Mechanical Ventilation During General Anesthesia

Transcription

1 In: General Anesthesia Research Developments ISBN: Editor: Milo Hertzog and Zelig Kuhn 2009 Nova Science Publishers, Inc. Chapter 5 Mechanical Ventilation During General Anesthesia Marco Luchetti * Department of Anesthesia and Intensive Care, A. Manzoni Hospital, Lecco, Italy) Abstract General anesthesia can depress ventilation, determining variations in pulmonary mechanics and alteration of gas exchange, often related to underlying anatomical and physiological status. A reduction in end expiratory lung volume and an increase in airway closure is common during general anesthesia or deep sedation in normal and obese individuals. Atelectasis causes a reduction of functional residual capacity (FRC) and ventilation perfusion mismatch or intrapulmonary shunt. Furthermore, airway closure can be injurious to the lungs, resulting in both inflammatory changes and disruption of lung architecture. Mechanical ventilation represented a major advance in the administration of anesthesia and allowed the performance of surgical operations once impossible. Until a few years ago, mechanical ventilation during general anesthesia was fairly simple, since the ventilators available for use in the operating rooms were not much sophisticated. Recently, the ventilators have increased in sophistication and this challenges the anesthesiologist to become more aware of the new modes and features. In particular, the concept of lung protective ventilation has been demonstrated to be applicable not only to intensive care ventilation but also to intraoperative ventilation, in order to reduce the risk of ventilator-induced lung injury. Positive end expiratory pressure (PEEP) is the primary means of maintaining alveolar recruitment and returning FRC towards awake values during controlled ventilation in the anesthetized patient. Recent clinical data suggest that the use of a * Correspondence Address: Department of Anesthesia and Intensive Care 1 A. Manzoni Hospital Via dell Eremo 9/ Lecco Italy. m.luchetti@fastwebnet.it

2 2 Marco Luchetti reduced tidal volume (6 ml/kg) with moderate levels of PEEP may be beneficial to prevent lung injury and postoperative complications. In this review, we describe the mechanisms responsible for the impairment of intraoperative respiratory function and discuss several aspects of mechanical ventilation that can be employed to improve patients outcome. Keywords: mechanical ventilation; general anesthesia; positive end-expiratory pressure; atelectasis; airway closure. Effects of Anesthetic Agents on Respiratory Function General anesthesia alters respiratory function significantly at every level, from upper to lower airways. Optimizing intraoperative ventilation requires appropriate understanding of the basic mechanisms responsible for gas-exchange impairment induced by anesthesia. In this review we will focus on the influence of general anesthesia on pulmonary function, describing the mechanisms responsible for the impairment of intraoperative respiratory function and discussing several aspects of mechanical ventilation that can be used to improve patients outcome. In combination with neuromuscular blockers, anesthetic agents cause a marked reduction in functional residual capacity (FRC) due to diaphragm and chest wall relaxation, thereby decreasing thoracic volume [1]. This decrease in lung volume induces atelectasis in the dependent lung regions that may persist in the postoperative period. Hence, arterial hypoxemia occurs from ventilation/perfusion mismatch and increase in shunt fraction. It has been demonstrated that the impairment in arterial oxygenation during anesthesia is more severe in the elderly, the obese, and smokers [2]. Hypoventilation, increased dead space ventilation, and increased carbon dioxide (CO 2 ) production are all possible causes of hypercapnia. Patients spontaneously tend to hypoventilate during anesthesia because breathing is more difficult (abnormal surgical position, increased airway resistance, decreased compliance) and the respiratory drive is decreased [3]. In addition, during general anesthesia and mechanical ventilation the dead space increases due to the gas volume in ventilatory circuit. The halogenated anesthetic agents at anesthetic concentrations affect ventilatory control at a number of sites. Halothane causes ventilatory depression by abolishing peripheral chemoreceptor drive, by depressing the central nervous system, and by suppressing the function of the intercostal muscles and diaphragm [3]. These actions are mediated by indirect actions on afferent, central, and efferent neural pathways, as well as direct actions on the lungs. The depressant effects of these drugs are further enhanced in patients with pulmonary disorders. Halothane, enflurane, isoflurane, desflurane, and sevoflurane have dose-related effects at steady-state anesthetic concentrations [3] including: decrease of tidal volume (TV); increase of end tidal CO 2 ; increase in ventilatory rate; depression of resting ventilation; depression of the ventilatory response to hypercapnia; and abolition of the response to hypoxia. Volatile anesthetics reduce bronchial smooth muscle tone, adversely affect mucociliary function, and dilate pulmonary vasculature. Inhibition of hypoxic pulmonary vasoconstriction

