1. Acute lung injury and outcomes after thoracic surgery
Marc Lickera, Pascal Fauconneta, Yann Villigera and Jean-Marie Tschoppb
a
Department of Anaesthesiology, Pharmacology and Purpose of review
Intensive Care, rue Micheli-du-Crest, University
Hospital of Geneva, Geneva and bDepartment of
The present review evaluates the evidence available in the literature tracking
Internal Medicine, Chest Medical Centre, Montana, perioperative mortality and morbidity as well as the pathogenesis and management of
Switzerland
acute lung injury (ALI) in patients undergoing thoracotomy.
Correspondence to Marc Licker, MD, Service Recent findings
´ ˆ `
d’Anesthesiologie, Hopitaux Universitaires de Geneve,
Rue Micheli-du-Crest, CH-1211 Geneva, Switzerland Over the last decade, despite increasing age and comorbid conditions, the operative
Tel: +41 22 3827439; fax: +41 22 3827403; mortality has remained unchanged for patients undergoing lung resection, whereas
e-mail: licker-marc-joseph@diogenes.hcuge.ch
procedure-related complications have declined. Better clinical outcomes are achieved
Current Opinion in Anaesthesiology 2009, in high-volume hospitals and when procedures are performed by a thoracic surgeon.
22:61–67
Postthoracotomy ALI has become the leading cause of operative death, its incidence
has remained stable (2–5%) and earlier diagnosis can be made by assessing the
extravascular lung water volume with the single-indicator dilution technique. The
pathogenesis of ALI implicates a multiple-hit sequence of various triggering factors (e.g.
oxidative stress and surgical-induced inflammation) in addition to injurious ventilatory
settings and genetic predisposition.
Summary
Knowledge of the perioperative risk factors of major complications and understanding of
the mechanisms of postthoracotomy ALI enable anesthesiologists to implement
‘protective’ lung strategies including the use of low tidal volume (VT) with recruitment
maneuvers, a goal-directed fluid approach and prophylactic treatment with inhaled
b2-adrenergic agonists.
Keywords
acute lung injury, lung resection, mechanical ventilation, thoracotomy, tidal volume
Curr Opin Anaesthesiol 22:61–67
ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907
Introduction Risk factors of operative mortality
Thoracotomies with lung resection are classified as inter- Outcomes following lung resection largely differ between
mediate-to-major surgical procedures with in-hospital specialized and nonspecialized medical centres.
mortality rates expected to be less than 2% for lobectomy Mortality rates as low as 2.2% have been reported in a
and less than 6% for pneumonectomy [1,2]. Among French survey including 15 183 patients managed by
512 578 thoracic procedures performed from 1988 to specialized thoracic teams, whereas fatality rates as high
2002 in the United States, several changes have been as 12% have been observed in the US nationally repre-
identified: surgical candidates are more likely to be older sentative samples of Medicare patients aged over 65 years
(mean age of 63 years), women (40%) and to undergo [4,5]. Qualified cardiothoracic surgeons devoting their
lobectomy instead of pneumonectomy due to earlier practice entirely or mainly to thoracic surgery achieve
diagnosis of cancer stages [3]. Despite higher comorbid better results than nonspecialized surgeons [6]. Improved
status, operative mortality has remained unchanged and short and long-term results are also achieved in hospitals
the length of hospital stay has become shorter along with with a high volume of any complex procedure, emphasiz-
a reduction of procedure-related complications. Nowa- ing the key role of multidisciplinary teams, the avail-
days, the main causes of mortality have shifted from ability of intensive care resources with an acute pain
cardiac and surgical complications towards infectious service as well as the implementation of scientifically
complications (pneumonia, empyema and sepsis) and evidence-based practices [7,8].
