Pathophysiology of Perioperative Lung Injury

Pathophysiology of Perioperative Lung Injury

ALEXANDER White, Andrew C. Steel


Postoperative pulmonary complications remain a significant cause of morbidity and mortality after surgery.1 Approximately 230 million major surgical procedures are conducted annually worldwide. Perioperative pulmonary complications are common, occurring in up to 59% of patients. Approximately 2.7% of surgical patients will develop severe acute lung injury (ALI) causing postoperative respiratory failure.2 The risk is not uniform, and is significantly higher in surgery on the esophagus (23.8%) than most orthopedic procedures. Should the patient recover from the episode and is discharged, the long-term prognosis for survivors of ALI is still significantly worse than those without ALI. A 2-year follow-up study reported that survivors of perioperative ALI required an average of two episodes of readmission and 6 days of hospital stay per year.2 Another study reported 30-day mortality to be 27% following thoracic surgery,3 and 90-day mortality to be 55%.4

The term “perioperative lung injury” has been known by a number of different terms in the past, including “permeability pulmonary edema” and “postoperative lung injury.”5 The current definition of perioperative lung injury is the development of acute respiratory distress syndrome (ARDS) immediately after surgery, using the Berlin definition of 20126 (Table 18.1). Although this definition is not without controversy, it is currently the most widely used and accepted definition.

Table 18.1

Berlin Definition of Acute Respiratory Distress Syndrome
Oxygenation Mild Moderate Severe
Timing Onset within 1 week of a known clinical insult
Chest imaging Bilateral opacifications not fully explained by pleural effusions or lobar collapse
Origin Not fully explained by cardiogenic pulmonary edema
PaO2/FiO2 ratio 200–300 with PEEP or CPAP ≥ 5 cm H2O 100–200 with PEEP ≥5 cm H2O PaO2/FiO2 < 100 with PEEP ≥5 cm H2O

Chest imaging may refer to a conventional chest x-ray or computed tomography thorax.

FiO2, Fraction of inspired oxygen; PaO2, partial pressure of oxygen taken from an arterial blood gas; PEEP, positive end expiratory pressure.



ARDS was initially described by Laennec in 1821, as a new syndrome characterized by pulmonary edema without heart failure.7 Subsequently, terms such as “double pneumonia” and “shock lung” were used to describe this syndrome, before the term “acute respiratory distress syndrome” was coined by Ashbaugh and colleagues in 1967.8 ARDS may result from intrapulmonary or extrapulmonary mechanisms, and indeed the cause is often multifactorial. It develops most commonly in the context of severe bacterial and viral pneumonia, nonpulmonary sepsis, aspiration, and trauma. Some of the less common causes of ARDS are included in Table 18.2. Perioperative lung injury results from a complex interaction between the patient’s physiologic state, the underlying surgical diagnosis and technique, and interaction with the mechanical ventilator. Although ARDS is a common entity, it is important to understand that there are many clinical pathologies that mimic ARDS and should be considered, especially in the absence of an inciting factor (Table 18.3).9

Table 18.2

Different Causes of Acute Respiratory Distress Syndrome
Intrapulmonary Extrapulmonary
Pneumonia Sepsis
Aspiration Trauma
Pulmonary contusion Acute pancreatitis
Fat embolism Cardiopulmonary bypass
Drowning TRALI
Inhalational injury Intracranial hemorrhage
Reperfusion syndrome  

TRALI, Transfusion associated acute lung injury.

Table 18.3

Diseases That May Be Mistaken for Acute Respiratory Distress Syndrome
Disease Characteristic Findings That May Help Differentiate From Acute Respiratory Distress Syndrome
Congestive heart failure Usually central symmetric interstitial and alveolar opacifications; pleural effusions, pulmonary venous congestion
Idiopathic pulmonary fibrosis Traction bronchiectasis, honeycombing, predominantly in bases, scattered ground glass opacification
Cryptogenic organizing pneumonia Bilateral, peripheral opacifications; diffuse or patchy ground glass opacifications, patchy air-space opacification, and small nodules
Nonspecific interstitial pneumonitis Interstitial opacifications, symmetric, peripheral, subpleural
Granulomatosis with polyangiitis Hemoptysis; alveolar and interstitial opacifications; multiple nodules 2–8 cm diameter, frequently with cavitation, may present with glomerulonephritis
Diffuse alveolar hemorrhage Hemoptysis; diffuse alveolar infiltrates, usually bilateral, increasingly bloody lavage return
Goodpasture syndrome Hemoptysis; may present with acute kidney failure, increasingly bloody lavage return
Acute hypersensitivity pneumonitis Presents within several hours of offending antigen
Acute eosinophilic pneumonia Eosinophilia
Drug-induced lung disease Known exposure to amiodarone, bleomycin, or other pneumotoxic drug

Modified from Guérin C, Thompson T, Brower R. The ten diseases that look like ARDS. Intensive Care Med. 2015;41:1099–1102.

