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Featured Articles: Narrative Review Article

Perioperative Lung Protection: Clinical Implications

Hol, Liselotte MD*; Nijbroek, Sunny G. L. H. MD*; Schultz, Marcus J. PhD†,‡,§,‖

Author Information
doi: 10.1213/ANE.0000000000005187

Abstract

See Article, p 1663

Worldwide, >300 million surgical procedures are performed each year, and indications for surgery remain expanding.1,2 To protect the airway and to ensure oxygenation and decarboxylation during general anesthesia for surgery, intubation and invasive ventilation are indispensable.

Invasive ventilation has a clear potential to harm lung tissue, even when applied for a relatively short period, for example, during general anesthesia for surgery. Postoperative pulmonary complications (PPCs) are, at least in part, dependent on the way intraoperative ventilation is applied. In other words, PPCs may be seen as “ventilator-induced lung injury” (VILI), which could be prevented by using so-called lung-protective ventilation strategies. PPCs occur frequently and are associated with worse outcome in surgical patients.3,4 Thus, every attempt to reduce the incidence of PPCs should be embraced to improve outcome in surgical patients.

After a concise description of the various ways through which ventilation can harm lung tissue, the effects of tidal volume (VT), positive end-expiratory pressure (PEEP), and the inspired oxygen fraction (Fio2) with intraoperative ventilation are discussed. Recommendations regarding these 3 seemingly easy to manage ventilator settings of invasive ventilation are provided at the end of this article.

VENTILATOR-INDUCED LUNG INJURY

Mechanical ventilation can harm lung tissue through “barotrauma,” “volutrauma,” “atelectrauma,” “oxytrauma,” and “biotrauma.” These 5 mechanisms have their own specific pathophysiological features but share similarities in their pathways to injure the lungs.5,6

Lungs are composed of 2 “force-bearing” structures, that is, elastin and collagen fibers. While elastin gives the lung the capacity to rebound after it has been stretched by inhalation, the so-called elastic recoil, collagen fibers are folded in resting position and unfold during inhalation until the maximum lung capacity is reached. These structures can bear a maximum pressure.7,8 Exceeding the pressure threshold results in overdistension of elastin and collagen fibers, which then rupture leading to gross air leaks, called “barotrauma,”6,9 or overdistension of open lung units resulting in lung edema, called “volutrauma.”10

“Atelectrauma” is a 2-fold challenge. Epithelia and the surfactant system are damaged by repetitive opening and closing of long units.11 In addition, airflow to poorly aerated atelectatic regions of the lungs can be severely limited, meaning that a major part of a single breath will move to the open lung units, further amplifying regional overdistension.12

Oxygen can cause so-called oxytrauma. Higher oxygen fractions means lower nitrogen fractions, and opposite to nitrogen, oxygen will be absorbed.13 Consequently, absorption atelectasis may occur, increasing the risk of atelectrauma. Next, oxygen radicals are produced that will disturb cell homeostasis with the potential consequence of inflammation, cell damage, and even cell death.6 Furthermore, invasive ventilation with a high Fio2 could result in hyperoxic vasoconstriction, which could compromise tissue oxygenation.

All these mechanisms together may result in local inflammation through local production and release of inflammation mediators that attract inflammatory cells, known as biotrauma. The inflammatory mediators and bacteria or bacterial products, if present, may leak into the systemic circulation, causing a systemic inflammation eventually leading to distant organ damage.

LUNG-PROTECTIVE VENTILATION

Table. - Recommendations of Lung-Protective Ventilation Strategies During Surgery
Volume
 VT 6–8 mL/kg PBW Adjust to lung size, based on PBW which is a function of patient’s height, and not actual body weight
Be aware that use of a low VT may lead to hypoxemia, which may require use of a higher Fio 2
Pressure
 PEEP 0–5 cm H2O Use higher PEEP only in case of hypoxemia not responding to an increase in Fio 2
PEEP may need to be individualized to avoid overdistension
Be aware that an increase in PEEP increases the risk of hypotension, which may need start of a vasopressor
 ΔP <15 cm H2O as a safety limit If ΔP increases, analyze the cause: it could be atelectasis or overdistension, but also the use of a VT that is too high
 Pplat <20 cm H2O Pplat could be used instead of the transpulmonary pressure
Be aware of its limitations, because a stiff chest wall may explain a rise in Pplat
Oxygen
 Fio 2 0.21–0.4 Avoid unnecessary use of high Fio 2 after intubation
Abbreviations: ΔP, driving pressure; Fio2, inspired oxygen fraction; PBW, predicted body weight; PEEP, positive end-expiratory pressure; Pplat, plateau pressure; VT, tidal volume.