the acute lung injury (ALI) syndrome with its most
severe form the acute respiratory distress syndrome Apart from these organizational factors, analysis of the
(ARDS). European Thoracic Surgery Database and of the French
0952-7907 ß 2009 Wolters Kluwer Health | Lippincott Williams Wilkins DOI:10.1097/ACO.0b013e32831b466c
Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

2. 62 Thoracic anaesthesia
Table 1 Overview of studies on the postthoracotomy acute lung injury syndrome
Incidence (%)
Reference n Risk factors Overall P L L Mortality (%)
Licker et al. [11] 879 MV, high Pinsp aw, fluid overload (first 24 h), 4.2 8.4 3.1 3.4 37
pneumonectomy, alcohol abuse
Ruffini et al. [12] 1221 NA 2.2 3.8 2 3.2 52
Kutlu et al. [13] 1139 Age 60 years, male sex, lung cancer, extended 3.9 6 3.7 1 64
resection
Alam et al. [14] 1428 ppoFEV1, ppoDLC0, fluid overload (intraoperative) 3.1 10.1 5.5 4.1 25
Dulu et al. [15] 2192 NA 2.5 7.9 3 0.9 40
Fernandez-Perez [16] 170a High VT (8.3 vs. 6.7 ml/kg), fluid overload NA 8.8 40
(intraoperative)
van der Werff et al. [17] 197 MV, high Pinspir aw, fresh-frozen plasma 2.5 100
Turnage et al. [18] 806 NA 2.6 100
Verheijen-Breemhar et al. [19] 243 NA 4.5 27
Waller et al. [20] 205 NA 4.4 56
Algar et al. [21] 242a Operative time, ppoFEV1, prior cardiac disease, 2.5 2.5
COPD, no chest therapy (preoperative)
Song et al. [22] 635 NA 3.6 48
Katzenelson et al. [23] 146a Prior chemotherapy, prior chemotherapy, FEV1 15 15
45% predicted, predicted postoperative lung
perfusion 55%, fluid overload (intraoperative)
COPD, chronic obstructive pulmonary disease; L, lesser resection than lobectomy; L, lobectomy; MV, mechanical ventilation; Pinspir aw, inspiratory
airway pressure; P, pneumonectomy; ppoDLCO, predicted postoperative diffusion lung capacity to carbon monoxide; ppoFEV1, predicted post-
operative forced expiratory volume in 1 s; VT, tidal volume; NA, not applicable.
a
Only pneumonectomy cases.
national dataset have identified independent risk factors from almost 100% to less than 40% owing to improved
of perioperative death: age, male sex, dyspnea score, ICU medical management (Table 1) [11–22].
functional performance status, American Society of
Anesthesiologists (ASA) score and the extent of surgical New semiinvasive monitoring tools have appeared in the
resection [4,9]. These models of risk have been validated perioperative arena providing valuable information for
in second sets of population, with good predictive accu- early diagnosis of ALI and haemodynamic treatment.
racies (c-index ! 0.85). The single-indicator thermal dilution method (Pulsion,
Munich, Germany) has been validated against the gravi-
metric method to assess the extravascular lung water
Epidemiology and diagnostic criteria of acute index (EVLWI) [23]. This simple technique has proven
lung injury sensitive to detect infraclinical variations in EVLWI, to
The guidelines set out by the American–European estimate a pulmonary vascular permeability index while
Consensus Conference on ARDS have been widely monitoring cardiac output using pulse contour analysis of
adopted to describe postthoracotomy ALI, previously the arterial pressure [24]. Pulmonary artery catheters
coined postpneumonectomy pulmonary oedema, low- have been replaced by ultrasound imaging for cardiocir-
pressure oedema or permeability pulmonary oedema. culatory assessment. Chest ultrasound scans can also be
Although the diagnosis of ALI/ARDS relies on specific used to detect excess lung water content. ‘Comet-tail
criteria [acute onset of hypoxemia, arterial oxygen pres- images’ fanning out from the lung surface and originating
sure (PaO2)/fraction of inspired oxygen (FIO2) less than from water-thickened interlobular septa have been
300 for ALI and less than 200 for ARDS, diffuse radio- shown to correlate closely with lung water content
logical infiltrates and no evidence of elevated hydrostatic [25,26].
