce : lo w er dur ing P V Pa O2 /FI O2 : hig he r dur ing P V Pa CO2 : lo w er dur ing P V Ca rd ia c su rg er y Kone r e t al. 20 04 10 5 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing ele ctiv e on-pum p cor ona ry a rt er y by pa ss g ra fting sur ge ry n=4 4 (1 ) P V V: 6T m L/k g PEEP : 5 c m H2 O n=1 5 (2 ) CV+P EEP V: 1T 0 m L/k g PEEP : 5 c m H2 O n=1 4 (3 ) CV+ZEEP VT : 1 0 m L/k g PEEP : 0 c m H2 O n=1 5 In flam m at or y m edia tor s in pla sm a: no diff er enc es be tw ee n g roup s f or TN Fα a nd IL-6 Pplat : lo w er dur ing P V com pa re d t o bot h CV gr oup s Shun t fr ac tion: lo w er dur ing P V c om pa re d to bot h CV+ ZEEP Pa O2 /FI O2 : hig he r dur ing v en tila tion w ith PEEP , (1 ) + (2 ) Zupa nc ic h e t al. 20 05 10 6 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing ele ctiv e on-pum p cor ona ry a rt er y by pa ss g ra fting sur ge ry n=4 0 PV V: 8T m L/k g PEEP : 1 0 c m H2 O n=2 0 CV V: 1T 0-1 2 m L/k g PEEP : 2 -3 c m H2 O n=2 0 In flam m at or y m edia tor s in pla sm a a nd B AL: IL-6 , I L-8 , lo w er dur ing P V in bot h. Pa CO2 : hig he r dur ing P V Re is M ira nda e t al. 2 00 5 93 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing ele ctiv e on-pum p cor ona ry a rt er y by pa ss g ra fting or v alv e sur ge ry n=6 2 (1 ) La te ope n lung VT : 4 -6 m L/k g PEEP : 1 0 c m H2 O st ar ting a t pos top I CU ar riv al n=1 8 (2 ) E ar ly ope n lung VT : 4 -6 m L/k g PEEP : 1 0 c m H2 O st ar ting a fte r in tuba tion n=2 2 (3 ) VT : 6 -8 m L/k g PEEP : 5 c m H2 O n=2 2 In flam m at or y m edia tor s in pla sm a: IL-8 de cr ea se d aft er CP B in bot h ope n lung g roup s; IL-1 0 de cr ea se d f as te r a fte r CP B in e ar ly ope n lung g roup Ev ide nc e of pe riope ra tiv e m yoc ar dia l in fa rc tion (c k-M B a nd E CG ): no diff er enc es be tw ee n gr oup s
56 Ab do mi na l s ur ger y W rig ge e t a l. 20 04 78 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing m ajor abdom ina l sur ge ry n=3 0 PV V: 6T m L/k g PEEP : 1 0 c m H2 O Paw Lim it 3 5 cm H2 O n=1 5 CV V: 1T 2-1 5 m L/k g ZEEP P Limaw it 3 5 cm H2 O n=1 5 In flam m at or y m edia tor s in pla sm a: no diff er enc es be tw ee n g roup s f or TN Fα, IL-1 , IL-6 , I L-8 , I L-1 0, IL-1 2 Pa O2 /FI O2 : no diff er enc es be tw ee n gr oup s Pa CO2 : hig he r dur ing P V W olt huis e t al. 20 08 10 7 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing a sur gic al pr oc edur e in g ene ra l ane st he sia ≥5 h n=4 6 PV V: 6T m L/k g PEEP : 1 0 c m H2 O n=2 4 CV V: 1T 0-1 2 m L/k g ZEEP n=2 2 In flam m at or y m edia tor s in pla sm a and B AL: lo w er m ye lope ro xida se a nd nuc le osom e le ve l in B AL dur ing PV Pa CO2 : hig he r dur ing P V PP Cs: no diff er enc es be tw ee n g roup s W eing ar te n e t al. 2 01 0 98 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s ag ed >6 5y unde rg oing m ajor ope n abdom ina l sur ge ry unde r ge ne ra l ane st he sia n=4 0 PV V: 6T m L/k g PEEP : 1 2 c m H2 O RM w ith s te pw ise PEEP inc re ase un til 1 5 cm H2 O n=2 0 CV V: 1T 0 m L/k g ZEEP no R M n=2 0 In flam m at or y m edia tor s in pla sm a: no diff er enc es be tw ee n g roup s Pa O2 /FI O2 + Pa CO 2 : hig he r dur ing P V Com plianc e hig he r a nd re sis tanc e lo w er dur ing PV Sp in al su rg er y M em ts ou di s e t al . 2 01 2 10 8 Pr ospe ctiv e, sing le -c en tr e, ra ndom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing ele ctiv e lum ba r de com pr ession
and fusion in prone