F1
Figure.:
Evolution of studies assessing intraoperative lung protective ventilation. Left, Randomized clinical trials of VT, PEEP, and Fio 2 in intraoperative ventilation during anesthesia for major nonthoracic surgery with pulmonary complications as (part of) the primary outcome. Studies were placed within the figure based on date of publication, and study details are shown per each study; (right) conclusions per each study. Selection of studies is limited to those evaluating an effect of ≥1 ventilatory interventions on pulmonary complications and clinically relevant outcomes in patients planned for nonthoracic surgical interventions. Fio 2 indicates inspired oxygen fraction; IMPROVE, Intraoperative Protective Ventilation; iPROVE, Individualized PeRioperative Open-lung Ventilation; mRCT, multicenter randomized clinical trial; PBW, predicted body weight; PEEP, positive end-expiratory pressure; PROBESE, Protective Intraoperative Ventilation With Higher Versus Lower Levels of Positive End-Expiratory Pressure in Obese Patients; PROVHILO, PROtective Ventilation using High versus LOw PEEP; sRCT, single-center randomized clinical trial; VT, tidal volume.

So-called lung-protective ventilation strategies aim to minimize the occurrence of the pathophysiological features of VILI, as described above. To prevent VILI, the amount of energy transferred from the mechanical ventilator to the patient should be limited to a bare minimum. To do so, VT and inspiratory pressures should be kept low to minimize the risk of barotrauma and volutrauma. Transpulmonary pressure, the best indicator of the amount of pressure applied to the lungs, is difficult to measure in routine practice. Therefore, plateau pressure is often used as a surrogate, although this comes with limitations. Plateau pressure does not represent the actual force on the lung fibers but the pressure needed to expand both all lung tissue in the lungs and the chest wall consisting of the rib cage and the diaphragm. Patients with a stiff chest wall, for example, during pneumoperitoneum, will have a high plateau pressure that cannot automatically be translated into lung overdistension.5 For most scenarios, a plateau pressure <20 cm H2O is advised, but the above-mentioned limitations should be taken into account and an individualized judgment is always recommended. PEEP can be applied to avoid the collapse of alveoli at the end of expiration, and Fio2 is minimized to prevent its direct and indirect side effects. The lion’s share of research on lung-protective ventilation strategies has been performed in critically ill and invasively ventilated patients. Consequently, most of the evidence regarding preventive measures originates from research performed in intensive care units (ICUs), much more than from research performed during intraoperative ventilation in the operating room (OR). There is, however, increasing evidence that what has been shown to be lung protective in critically ill patients also protects the lungs in patients receiving invasive ventilation for a much shorter period of time, during general anesthesia for surgery (Figure;Table).

TIDAL VOLUME

Because ventilation with a high VT can prevent or minimize atelectasis,14,15 in the past it was common practice to use high VTs of 800–1000 mL, which translates to VTs as high as 10–15 mL/kg predicted body weight (PBW). The reduction in ventilation–perfusion mismatch reduced the need for a high Fio2 and high PEEP. The landmark acute respiratory distress syndrome (ARDS) network study called “ARMA”(ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome) showed ventilation with a low VT to reduce mortality in critically ill ICU patients with ARDS,16 very probably by preventing volutrauma. Later studies found that the beneficial effects of ventilation with a low VT were not limited to ICU patients with ARDS. Indeed, also ICU patients without ARDS may benefit from ventilation with a low VT.17 This benefit was confirmed by several meta-analyses,18–21 and nowadays it is common practice to use a low VT in all ICU patients, that is, irrespective of presence or absence of ARDS.