3 Mechanical Ventilation During General Anesthesia 3 (HPV) by inhalational anesthesia is well recognized [4]. Identification of the molecular targets of halothane and their involvement in HPV are beginning to elucidate the mechanisms of this inhibition [5]. However, the newer inhalation anesthetics isoflurane, desflurane, and sevoflurane, for the most part, appear not to cause significant depression in clinically relevant doses. In physiologic conditions, pulmonary surfactant decreases the work of breathing by reducing surface tension at the fluid-gas interface. In vitro, halothane and isoflurane have been demonstrated to reduce phosphatidylcholine synthesis by alveolar cells in a dosedependent manner [6,7]. This reduction in phosphatidylcholine production was more pronounced with longer durations of exposure to halothane and was reversible within 2 hours after the agent was discontinued [6]. Propofol is used for induction and maintenance of general anesthesia and as a sedative for monitored anesthesia care. Upon induction, TV and resting ventilation quickly decrease. Depending on the infusion rate, patients can be apneic for more than 3 minutes [8]. Apnea is more likely to occur if patients are anxious and thus hypocapnic. At lower infusion rates apnea does not occur. Narcotics induce ventilatory depression (as well as analgesia) by binding to µ- receptors. These receptors are found in the brain, brainstem, spinal cord, and carotid bodies. Animal studies indicate that narcotics affect ventilatory control from within the central nervous system, but it is not known whether this is a local effect at the respiratory integration centers or by projection from other sites [3]. The newer µ-receptor agonists, such as alfentanil, sufentanil, and remifentanil, have advantages over older ones, such as morphine, in terms of their pharmacokinetic properties and influences on the cardiovascular system, but they all depress ventilation [3]. For example, continuous infusion of low-dose alfentanil reduces resting ventilation by 25% [9]. The return of ventilation to baseline once an infusion is stopped depends on the pharmacokinetic and pharmacodynamic properties of the drug, as well as the duration of infusion. When sedatives, analgesics, intravenous and inhalational anesthetics are combined, they potentiate each other and may induce respiratory depression more severe than that caused when they are used as sole agents. A reduction in end expiratory lung volume (EELV) and an increase in airway closure with concomitant tidal closure is common during general anesthesia or deep sedation [10]. Peripheral airways have no cartilage and so they can easily collapse at low EELV (airway closure). Tidal airway closure occurs when the closing volume exceeds the EELV. Compliance during general anesthesia is decreased due to the reduction of FRC and the formation of atelectatic areas. FRC reduction has several major effects on pulmonary function. In particular, it influences pulmonary mechanics, ventilation and perfusion distribution, and gas exchange. During anesthesia and mechanical ventilation in the lateral decubitus position, the dependent lung is compressed by the weight of the mediastinum and by the hydrostatic pressure gradient favored by the movement of the diaphragm toward the non dependent lung. Therefore, the majority of the TV is distributed to the nondependent lung, while perfusion goes prevalently to the dependent lung. This results in ventilation/perfusion mismatch and gas exchange impairment [11].

4 4 Marco Luchetti General Anesthesia and Ventilator-Induced Lung Injury During mechanical ventilation the end-inspiratory transpulmonary pressure (stress) fluctuates and this is thought to be the main cause of ventilator-induced lung injury (VILI) [12]. The ratio between TV and EELV (strain) may also play a role. Several mechanisms that may lead to VILI have been identified: Regional over-distension due to local stress. Cyclic recruitment and de-recruitment of unstable lung units. Surfactant depletion, inactivation and aggregate conversion. Cell and tissue stress between neighboring structures with different mechanical properties. Recent animal studies demonstrated that mechanical ventilation at low EELV may cause permanent mechanical alterations and histological damage to peripheral airways in normal lungs [13,14]. Peripheral airway injury consists mainly of epithelial necrosis in the membranous and respiratory bronchioles, and disruption of alveolar-bronchiolar attachments. It has been suggested that these alterations are the consequence of abnormal stresses that develop locally as a result of cyclic opening and closing of peripheral airways with tidal ventilation at low lung volumes. Such stresses are enhanced due to increased surface tension caused by surfactant depletion or inactivation, which can occur during ventilation at low lung volumes [15]. The morphological-functional alterations described above seem to be avoided when normal EELV is preserved by application of moderate levels of positive end-expiratory pressure (PEEP). The inflammatory response seems to play a minor role in peripheral airway damage induced by physiological TV [16]. This is suggested by the lack of relation between the number of polymorphonuclear leucocytes per unit length of alveolar septa and the increase in airway resistance. Furthermore, there was no significant cytokine release in serum and bronchoalveolar lavage fluid. However, another study [17] showed that mechanical ventilation with physiological TV in healthy lungs induced pro-inflammatory cytokine gene transcription. Recent data suggest that mechanical ventilation at injurious as well as physiologic TV may affect the extracellular matrix (ECM) structure and function [18]. The ECM is the extracellular extravascular compartment of the lung, interposed between the endothelial and epithelial cells layers. It is composed of insoluble macromolecules, like collagens, elastin, hyaluronic acid and proteoglycans, which form a skeleton supporting interstitial fibroblasts and macrophages. The lesional effect of mechanical ventilation on the ECM may depend upon several factors: increased transpulmonary pressure; reversed distribution of intrathoracic pressures; heterogeneous distribution of ventilation; and reduction of pulmonary lymphatic drainage [19]. The observation that mechanical ventilation results in proteoglycan breakdown and glycosaminoglycan fragmentation suggests the role that these molecules may play in the subsequent pathophysiologic process. They may be important in influencing the altered mechanical behaviour of the lung parenchyma and in contributing to the subsequent inflammatory events and to the altered biological characteristic of VILI [20].