position unde r g ene ra l ane st he sia n=2 6 PV V: 6T m L/k g PEEP : 8 c m H2 O n=1 3 CV V: 1T 2 m L/k g ZEEP n=1 3 In flam m at or y m edia tor s in pla sm a: no diff er enc es be tw ee n g roup s Pa CO2 : hig he r dur ing P V BA L, br onchoalv eolar la vag e; CK -MB , muscle -br ain ty pe cr ea tine k inase ; CP B, c ar diopulmonar y by pass; CV , c on ve ntional ve ntila tion; E CG, e le ctr oc ar diog ram; EVL W I, ex tr av ascular lung w at er inde x; FI O2 , inspir ed frac tion of oxy ge n; ICA M , in te rc ellula r a dhe sion m ole cule ; ICU , in te nsiv e ca re unit ; I L, in te rle uk in; Paw , air w ay pr essur e; Ppeak . pe ak pr essur e; Ppla t , pla te au pr essur e; Pa CO2 , partial p ressu re of art eri al carb on d io xi de; PaO 2 , p artial p ressu re of art eri al o xy gen ; P aO2 /F IO2 , r atio o f p artial p ressu re of art eri al o xy gen to in sp ired fr actio n of oxy gen ; PE EP , p osi tiv e end–e xpir at or y pr essur e; PMN, polymorphonuclear le uk ocy te; PPCs, pos tope ra tiv e pulmonar y compl ica tions; PV , pr ot ectiv e ven tila tion; OL V, one-lung ven tila tion; Raw , air w ay resis tance; RM, recrui tmen t manoeu vr e; sICAM, sol ubl e in ter cel lul ar adhesi on mol ecu le; TNF α, tumour necr osi s f act or al pha; TL V, tw o-l ung ven til ation; VT , tidal v ol ume; ZEEP , z er o end–e xpi ra tor y pr essur e
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Recent evidence for intraoperative protective ventilation
Randomized controlled trials using non-clinical primary outcomes
The literature search identified eleven RCTs that compared a protective ventilation strategy with a protective ventilation strategy during general anesthesia for surgery with regard to non-clinical primary outcome in patients undergoing thoracic surgery,78,82,83,103,104 cardiac surgery,93,105,106
abdominal surgery,78,98,107 or spinal surgery,108 as depicted in table 3. In eight RCTs the protective
ventilation strategy consisted of both lower tidal volumes and higher levels of PEEP;78,83,98,103,105-108
in two RCTs, it consisted of either lower tidal volume,82 a higher level of PEEP.93 In one RCT, lung
recruitment manoeuvres were used during the protective ventilation strategy.104
The effects on inflammatory responses are slightly contradictory. While four RCTs showed no difference in local levels of inflammatory mediators between patients on protective and those on non-protective ventilation,78,98,105,108 six RCTs showed that protective strategies were associated
with lower levels of inflammatory mediators.82,83,93,103,106,107
Randomized controlled trials using clinical primary outcomes
In total, 8 RCTs were identified that compared a protective ventilation strategy with a non-protective ventilation strategy during surgery with regard to a clinical primary outcomes in patients planned for abdominal surgery,86,109-111 thoracic surgery,85,112 cardiac surgery,113 or spinal
surgery,114 as shown in table 4. In four RCTs the protective strategy consisted of both lower tidal
volumes and higher levels of PEEP,110-112,114 in the four remaining RCTs it consisted of either lower
tidal volumes,85,109,113 or higher levels of PEEP.86
Four trials reported on PPCs in the first postoperative days, including bronchitis, hypoxemia, and atelectasis,114 pneumonia, need for invasive or non-invasive ventilation for acute respiratory failure,110
a modified “Clinical Pulmonary Infection Score” and chest x–ray abnormalities,111 and hypoxemia,
bronchospasm, suspected pulmonary infection, pulmonary infiltrate, aspiration pneumonitis, development of ARDS, atelectasis, pleural effusion, pulmonary oedema, and pneumothorax.86
In a Chinese single-centre RCT,114 investigators compared protective ventilation (tidal volume 6
mL/kg and 10 cmH2O PEEP) versus non-protective (tidal volume 10 to 12 mL/kg and 0 cmH2O
PEEP) in 60 elderly American Society of Anesthesiologists class II and III patients scheduled for spinal surgery. Patients receiving protective ventilation had less PPCs.