The advantages of invasive ventilation with a low VT in critically ill patients were initially seen as irrelevant for surgical patients because of their relatively healthy lungs and because ventilation in these patients lasts a much shorter time than in ICU patients. Several clinical studies, however, showed intraoperative ventilation with a low VT to affect respiratory system compliance,22,23 to lower airway pressures,22,24,25 and to reduce production and release of inflammatory mediators.26 It took several years before studies showed benefit of intraoperative ventilation with a low VT with respect to patient-centered outcomes, like the need for postoperative reintubations,24,27 ICU admissions,23 and duration of stay in ICU and hospital.23,24 Three randomized clinical trials (RCTs) convincingly showed that an intraoperative ventilation strategy with a low VT to prevent against development of PPCs.28–30 However, in these studies, ventilation with a low VT of 6–8 mL/kg PBW was combined with higher PEEP, from 6 to 12 cm H2O,28–30 making it challenging to determine what caused the reduction in PPCs, the use of a lower VT, or a higher PEEP.

Indirect evidence for benefit of intraoperative ventilation with a low VT came from 2 recent RCTs, 1 in nonobese patients31 and 1 in obese patients.32 Both studies compared ventilation with no or low PEEP with ventilation using high PEEP of 12 cm H2O, but always using a low VT. These 2 studies showed no benefit of higher PEEP, suggesting that benefit found in the RCTs above28–30 presumably was not caused by a higher PEEP, but rather a lower VT. One conventional meta-analysis and 1 “individual patient data” meta-analysis confirmed the hypothesis that benefit from lung-protective intraoperative ventilation with a low VT and high PEEP comes from the use of a low VT.33,34

POSITIVE END-EXPIRATORY PRESSURE

Formation of atelectasis is one of the main challenges in invasive ventilation. It increases the risk of ventilation-associated lung trauma11 and leads to mismatches between ventilation and perfusion, thereby impairing oxygenation.11 PEEP prevents or at least minimizes lung collapse by stabilization of alveoli at the end of expiration.35 In the ICU, PEEP is increasingly used, in patients with ARDS as well as in patients who receive invasive ventilation for another reason. In ICU patients, PEEP has been shown to improve oxygenation, thereby allowing use of lower Fio2.36–38 Despite this benefit, it remains uncertain whether use of high PEEP itself translates into a better outcome. Three large individual RCTs of higher versus lower PEEP in ARDS patients actually showed no benefit.36,37,39 Opposite to the finding in 1 individual, patient data meta-analysis of these 3 studies, suggesting higher PEEP to improve survival in patients with more severe forms of ARDS,40 1 recent RCT of higher PEEP in patients with severe ARDS showed increased mortality with use of higher PEEP.41 It is highly uncertain whether ICU patients who receive invasive ventilation for another reason than ARDS benefit from higher PEEP—1 study testing the effects of higher PEEP in these patients is underway.42

Atelectasis occurs in a majority of patients receiving general anesthesia for surgery.43 Several mechanisms are being held accountable, including small airways closure,44–46 compression of lung structures,47–50 surfactant dysfunction,51 and absorption of gases used during intraoperative ventilation.52,53 Use of muscle relaxation and high Fio2 further increases the risk of large atelectasis.43,54,55 In addition, use of a low VT could increase this challenge. The adverse effects of atelectasis are not limited to the intraoperative period; atelectasis can persist postoperatively for several days and it is associated with an increased risk for developing PPCs, such as ARDS.54 Many studies have shown intraoperative ventilation with higher PEEP to be efficient in reducing atelectasis, thus decreasing ventilation-perfusion mismatch and reducing the need of supplying high proportions of oxygen.56 Unfortunately, this reduction in atelectasis may not necessarily result in a better clinical outcome.57

Two RCTs, both in patients who received intraoperative ventilation with a low VT, evaluated the effect of low versus high PEEP. These trials failed to show benefit of a high PEEP strategy.31,32 However, the beneficial effects of high PEEP could have been masked by its potential disadvantages. It is well known that a patient’s clinical status influences the compliance of the lungs.58 High PEEP could minimize atelectasis, and thus prevent against atelectrauma, but may also induce overdistension, and thus lead to volutrauma. To encounter this interpersonal variance, it has been suggested that PEEP should be titrated individually, to the best compliance of respiratory system (Crs) or to the lowest driving pressure (ΔP).59

ΔP could serve as 1 measure to individualize PEEP further, because a high ΔP may indicate both atelectasis as overdistension. In contrast to critically ill patients with ARDS, surgery patients usually have healthy and thus compliant lung tissue. In patients with ARDS, it has been suggested to keep the ΔP <15–20 cm H2O.60,61 What ΔP to target or accept during intraoperative ventilation is less certain. The findings of 1 meta-analysis suggests that ΔP rarely exceeds 20 cm H2O in surgical patients.59 If this pressure limit is reached, a simple reason for an elevated ΔP should be looked for, such as selective intubation of the right or left lung. A rise in ΔP is strongly associated with development of PPCs in 1 meta-analysis.59