capillary pressure], a wide spectrum of lung injuries is
encountered [10]. Importantly, two clinical patterns of
postthoracotomy ALI should be distinguished corre- Clinical risk factors and pathophysiology of
sponding to different pathogenic triggers: ALI develop- postthoracotomy acute lung injury
ing within 48–72 h after lung resection (primary ALI) and Several risk factors of the early form of postthoracotomy
a delayed form triggered by postoperative complications ALI have been identified in cohorts of thoracic surgical
such as bronchoaspiration or pneumonia [11]. patients. Using multivariate regression analysis, the
strongest predictors of postthoracotomy ALI are related
Contrasting with other cardiopulmonary complications, to the preoperative condition of the patient (severe
the incidence of postthoracotomy ALI has not shown any pulmonary dysfunction and chronic alcohol consump-
noticeable decrease over the last two decades (between 2 tion) and to perioperative medical care (extended lung
and 4%) although the case-fatality rate has decreased resection, ‘injurious’ ventilation and fluid overhydration)
Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

3. ALI and outcomes after thoracic surgery Licker et al. 63
[11]. Moreover, the occurrence of ALI is more frequently [e.g. antioxidant, heat-shock protein, p75 receptor for
reported after right pneumonectomy in elderly patients tumor necrosis factor (TNF)-a] counteract the initial
with colonized airways or in those requiring multiple inflammatory and oxidative responses [38,39]. The in-
transfusions or receiving neoadjuvant chemoradiotherapy creased permeability of the alveolar–capillary barrier along
[27–29]. with a decreased lung compliance initially results from the
disruption of intercellular endothelial cell junction, cytos-
Rather than a unified stereotyped response, a multiple- keleton contraction and alveolar cell death consequent
hit sequence of deleterious events likely interacts to activation of endothelial/epithelial cell receptors by
resulting in alveolar epithelial and capillary endothelial systemic/alveolar inflammatory mediators [e.g. thrombine,
injuries, with alterations in extracellular matrix (ECM), vascular endothelial growth factor (VEGF), transforming
ultimately leading to the characteristic histopathological growth factor-beta (TGF-b) and thromboxane A2 (TxA2)]
features of ALI [30]. [40–42].
The ‘neutrophil hypothesis’ suggests that circulating Clinical studies
neutrophils are activated by proinflammatory mediators In the ICU setting, the benefits of a protective lung
such as granulocyte and macrophage–colony stimulating ventilation (PLV) strategy have been clearly documented
factors in concert with various chemokines. These neu- in large observational studies and meta-analysis of random-
trophils experience delayed apoptosis and sustained ized controlled trials (RCTs) [43]. In clinical practice, PLV
release of proteolytic enzymes, reactive oxygen inter- entails the delivery of low VT (less than 7 ml/kg) with
mediates/reactive nitrogen intermediates (ROIs/RNIs) pressure-limited ventilation (less than 30 cm of H2O) and
as well as proinflammatory mediators [31]. the application of positive end-expiratory pressure (PEEP)
with periodic recruitment maneuvers [44].
The ‘epithelial hypothesis’ emphasizes the role of both
lung parenchymal cell apoptosis and chemotactic/inflam- During short periods of mechanical ventilation (4–6 h),
matory responses, which are associated with increased atelectatic areas are common and so-called ‘low-volume’
expression of Fas on epithelial cells, along with enhanced injuries may result from repetitive opening and closing of
extravasation of Fas ligand-expressing cells [32]. unstable lung units owing to inactivation of surfactant and
excessive mechanical stress between neighboring lung
Ventilatory strategy areas [45,46].
Recent experimental and clinical studies have empha-
sized the ‘injurious’ aspects of physical stress and hyper- Several RCTs including surgical patients with healthy
oxia associated with mechanical ventilation that may lungs have questioned whether different ventilatory set-
trigger inflammatory changes at the alveolar–capillary tings could modulate pulmonary/systemic inflammation
barrier in ‘vulnerable’ surgical patients as characterized while influencing oxygenation index and respiratory
by genetic factors, disrupted lympathic vessels and pro- mechanical properties [47]. As summarized in Table 2
inflammatory circulating mediators associated with pre- [48–59], no benefit could be demonstrated by varying the
existing lung disease or surgical trauma. VT for surgical procedures lasting less than 5 h [48,49]. In
contrast, in all studies, except one including more severe
Basic science surgical stresses (e.g. major operations exceeding 5 h and
Even ‘physiological’ low VT (4–8 ml/kg) delivered over cardiac surgery), intraoperative ventilation with lower VT
several hours in healthy lungs may produce subtle lung (5–6 ml/kg) and PEEP was associated with stable or
injuries: neutrophil infiltration, rupture of alveolar–bron- improved oxygenation, reduced expression of alveolar
chial attachment and chondroitin–sulfate proteoglycan and systemic inflammation and reduced procoagulant
fragmentation in the ECM [33]. With larger VT, there is activity in the bronchoalveolar lavage fluid (BALF) [50–
further macromolecular fragmentation, activation of 55]. In agreement with these data, Lee et al. [57] reported a
matrix metalloprotease and upregulation of collagen syn- trend for lower incidence in pulmonary complications and
thesis in the ECM that represent an autoregulatory for shorter intubation periods in patients ventilated with
response to maintain low pulmonary compliance while small VT (6 vs. 12 ml/kg) after major noncardiac surgery.