In a French multi-centre trial (Intraoperative PROtective VEntilation, IMPROVE),110 protective
ventilation (tidal volume 6 to 8 mL/kg and PEEP 6 to 8 cmH2O) was compared with non-protective
ventilation (tidal volume 10 to 12 mL/kg and 0 cmH2O PEEP in 400 non-obese patients at
intermediate to high risk of pulmonary complications after planned major abdominal surgery. The primary outcome (postoperative pulmonary and extra–pulmonary complications) occurred less often in patients receiving ‘protective’ ventilation. Such complications have been ascribed to the release of inflammatory mediators by the lungs into the systemic circulation, affecting the lungs,115 as well as peripheral organs.50 These patients also had a shorter length of hospital
58 Ta bl e 4 . R an do mi zed c on tr ol led tri al s u si ng cl in ic al p rima ry o ut co mes Re fer en ce/ Yea r p ub lis hed St ud y d es ign Pa tien t p op ul atio n/ N umb er In ter ven tio n Co nt ro l gr ou p Cl in ic al p rima ry ou tc omes Sec on da ry o ut co mes Th or aci c s ur ger y M aslo w e t. a l. 20 13 11 2 Pr ospe ctiv e, sing le -ce nt re , r andom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing e le ctiv e pulm onar y r ese ction= 34 PV V: 5T m L/k g, TL V a nd O LV PEEP : 5 c m H2 O , TL V and OL V n=1 7 CV V: 1T 0 m L/k g, TL V and OL V ZEEP , TL V a nd OL V n=1 7 Ra te of a te le ct asis: lo w er w ith CV ; le ng th of hospit al st ay : no diff er enc es be tw ee n g roup s Pa CO 2 a bd de ad spa ce : hig he r dur ing P V Cdy n : hig he r dur ing CV She n e t al. 2 01 3 85 Pr ospe ctiv e, sing le -ce nt re , r andom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing e le ctiv e thor ac osc opic esopha ge ct om y n=1 01 PV V: 8T m L/k g, TL V VT : 5 m L/k g OL V PEEP : 5 c m H2 O , TL V and OL V n=5 3 CV V: 8T m L/k g, TL V VT : 8 m L/k g OL V ZEEP , TL V a nd OL V n=4 8 PP Cs: lo w er ra te w ith P V M or ta lit y: no diff er enc e be tw ee n gr oup s Pa O2 /FI O2 and Pa CO 2 : hig he r dur ing P V In flam m at or y m edia tor s in BA L: lo w er IL-1 ß, IL-6 a nd I L-8 Ca rd ia c su rg er y Sunda r e t al. 2 01 1 11 3 Pr ospe ctiv e, sing le -ce nt re , r andom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing e le ctiv e ca rdia c sur ge ry n=1 49 PV V: 6T m L/k g PEEP /FI O2 : a cc or ding to A RDS N et w or k ta ble n=7 5 CV V: 1T 0 m L/k g PEEP /FI O2 : ac cor ding to AR DS N et w or k ta ble n=7 4 Ra te of r ein tuba tion: lo w er w ith P V N um be r of pa tie nt s re quir ing v en tila tion 6h pos tope ra tiv ely : lo w er w ith P V Ga s e xc ha ng e: no diff er enc e be tw ee n g roup s Ab do mi na l s ur ger y Tr esc han e t al. 20 12 10 9 Pr ospe ctiv e, sing le -ce nt re , r andom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing e le ctiv e uppe r abdom ina l sur ge ry ≥3 h unde r c om bine d ge ne ra l and e pidur al ane st he sia n=1 01 PV V: 6T m L/k g PEEP : 5 c m H2 O n=5 0 CV V: 1T 2 m L/k g PEEP : 5 c m H2 O n=5 1 Ra te of a te le ct asis: lo w er w ith CV Pa O2 /FI O2 : hig he r dur ing CV Cdy n a nd R aw : hig he r dur ing CV Pa O2 a t pos tope ra tiv e da y 5 : hig he r w ith CV