A strategy of titrating PEEP against Crs or ΔP was tested in 2 RCTs, with moderate success.62,63 Here it is worth to mention that 1 study was not powered to test a difference in occurrence of PPCs between the 2 study arms,62 and the other was probably too underpowered to draw firm conclusions.63

Use of higher PEEP has 1 important disadvantage. Higher PEEP increases the intrathoracic pressure and as such may lead to hypotension, often mandating intraoperative administration of vasoactive drugs.31,32 It remains uncertain whether this disadvantage should withhold anesthesiologists from using higher PEEP in intraoperative ventilation during general anesthesia for surgery.

OXYGEN FRACTION

Higher Fio2 is used to avoid hypoxemia, especially when intraoperative ventilation uses a low VT and lower or no PEEP. Formation of so-called reactive oxygen species (ROS) can theoretically improve wound healing. Liberal oxygen could promote the ROS formation. However, intraoperative ventilation with higher Fio2 can result in hyperoxic vasoconstriction, compromising tissue oxygenation. Hyperoxic vasoconstriction is particularly dangerous in patients with cardiac ischemia, because it could increase myocardial injury.64 Furthermore, in patients with heart failure, an increased afterload could worsen left ventricular function. In addition, use of higher Fio2 may result in more reabsorption atelectasis.65

In critically ill patients under invasive ventilation, Fio2 easily exceeds 40%,66,67 and hyperoxia is frequently seen in these patients.68,69 In patients after cardiac arrest and cardiopulmonary resuscitation, hyperoxia is independently associated with increased in-hospital mortality.70,71 In patients with brain injury, hyperoxia is associated with an increased mortality rate and a longer hospital stay.72 In ICU patients in general, hyperoxia is associated with an increased mortality.73 One RCT comparing hyperoxia to normoxia in septic patients was prematurely stopped because of increased mortality in the hyperoxia patients.74 Systematic reviews75–77 and 1 meta-analysis78 confirm the finding that hyperoxia could be harmful. One recently performed RCT, however, suggested no benefit of ventilation with a low Fio2.79 In this study in ARDS patients, 28-day mortality was not dependent on the 2 oxygen strategies compared. It should be mentioned, though, that patients in the control arm were already treated with a low Fio2, lower than that used in previous studies, and like hyperoxia, hypoxia could be harmful as well. Indeed, a database analysis showed that not only time spent in hyperoxia but also time spent in hypoxia was associated with mortality. An intermediate oxygen saturation between 95% and 99% was associated with reduced mortality in critically ill patients.80 While results of studies testing the effects of low versus intermediate Fio2,81–83 such as the above-mentioned RCT by the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) investigators, make it difficult to permit for a definitive judgment,77 it seems justified to avoid invasive ventilation with high Fio2 in critically ill patients.

The conflicting results could, at least in part, be explained by the fact that there are, as yet, no clear cutoffs for hyperoxia. Consequently, these cutoffs vary widely in the literature, complicating interpretation of trials assessing the effects of hyperoxia.

Evidence for harm of hyperoxia in intraoperative ventilation is less convincing. Ventilation with a high Fio2 during surgery allows the anesthesiologist to “buy some time” in case of clinical emergencies. Additionally, the application of high Fio2 during surgery promotes tissue oxygenation and might enhance oxidative killing by neutrophils,84 hypothetically preventing surgical site infections (SSIs). One recent RCT found an association between higher Fio2 and major respiratory complications and mortality.85 However, a post hoc analysis and review failed to show an association between intraoperative ventilation with high Fio2 and the occurrence of PPCs.86,87 Two RCTs and 1 meta-analysis could not confirm benefit of the use of higher Fio2 with regard to mortality or duration of hospitalization.88–90 Previous guidelines by the World Health Organization recommend using a higher Fio2 (0.8) in patients undergoing general anesthesia for surgery, also to reduce SSIs.91 However, in line with results from systematic reviews,87,92,93 this recommendation was less strict in a more recent version of the guidelines.94