Several comorbidities and exposures have been implicated in elevating the risk for developing ALI, and or worse outcomes, including excessive alcohol consumption,10 cigarette smoking,11 and environmental pollutants.12 Data from the United States and the United Kingdom suggest there is also an association between mortality, ethnicity, and gender. Black, Asian, and minority ethnicity patients and male patients have a higher than average mortality from ALI than White and female patients.13 The biologic cause for such disparities, beyond social inequality, is not clear. Erickson and colleagues concluded that it appeared to be mediated by increased severity of illness at presentation for Black patients but could not explain the increase seen among Hispanics in the United States.13


The plain chest radiograph appearance that is consistent with ARDS is that of bilateral diffuse alveolar opacification, although it has been demonstrated that there is significant interobserver variability, and the findings may be subtle.14 As the severity worsens, the consolidation becomes more apparent.14 Computed tomography (CT) scanning of patients with ARDS reveals a more detailed picture of the heterogeneous nature of the lung injury than chest x-ray. The information gained from the CT scan can help quantify the extent of the abnormalities and localize them.15

The classic findings of early ARDS on CT scan are: (1) normal (or near-normally) aerated lung regions with minimal pathologic findings, most commonly in the least dependent zones of the lung. These tend to be ventral when the patient is supine; (2) a hazy increase in lung attenuation, with preservation of bronchial and vascular margins, known as ground glass opacification in the middle lung; and (3) consolidative changes in the most dependent (dorsal) zones of the lung, appear as a homogeneous increase in lung attenuation that obscures bronchovascular margins in which air-bronchograms may be present.15,16

Lung ultrasound (LUS) is being used with increasing frequency to aid in the diagnosis of ARDS, and to help differentiate it from other lung pathologies (see Ch. 54). It has been demonstrated that LUS can identify the principal pathologic findings in ARDS with reasonable sensitivity and specificity.17 International evidence-based recommendations for the use of LUS were established in 2012.18 LUS is recommended as a tool to help evaluate and differentiate between fibrotic lung disease, pulmonary edema, and ARDS.18

The four main patterns that are seen on LUS are summarized from these guidelines as follows:

  1. 1. Normally aerated lung, represented by lung sliding and artifactual horizontal repetitions of the pleural line, known as A-lines.
  2. 2. Alveolar-interstitial syndrome, represented by the presence of three or more discrete laser-like vertical hyperechoic reverberation artifacts arising from the pleural line, extending to the bottom of the screen without fading, and moving synchronously with lung sliding, known as B-lines.
  3. 3. Consolidation, represented as a subpleural area consisting of tissue-like echodensities interlaced with echo-poor areas which are indicative of dynamic air bronchograms.
  4. 4. Pleural effusions, represented by an anechoic space between the parietal and visceral pleura, with respiratory movement of the lung within the effusion.18,19

When compared with CT scanning, LUS has shown reasonable sensitivity and specificity (82.7%–92.3% and 90.2%–98.6%, respectively) in the diagnosis of ARDS.19 Its portability, lack of radiation, and steep learning curve make it an ideal tool in many situations to assist in diagnosis ARDS.

The Normal Lung

The alveolocapillary barrier separates alveolar gas from pulmonary blood. It is by necessity extremely thin and has a large surface area to allow sufficient and rapid diffusion of gases. The alveolar epithelial cells form the external layer and the endothelial cells the internal layer. Both cell layers are supported by their respective basement membranes and separated by the pulmonary interstitial space—a “potential space” in the gas exchange regions. Type I alveolar epithelial cells are large, extremely flattened cells that cover approximately 95% of the lung’s surface area. These cells form a thin lining over the external interface (alveolar surface) and bind to adjacent cells via tight intercellular junctions. The cuboidal type II alveolar epithelial cell is the more complex and metabolically active alveolar cell; whose functions include: surfactant production, proliferation, and differentiation into type I cells following injury, and sodium and chloride ion transport.20 The pulmonary endothelial cells line the capillaries within the lung parenchyma (Fig. 18.1).