protecting the ECM against fluid overload [34–36]. Inter-
estingly, induction of unilateral ventilator-induced injury In patients undergoing thoracotomy and requiring one-
(VILI) in one lung with high VT does not trigger a lung ventilation (OLV), three RCTs have evaluated
concomitant inflammatory response in the contralateral the impact of different ventilatory settings. Schilling
normally ventilated lung [37]. et al. [58] found reduced alveolar concentrations of
TNF-a and soluble intercellular adhesion molecules
Ventilation with large VT is not sufficient per se to induce (ICAMs) in patients ventilated with small vs. large VT
ALI in healthy lungs, as defense and repair mechanisms (5 vs. 10 ml/kg). Confirming these positive results,
Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

4. 64 Thoracic anaesthesia
Table 2 Randomized controlled trials assessing the effects of different modes of ventilation
Reference n Type of surgery Ventilation strategy Effects of low vs. high VT
Two-lung ventilation
Wrigge et al. [48] 39 Visceral, orthopedic 5 ml/kg ZEEP vs. 5 ml/kg Similar plasma cytokine levels
and vascular 10 cmH2O PEEP vs.
15 ml/kg 10 PEEP
Wrigge et al. [49] 32 Visceral 6 ml/kg 10 cmH2O PEEP Similar time course of cytokines in tracheal
vs. 12–15 ml/kg ZEEP aspirate and plasma
Choi et al. [50] 40 Visceral 6 ml/kg cmH2O PEEP Thrombin–antithrombin complex, activated
vs. 12 ml/kg ZEEP protein C in BALF, thrombomodulin
in BALF
Wolthuis et al. [51] 40 Visceral 6 ml/kg 10 cmH2O PEEP Similar levels of TNF-a, IL-1, MIP-1 in BALF,
vs. 12 ml/kg ZEEP IL-8 in BALF, myeloperoxidase and
elastase in BALF, similar levels of IL-6 and
IL-8 in plasma
Reis-Miranda et al. [52] 62 Cardiac 4–6 ml/kg 10 cmH2O IL-8 and IL-10 in plasma
PEEP þ RM vs.
6–8 ml/kg 3 cmH2O PEEP
Chaney et al. [53] 25 Cardiac 6 ml/kg 10 cmH2O PEEP PaO2/FIO2, static lung compliance
vs. 12 ml/kg ZEEP
Zupancich et al. [54] 40 Postcardiac 6 ml/kg 10 cmH2O PEEP IL-6 and IL-8 in BALF and plasma
vs. 10–12 ml/kg
3 cmH2O PEEP
Koner et al. [56] 44 Cardiac 6 ml/kg 5 cmH2O PEEP Similar plasma TNF-a and IL-1, similar
vs 0.10 ml/kg ZEEP vs. PaO2/FIO2
10 ml/kg 10 cmH2O PEEP
Lee et al. [57] 103 General 6 vs. 12 ml/kg Pulmonary infection, duration of MV
Wrigge et al. [55] 44 Cardiac 6 ml/kg 10 PEEP TNF-a in BALF, similar plasma cytokine levels
vs. 12 ml/kg ZEEP
One-lung ventilation
Wrigge et al. [49] 32 Lung resection 6 ml/kg 10 cmH2O PEEP Similar time course of cytokines in tracheal
vs. 12–15 ml/kg ZEEP aspirate and plasma
Schilling et al. [58] 32 Lung resection 5 ml/kg ZEEP vs. 10 ml/kg ZEEP TNF-a and sICAM in BALF, similar levels of
albumine, elastase, IL-8 and IL-10
Michelet et al. [59] 52 Esophagectomy 5 ml/kg 5 cmH2O PEEP vs. IL-1, IL-6, IL-8 in plasma, PaO2/FiO2 and
9 ml/kg ZEEP lung water content, duration of MV
BALF, bronchoalveolar lavage fluid; MV, mechanical ventilation; PaO2/FIO2, ratio of arterial oxygen pressure to fractional inspiratory oxygen pressure;
PEEP, positive end-expiratory pressure; RM, recruitment maneuver; sICAM, soluble intercellular adhesion molecules; TNF, tumor necrosis factor;
ZEEP, zero-end expiratory pressure.