Ch apt er 3 59 Futie r e t al. 2 01 3 11 0 Pr ospe ctiv e ra ndom ize d con tr olle d m ulti-ce nt re st udy Adult s pa tie nt s a t in te rm edia te to hig h risk of pulm ona ry com plic ations unde rg oing m ajor abdom ina l sur ge ry n=4 00 PV V: 6T -8 m L/k g PEEP : 6 -8 c m H2 O n=2 00 CV V: 1T 0-1 2 m L/k g ZEEP n=2 00 Com posit e pr im ar y out com e of m ajor pulm onar y or ex tr apulm ona ry com plic ations: lo w er w ith P V Re duc ed ra te of a te le ct asis, pne um onia , ne ed f or ve ntila tion w ithin 7 da ys a nd se psis w ith PV . Re duc ed le ng th of hospit al st ay w ith P V Se ve rg nini e t a l. 20 13 11 1 Pr ospe ctiv e, sing le -ce nt re , r andom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing e le ctiv e ope n abdom ina l sur ge ry ≥2 h n=5 6 (1 e xc lude d) PV V: 7T m L/k g PEEP : 1 0 c m H2 O n=2 8 CV V: 9T m L/k g ZEEP n=2 7 Pulm ona ry func tion te st s: im pr ov ed w ith PV M odifie d Clinic al P ulm onar y In fe ction Sc or e: lo w er w ith P V Pa O2 at pos tope ra tiv e da ys 1 , 3, 5 : hig he r w ith P V Ra te of c he st x -r ay abnor m alitie s: lo w er w ith P V Le ng th of hospit al s ta y: no diff er enc e be tw ee n g roup s PR O VE N et w or k In ve stig at or s 20 14 86 Pr ospe ctiv e, in te rna tiona l, m ultic en te r, ra ndom ize d con tr olle d t ria l Adult s pa tie nt s a t in te rm edia te to hig h risk of pulm ona ry com plic ations unde rg oing m ajor abdom ina l sur ge ry n=9 00 PV V: 8T m L/k g PEEP : 1 2 c m H2 O RM w ith s te pw ise inc re ase of V T a fte r induc tion a nd be for e ex tuba tion n=4 45 CV V: 8T m L/k g PEEP : 0 -2 c m H2 O n=4 49 Ra te of P PCs: no diff er enc e be tw ee n gr oup s Ra te of in tr aope ra tiv e hy pot ension a nd a m oun t of va soac tiv e dr ug s g iv en: hig he r dur ing P V Ra te of de sa tur ation: lo w er dur ing P V M or ta lit y and le ng th of hospit al s ta y: no diff er enc e be tw ee n g roup s Sp in al su rg er y Ge e t a l. 2 01 3 11 4 Pr ospe ctiv e, sing le -ce nt re , r andom ize d con tr olle d t ria l Adult pa tie nt s unde rg oing spine fusion n=6 0 PV V: 6T m L/k g PEEP : 1 0 c m H2 O RM e ve ry 1 5m in n=3 0 CV V: 1T 0-1 2 m L/k g ZEEP n=3 0 Ra te of P PCs, lo w er w ith P V Pa O2 /FI O2 , hig he r dur ing P V ARDS, acut e respir at or y di str ess syndr ome ; B AL , br onchoalv eolar la vag e; CV , c on ve ntional ven tila tion; FIO 2 , inspir ed fr action of oxy gen; ICU , in tensiv e car e unit; IL , in terleukin; PaC O2 , partial pr essur e of art erial c arbon di oxide; PaO 2 , partial pr essur e of art eri al o xy gen; Pa O2 /FIO 2 , r atio of partial pr essur e of art erial oxy gen to inspi red fr action of oxy gen; PEEP , posi tiv e en d–e xp ira to ry pr essu re; PPC s, po st op er ativ e pu lmo nar y co mp lic atio ns; PV , p ro tectiv e ven til atio n; OL V, on e-l un g ven til atio n; Raw , ai rw ay resi st an ce; RM, recru itmen t man oeu vr e; TL V, tw o-lung v en tila tion; VT , tida l v olum e; ZEEP , z er o e nd–e xpir at or y pr essur e
60 Fi gu re 5 . O dd s r ati os fo r p os to pe ra tive p ul m on ar y c om pl ic ati on s o f “ pr ot ec tive ” ve rs us “ no n-pr ot ec tive ” ve nti la tio n i n tr ia ls
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An Italian single–centre trial111 investigated the effectiveness of protective ventilation (tidal
volume 7 mL/kg and 10 cmH2O PEEP with recruitment manoeuvres) versus non–protective
ventilation (tidal volume 9 mL/kg and zero end-expiratory pressure) in 56 patients scheduled for open abdominal surgery lasting more than 2 hours. The modified “Clinical Pulmonary Infection Score” was lower in patients receiving protective ventilation. These patients also had fewer chest x–ray abnormalities and higher arterial oxygenation compared to patients receiving non-protective ventilation.