5 Mechanical Ventilation During General Anesthesia 5 General Anesthesia and Atelectasis At the beginning of the last century, Pasteur noted: when the true history of postoperative lung complications comes to be written, active collapse of the lung, from deficiency of inspiratory power, will be found to occupy an important position among determining causes [21]. Indeed, atelectasis occurs regularly during general anesthesia induction [22], persists postoperatively [23] and may contribute to significant morbidity [24,25] and additional healthcare costs [26]. Atelectasis on a CT scan is defined as pixels with attenuation values of -100 to +100 Hounsfield units (HU) [27]. These occur in the most dependent parts of the lungs and are found in almost 90% of all patients who are anesthetized [27]. They develop with both i.v. and inhalational anesthesia and whether the patient is breathing spontaneously or is paralyzed and ventilated mechanically [28]. The only anesthetic so far tested that has not produced atelectasis is ketamine [29], although when the patient was paralyzed, atelectasis also appeared in these subjects. Most atelectasis occurs near the diaphragm in the supine patient and less towards the apex. Pulmonary atelectasis during anesthesia and the postoperative period may be caused by a variety of factors, which have been classified into three basic mechanisms [2]. Compression atelectasis occurs when the transmural pressure distending the alveolus is reduced. Absorption atelectasis occurs when less gas enters the alveolus than is removed by uptake by the blood. Loss-of-surfactant atelectasis occurs when the surface tension of the alveoli increases because of reduced surfactant action. Absorption and compression are the two mechanisms most implicated in perioperative atelectasis formation. High oxygen concentration has often been associated with atelectasis formation. When an FIO2 of 1.0 is used after a vital capacity maneuver (VCM), atelectasis recurs within 5 min [30]. On the other hand, when 40% oxygen is used, atelectasis will not recur for at least [31] min [30,32]. In order to avoid atelectasis formation, lower oxygen concentration has been suggested during induction and maintenance of general anesthesia. Recently, it has been shown that during general anesthesia, morbidly obese patients had more atelectasis than non-obese patients. Atelectasis persisted for at least 24 h in morbidly obese patients whereas it disappeared in the non-obese [33]. Atelectasis during anesthesia is found in all ages, from the newborn [34,35] to the elderly [36], and its magnitude seems to be independent of age in adults. Since most of atelectasis appearing during general anesthesia resolves within 24 h after surgery [37] one may argue that there is no need to prevent atelectasis since it may have no long-lasting effects. Nevertheless, patients do develop perioperative respiratory complications [25,38]. Since the number of anesthetic procedures in the Western world is considerable, even a small fraction of complications results in a large number of patients.