Michelet et al. [59] reported an attenuated systemic proin- trigger formation of ROIs/RNIs and induce complex
flammatory response [lower plasma levels of interleukin patterns of cell death. These findings have been con-
(IL)-6], reduced EVLWI and improved oxygenation index firmed in animal and human studies.
allowing earlier extubation in patients undergoing esopha-
gectomy who received low VT (5 ml/kg) with a PEEP level In rabbits ventilated with large VT and moderate hyperoxia
of 5 cmH2O (compared with VT of 10 ml/kg with zero (FIO2 ¼ 0.5), Sinclair et al. [60] reported a loss of alveolar–
PEEP). In contrast, Wrigge et al. [49] failed to document capillary barrier integrity and larger increase in local
any difference in systemic inflammatory markers, blood inflammatory mediators (IL-8 and TNF-a) than animals
oxygenation index and respiratory mechanics between exposed either to room air or to hyperoxia without large VT.
thoracic surgical patients assigned to receive either mech- Consistent with these results, Funakoshi et al. [61]
anical ventilation with VT of 6 ml/kg and PEEP of reported an upregulation of proinflammatory cytokines
10 cmH2O or a VT of 12–15 ml/kg without PEEP. and myeloperoxidase upon reventilation, though indices
of pulmonary capillary permeability remained unchanged.
Although a growing body of scientific knowledge indicates Likewise, in anesthetized pigs subjected to thoracotomy
that the ‘traditional’ ventilatory settings may be injurious and OLV (VT of 10 ml/kg, PEEP of 5 cmH2O and FIO2 of
in the healthy lungs, a clear demonstration of clinical 0.4), Kozian et al. [62] showed hyperperfusion, ventilation–
outcome benefits induced by LPV is still lacking. There- perfusion mismatch and diffuse tissue damage that pre-
fore, we are awaiting the results of well designed RCTs dominated in the dependent nonoperated lung.
with sufficient power and pertinent clinical endpoints,
comparing conventional ventilation to LPV protocols. In three patients with reexpansion pulmonary oedema,
Her and Mandy [63] observed leukocyte-mediated ALI
Hyperperfusion and oxidative injuries in the contralateral lung along with decreased leuko-
In-vitro studies have shown that cyclic stretch and hyper- cytes and platelet counts upon reoxygenation of the col-
oxic exposure of lung epithelial and endothelial cells lapsed lung. In another clinical study involving patients
Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

5. ALI and outcomes after thoracic surgery Licker et al. 65
undergoing lobectomy, Cheng et al. [64] reported for- have been incriminated as initiating or aggravating factors
mation of ROIs during lung reinflation after OLV (VT of [71]. Likewise, the interactions with ROIs/RNIs and
10 ml/kg and FIO2 of 1.0) although antioxidant markers nuclear factor-kB-dependent activation of the inducible
and EVLWI remained unchanged. nitric oxide synthase may result in downregulation of b2-
adrenergic receptor in response to surgical trauma and
Taken together, these data suggest that hyperoxic/ OLV/reoxygenation. Hence, early and severe interstitial/
mechanical injuries predominate in the nonoperated alveolar lung edema may develop in patients with
lung, whereas the operated lung is prone to atelectasis deficient b-adrenergic-mediated fluid clearance mechan-
formation due to impaired surfactant and direct surgical isms.