Finally, in an international multicenter trial conducted in Europe and the Americas (PROtective Ventilation using HIgh versus LOw PEEP, PROVHILO),86 the PROtective VEntilation (PROVE)
Network–investigators compared PEEP of 12 cmH2O combined with recruitment manoeuvres
versus PEEP of 2 cmH2O without recruitment manoeuvres in 900 non-obese patients at high risk
for postoperative pulmonary complications planned for open abdominal surgery under ventilation at tidal volumes of 8 mL/kg. The incidence of PPCs was not different between patients receiving protective ventilation and patients receiving non-protective ventilation.
Challenges of studies using bundles
As shown in preceding subsections “Randomized controlled trials using non-clinical primary outcomes” and “Randomized controlled trials using clinical primary outcomes”, most RCTs addressing intraoperative mechanical ventilation compared bundles of interventions consisting of tidal volumes and levels of PEEP, usually accompanied by a lung recruitment maneuver.110-112,114
Notably, recruitment manoeuvres differed between the trials. In the Italian single-centre RCT,111
investigators used incremental titration of tidal volumes until a plateau pressure of 30 cmH2O,
directly after induction of anesthesia, after any disconnection from the ventilator and immediately before extubation, similar as in PROVHILO.86 In IMPROVE,110 recruitment was performed with a
continuous positive airway pressure of 30 cmH2O for 30 seconds every 30 minutes, also known
as sustained inflation, after tracheal intubation. Finally, in the Chinese single-centre RCT,114 the
recruitment manoeuvres followed a similar approach, but to plateau pressures of up to 35 cmH2O, and they were performed every 15 minutes. It is difficult, if not impossible to conclude
from these trials what caused the benefit: tidal volume reduction or increase of PEEP, or both, and to determine the role of recruitment manoeuvres. Moreover, to what extent the recruitment manoeuvre has succeeded in reopening lung has not been analysed in the different studies. The results of the PROVHILO trial, however, suggest that low tidal volumes rather than PEEP combined with lung recruitment manoeuvres are responsible for lung protection in the intraoperative period. This interpretation is also supported by an analysis of different studies on the odds ratios of lower tidal volumes,85,109,113 higher levels of PEEP,86 as well as their
combination,110-112,114 regarding the development of PPCs (figure 5).
Certainly, these conclusions are only valid for the studied population, that is, non-obese patients at risk of PPCs undergoing elective abdominal surgery. Other patient populations could still benefit from higher levels of PEEP and recruitment manoeuvres.
Challenges of composite outcome measures
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to ensure adequate statistical power of a trial.8 It is reasonable to combine related outcomes
that represent different aspects of a single underlying pathophysiological process, like PPCs for VILI. There are, though, two major limitations regarding the use of composite outcomes. First, the component variables can differ importantly in terms of severity and frequency. Second, differences in the frequency of component variables in a composite outcome may be masked. Drawbacks of protective ventilation
The term “protective” in the context of mechanical ventilation implies a decrease in the major components of VILI, namely atelectrauma, volutrauma and biotrauma. However, a strategy that is protective to lungs may also cause harm to other organ systems. The potential for harm caused by protective ventilation was reported in PROVHILO,86 in which patients receiving higher PEEP
and lung recruitment manoeuvres developed intraoperative hypotension more frequently and needed more vasoactive drugs. These findings are at least in part in line with the finding that protective ventilation was associated with a higher incidence of intraoperative hypotension in the French trial.110
Figure 6. Settings of VT (Panel A) and PEEP (Panel B) according to observational studies of
mechanical ventilation in the operation room; and settings of VT (Panel C) and PEEP (Panel D)
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Standard of care versus unusual settings: Were the control groups of recent trials representative of clinical practice?