• Fig. 18.1 The normal alveolus. Schematic representing the continuous monolayer of thin type I alveolar cells (allowing gas exchange), and the type II alveolar cells (which produce surfactant). (Modified from Adeniji K, Steel AC. Effects of intraoperative fluid management on postoperative outcomes after lobectomy. Anesthesiol Clin 2012;30:573–590.)

Pathophysiology of the Injured Lung

The pathology of the injured lung in ARDS was first described in 1977 by Marianne Bachofen and Ewald Weibel in their seminal publication on respiratory insufficiency in septicaemia.21 Since their early clinical and pathologic descriptions, considerable basic and clinical research has been devoted to understanding the pathogenesis and determinants of clinical outcomes in ALI.


There has been significant investment in research to identify genetic factors that: increase susceptibility to ALI or delineate genetic subtypes. The advantages of identifying the “gene for ALI” would be to determine those at risk and to appropriately match intervention(s) with subtype.

Although no specific gene has been identified for ARDS, there has been some success identifying candidates that are associated with the pathologic mechanisms that in turn confer higher mortality, for example, lung vascular permeability and the angiopoietin 2 gene (ANGPT2).22

Pathologic Phenotype

The pathologic phenotype of ALI is “diffuse alveolar damage,” (Fig. 18.2). The degree of alveolar epithelial injury and increased vascular permeability, leading to the formation of pulmonary edema, is a valuable predictor of outcome. Biopsies taken from the lungs of patients, within the first 7 days of ALI, display the histologic features of cell death, epithelial hyperplasia, inflammation, disordered coagulation, and fibrinolysis. In addition, there is an alveolar cellular infiltrate, rich with neutrophils, macrophages, and erythrocytes. The normal alveolar epithelium of type I and type II alveolar cells is anatomically and functionally disrupted. The tight barrier that selectively restricts the movement of solutes is denuded and becomes lined by fibrin-rich hyaline exudates.23

• Fig. 18.2 The injured alveolus. Schematic representing the effects (red arrows) of the inflammatory cascade on cellular components of the alveolar capillary barrier that influence prognosis. ALI, Acute lung injury; NFkB, nuclear factor κB; SpD, surfactant protein D. (From Adeniji K, Steel AC. Effects of intraoperative fluid management on postoperative outcomes after lobectomy. Anesthesiol Clin 2012;30:573–590. With permission.)

Edema Formation

The reabsorption of fluid in the alveolus depends on the integrity and health of the barrier of type I and type II alveolar cells. This monolayer of cells is linked by tight junctions and adherens junctions, and both are key to the transport of ions and fluid from the airspace. Loss of epithelial integrity and injury to type II cells will disrupt normal fluid and cellular transport; leading to impaired fluid removal from the alveolar space,24 septic shock in patients with pneumonia,25 and impaired surfactant production.26

Surfactant Production

The type II alveolar epithelial cell is the more complex alveolar epithelial cell. It is a highly metabolically active cell, most appreciated for the synthesis and secretion of pulmonary surfactant proteins. There are four such proteins, A to D, responsible for reducing alveolar surface tension, enabling them to remain open. Dysfunction contributes to inhomogeneous airspace collapse, and low levels of protein D are associated with increased mortality.

Surfactant release is initially enhanced by high-volume ventilation. However, the increased surface area of the alveoli increases the rate at which surfactant is released, eventually exceeding the rate of production.27 Higher tidal volumes also increase the conversion of the large aggregate surfactant on epithelial cells. Eventually, the basement membrane gives way, leading to alveolar hemorrhage.28 Finally, the increasing alveolar pulmonary edema fluid contains serum proteins and proteases that disable surfactant proteins.29

The clinical significance of flooding of the alveolar airspaces is that it rapidly impairs adequate ventilation, resulting in hypoxemia from ventilation-perfusion mismatch and intrapulmonary shunt. Additional right-to-left shunt from reabsorption atelectasis, secondary to alveolar denitrogenation, may also contribute when high levels of oxygen are administered.30 In the presence of protein-rich pulmonary edema fluid, cellular infiltrate, and a reduction in functionally active surfactant, will results in a dramatic reduction in thoracic compliance.

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Oct 6, 2021 | Posted by in ANESTHESIA | Comments Off on Pathophysiology of Perioperative Lung Injury
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