manipulation. An imbalance between antioxidants and
excess production of RNIs/ROIs has been incriminated
in perpetuating the inflammatory process and causing Novel perioperative approaches
cellular damage by oxidizing nucleic acids, proteins and Preliminary data suggest some advantages for volatile
membrane lipids [65]. anesthetics during OLV. Indeed, desflurane has been
associated with lesser recruitment of neutrophils and
Genetic factors reduced concentrations of inflammatory biomarkers in
Only a fraction of patients exposed to ALI-inciting events the BALF [elastase, soluble intercellular adhesion mol-
progress to the full clinical syndrome. Hence, major ecules (sICAM), TNF-a, IL-8 and IL-10] than propofol
interest has been focused on the identification of genetic anesthesia [73].
factors characteristic of ALI susceptibility. Relevant gene
variants or single-nucleotide polymorphisms (SNPs) in Regarding ventilatory settings, the emerging concept of
these ALI candidate genes have been tested for differ- PLV based on the ‘open-lung approach’ aims to limit
ences in allelic frequency in cohort studies [66]. This alveolar distension with low (but physiological) VT while
approach has yielded a number of candidate genes con- attenuating the loss of functional residual volume and
tributing towards an ALI phenotype, namely genes cod- preventing the formation of atelectasis with PEEP and
ing for angiotensin-converting enzyme (ACE), surfactant lung recruitment maneuvers [74,75]. Using ‘low VT’
protein B, heat-shock protein 70, pre-B-cell colony combined with PEEP does not favor the development
enhancing factor, myosin light-chain kinase and macro- of atelectasis, whereas the pressure-controlled mode of
phage migration inhibitory factor. ventilation (vs. volume-controlled mode) may lower peak
airway pressure with similar blood oxygenation indices, at
Using microarray technology, the transcription factor least in patients without severe lung disease [76,77].
Nrf2 (NF-E2 related factor 2) has been shown to up-
regulate the protective detoxifying enzymes in response Controversies still surround the question of the optimal
to oxidative stress [67]. Genetic disruption of the Nrf2 FIO2; high levels (60–80%) may reduce the risk of surgi-
has been associated with an overexpression of proinflam- cal-site infections but promote atelectasis and ROI for-
matory cytokines and increased risk of ALI due to hyper- mation [78]. Conversely, low–moderate FIO2 (30–50%)
oxia and high VT. In line with these results, Marzec et al. might be an appropriate compromise to ensure satisfactory
[68] identified six novel SNPs for Nrf2 in a nested case– blood oxygenation and limit secondary lung injuries.
control study. Patients with the À617 SNP (A/or C/A
allele) were at greater risk of posttrauma ALI relative to Considering the importance of the hydrostatic pulmonary
patients bearing the wild type (À617 C) [odds ratio (OR) pressure, a restrictive or goal-directed fluid approach
6.4; 95% confidence interval (CI) 1.3–30.8]. coupled with the assessment of intrapulmonary fluid
volume is strongly recommended for the intraoperative
In patients undergoing esophagectomy (n ¼ 152), pul- period and the first 24–48 h after major lung resection.
monary morbidity has been associated with an ACE
insertion/deletion polymorphism; the D/D genotype Postoperatively, high-risk thoracic patients may benefit
was found to be highly predictive of major pulmonary from noninvasive ventilation and inhaled b2-adrenergic
complications (adjusted OR 3.12; 95% CI 1.01–9.65) [69]. therapy. In a small RCT including 32 patients with a
moderate degree of chronic obstructive pulmonary dis-
Edema clearance mechanisms ease, better postoperative recovery of pulmonary func-
Removal of the excess intraalveolar fluid is mainly influ- tion was reported when noninvasive pressure support
enced by epithelial b-adrenergic receptors and lectin-like ventilation was applied prophylactically before and
domain of TNF-a that regulate the active sodium trans- shortly after lung resection [79]. In 21 patients at high
port through alveolar type I and II cells [70–72]. In heart risk of pulmonary edema from either a cardiogenic or
failure, high-altitude lung edema and various models of noncardiogenic cause, the impact of aerosolized broncho-
ALI, alterations in these b-adrenergic signaling pathways dilators has been investigated using the single-dilution
Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

6. 66 Thoracic anaesthesia
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