In RCTs addressing intraoperative protective mechanical ventilation, the strategy used to treat control groups can play an important role when drawing conclusions for daily practice of general anesthesia. Metaanalyses suggest that lower tidal volumes are protective not only during long-term ventilation in critically ill patients,116,117 but also short-term ventilation during
general anesthesia for surgery.117 Accordingly, anaesthesiologists have been using tidal volumes of
approximately 8 to 9 mL/kg on average, and seldom higher than 10 mL/kg,74 as also illustrated in
figure 6A. In contrast to this practice, the tidal volumes used in the control groups of recent RCTs were as high as 9111 to 12 mL/kg110, except to PROVHILO (figure 6B),86 which used a tidal volume of
7 mL/kg both in the intervention and in the control group. Similarly, levels of PEEP in the control arms of three out of four recent RCTs110,111,114 on protective mechanical ventilation were much
lower than the standard of care at the moment the respective studies were designed (figure 6C and 6D). Taken together, these facts suggest that, among the most important recent RCTs on intraoperative protective mechanical ventilation, only the PROVHILO trial used a control group that reproduced the standard of anesthesia care at the time it was conducted. Accordingly, the PROVHILO trial addressed a major question regarding mechanical ventilation during anesthesia, namely whether the combination of high PEEP with recruitment manoeuvres confers protection against PPCs. In this study, high PEEP was not individualized, but based on previous findings from computed tomography67,88,89 and physiological studies.90,92
Intraoperative mechanical ventilation according to the
utmost recent evidence
A number of reviews and commentaries have suggested that intraoperative mechanical ventilation for surgery should consist of low tidal volumes (6 to 8 mL/kg), moderate levels of PEEP (6 to 8 cmH2O), and periodic lung recruitment manoeuvres (e.g. every 30 min).5, 118-120 However,
previous reviews and recommendations have been based on bundles, which do not permit to infer on the contribution of individual measures. Furthermore, the results of the largest RCT in this field (PROVHILO) could not be taken into account. Also, a recommendation regarding the use of positive pressure ventilation during induction and emergence of anesthesia, as proposed recently,119 is not supported by outcome data. Currently, the only recommendations that can
be given for clinical practice are summarized in figure 7. In non-obese patients without ARDS121
undergoing open abdominal surgery, mechanical ventilation should be performed with low tidal volumes (approximately 6 to 8 mL/kg) combined with low PEEP (≤ 2 cmH2O), since higher PEEP
combined with recruitment manoeuvres does not confer further protection against PPCs and can deteriorate the hemodynamics. If hypoxemia develops and provided that other causes have been excluded (e.g. hypotension, hypoventilation, pulmonary embolism etc.), the FiO2 should
be increased first, followed by increase of PEEP, and recruitment manoeuvres based on stepwise increase of tidal volume during regular mechanical ventilation, according to the rescue algorithm described in the PROVHILO trial,86 provided no contra-indication is present. In patients with
ARDS121 undergoing open abdominal surgery, intraoperative mechanical ventilation should be
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severe ARDS.124 If the target PaO
2 (55 to 80 mmHg) or SpO2 (88 to 95%) cannot be achieved,
a maximal lung recruitment manoeuvre with a decremental PEEP trial can be considered.125
Future perspectives
Despite the increasing number of highly qualitative RCTs on intraoperative mechanical ventilation, a number of issues remain unaddressed. While metaanalyses strongly suggest that low tidal volumes during intraoperative mechanical ventilation protect against postoperative pulmonary events, no single RCT has been able to prove this claim. Since metaanalyses in this field frequently include studies that tested intervention bundles, for example low tidal volume and high PEEP with recruitment manoeuvres versus high tidal volumes without PEEP, the estimation of the effects of single measures, for example low tidal volume or PEEP, is prone to criticism. Therefore, RCTs are most relevant for clinical practice if they test single interventions, and if control groups reproduce current standards. Whereas direct testing of the hypothesis that intraoperative low tidal volumes protect against PPCs is still lacking, ethical issues preclude such a trial.
Figure 7. Proposed settings of protective mechanical ventilation in non-obese patients during open abdominal surgery according to the concept of intraoperative permissive atelectasis