POSTOPERATIVE VENTILATION

Surgical patients may require postoperative ventilation. Thoracic and abdominal surgery, general anesthesia, and postoperative analgesia could all impair respiratory function. Inhalation anesthetics can cause hypoxic pulmonary vasoconstriction, and total intravenous anesthesia and certain analgesics can blunt the hypercapnic ventilation drive. Furthermore, atelectasis and alterations in the shape of the diaphragm due to thoracic or upper abdominal surgery can reduce lung volume. Other common reasons for the requirement of postoperative ventilation are residual curarization, hypothermia, and cardiopulmonary stress.95

Research on postoperative ventilation is in its infancy, but it seems that surgical patients receive comparable ventilation strategies during and after surgery (Marcus J. Schultz, MD, PhD, Department of Intensive Care, Amsterdam University Medical Centers, Location ‘Amsterdam Medical Center,’ Amsterdam, the Netherlands, personal communication, January 13, 2020, on behalf of the LAS VEGAS investigators). One recent RCT compared ventilation with low PEEP with ventilation with high PEEP in patients after cardiac surgery. This RCT showed that ventilation with high PEEP resulted in less severe PPCs and a shorter ICU and hospital stay, without increasing the incidence of barotraumas. No difference in mortality was found.96 These findings are, at least in part, consistent with a retrospective analysis showing the application of high PEEP in patients after cardiac surgery to improve pulmonary compliance and oxygenation.97 However, that analysis failed to show an association between ventilation with high PEEP and other clinical outcomes. Of note, the patients in these 2 studies were not entirely comparable, because the first study limited participation to patients who developed hypoxemia in the postoperative period. Most likely, these patients have benefited more from ventilation with high PEEP because they had significant atelectasis, as was also suggested by electrical impedance tomography. Furthermore, ΔP was significantly lower in the high PEEP group compared to the low PEEP group, implying that PEEP was able to recruit collapsed lung tissue.59

In conclusion, it remains uncertain whether, and also which patients could benefit from postoperative ventilation with higher levels of PEEP, and additional research is needed.

RECOMMENDATIONS

Nowadays, the concept of ventilation with a low VT is widely accepted and embraced in the OR. The disadvantages of ventilation with a high VT are well recognized both in critically ill patients as in patients with relatively healthy lungs receiving invasive ventilation for a shorter duration on the OR. Use of a low VT could result in hypoxemia, but this can be compensated by using a higher Fio2. The search for the optimal level of PEEP in the OR has not yet been finalized. Ventilation with higher PEEP (10–12 cm H2O) may be without clinical benefit because studies so far have shown no protection against development of PPCs. There are even arguments against use of higher PEEP, seeing its effect on circulation and the need for intraoperative administration of vasoactive drugs. For now, it remains uncertain whether the application of higher Fio2 during surgery is truly beneficial. While there seem to be no substantial reasons to avoid hyperoxia, convincing evidence supporting the use of higher Fio2 than necessary for normoxemia is lacking too.

Most studies of lung-protective ventilation during general anesthesia for surgery included patients undergoing 2-lung ventilation during open or closed abdominal surgery. It is uncertain if the interventions mentioned above translate in benefit in patients who need one-lung ventilation. Currently, 1 study (Protective Ventilation with Higher Versus Lower PEEP During General Anesthesia for Thorax Surgery [PROTHOR]) assesses the effects of high PEEP in patients receiving one-lung ventilation during thoracic surgery.98 Patients included in this study are ventilated with low PEEP of 5 cm H2O or high PEEP of 10 cm H2O.

The Driving Pressure during General Anesthesia for Open Abdominal Surgery (DESIGNATION) trial compares an individualized high PEEP strategy with a standard low PEEP strategy.99 Finally, research on the effects of hyperoxia during surgery is ongoing.

In conclusion, intraoperative ventilation should use a low VT. We favor the use of a lower PEEP. Ventilation with a high PEEP should only be considered if desaturations occur that do not respond to an increase in Fio2. Because intraoperative PEEP may in fact induce lung overdistension and is strongly associated with hemodynamic compromise, PEEP needs to be titrated carefully and very possible also individually.

DISCLOSURES

Name: Liselotte Hol, MD.

Contribution: This author helped draft and finalize the manuscript.

Name: Sunny G. L. H. Nijbroek, MD.

Contribution: This author helped draft the manuscript.

Name: Marcus J. Schultz, PhD.

Contribution: This author helped draft and supervise the finalization of the manuscript.

This manuscript was handled by: Alexander Zarbock, MD.

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