6 6 Marco Luchetti Mechanical Ventilation Mechanical ventilation represented a major advance in the administration of anesthesia and allowed the performance of surgical operations once impossible. However, it has several disadvantages that should be taken into account: loss of physiological humidification and heating of inspired gases; lung barotrauma which disrupts bronchioles and alveoli depending on TV, peak and plateau inspiratory pressures; occurrence of hypo- or hyperventilated areas in relation to their different compliances and resistances; need for deep general anesthesia or full muscle relaxation; possibility of tracheal tube obstruction or dislocation, and other technical problems. Until a few years ago, mechanical ventilation during general anesthesia was fairly simple, since the ventilators available for use in the operating rooms were not much sophisticated. Recently, the ventilators have increased in sophistication and this challenges anesthesiologists to become more aware of the new modes and features. In particular, the concept of lung protective ventilation has been demonstrated to be applicable not only to intensive care ventilation but also to intraoperative ventilation, in order to reduce the risk of VILI. Volume-Controlled Ventilation (VCV) Ventilation Modes With volume ventilation, a preset volume of gas is delivered to the patient over a time determined by the clinician [39]. Once that volume of gas has been delivered, the flow stops and passive expiration occurs. Because the area under a flow time curve defines volume, the TV remains fixed and uninfluenced by the patient s effort. VCV with constant (square wave) inspiratory flow is the most widely used breath delivery mode. With VCV, the patient is guaranteed to receive the set volume, but airway pressure will increase in response to decreased lung or chest wall compliance, increased airway resistance or anything else that restricts the delivery of that volume of gas, potentially exposing the patient to the risk of high airway pressures. Because pressure will vary in volume-targeted modes of ventilation, careful monitoring and assessment of respiratory system compliance and resistance are necessary. Pressure-Controlled Ventilation (PCV) During pressure-limited ventilation, as soon as the inspiratory valve opens, the circuit is pressurized to the set peak inspiratory pressure. This pressure is then held for the duration of the set inspiratory time. Gas flow is initially high and then diminishes over the course of the inspiratory phase of the breath (decelerating flow pattern). Thus, with pressure cycled

7 Mechanical Ventilation During General Anesthesia 7 ventilation, we can keep the alveoli fully inflated for a longer portion of the inspiratory phase, enhancing both gas exchange and lung inflation, and achieve equal volumes with lower inflating pressures. This mode requires that the exhaled volumes and minute ventilation are monitored to ensure that adequate ventilation is being delivered in the face of changes in compliance or resistance [40]. Despite its popularity, PCV has not been proved superior to other modes of mechanical ventilation. Although it is associated with lower peak air way pressures, the impact on lung mechanics, gas exchange, and risk of macro and microscopic barotrauma is variable. The adjustable flow rates and pressure limitations may be useful in certain populations. The potential for lung recruitment through increased mean airway pressure makes this an attractive mode in patients with large shunt fractions. Any potential benefit depends on the nature and timing of the lung injury, however, and may be offset by shear- and stress-related volu- and atelectrauma. Implementation of PCV requires a practical understanding of the relationship between flow, time, and pressure. Unlike VCV, in which TV is guaranteed, gas delivery in PCV varies in complex ways. Careful observation, however, can make this a safe and effective method of ventilatory support. Pressure Regulated Volume Controlled Ventilation (PRVC) This is pressure-limited time-cycled assist/control mode combining the best aspects of both volume and pressure ventilation, where volume targets are reached with limits on inspiratory pressure and decelerating flow patterns are generated [41]. The ventilator automatically, breath by breath, adapts the inspiratory pressure support according to the changes in mechanical properties of the lung and thorax, while maintaining TV and minute volume constant. PRVC adjusts inspiratory pressure to target a set TV, based on the TV of the previous breath. Breath to breath increment is limited to 3 cmh2o, up to 5 cmh2o below the set upper pressure limit. The lowest possible pressure level is used to deliver the preset tidal and minute volume. Because pressure adjustment is based on the previous breath, variable patient respiratory effort will cause fluctuations in delivered TV. Pressure Support Ventilation (PSV) More than 30 years ago it was demonstrated that active contraction of the diaphragm during spontaneous breathing expands dependent lung regions better than a passive imposed breath of similar volume [42]. PSV is designed to support spontaneous ventilation during the inspiratory phase [43]. The patient triggers each breath by opening the demand valve of the ventilator. The operator can set the trigger threshold level for the inspiratory flow rate at which that breath is sensed. A supplementary gas flow is delivered to the inspiratory circuit to produce a positive inspiratory pressure at a preset value. The cycles are pressure limited and there is no preset TV. The patient regulates the respiratory rate, inspiratory and expiratory time and TV.

8 8 Marco Luchetti PSV has proven especially useful with supraglottic airway devices like the laryngeal mask airway (LMA). Unlike controlled ventilation, it is usually well tolerated during light levels of anesthesia [44]. One Lung Ventilation (OLV) Anesthesia causes a decrease in the FRC of the dependent lung and an improvement in nondependent lung FRC, resulting in preferential ventilation of the upper lung. Muscle relaxation and institution of positive pressure ventilation cause a further shift toward upper lung predominance in ventilation. Static displacement of the relaxed diaphragm by abdominal contents and the gravity force of the mediastinum restrict the lower lung, resulting in additional decreases in its compliance. Opening of the chest further deteriorates lower lung ventilation, as the loss of negative intrapleural pressure releases the mediastinal weight onto the lower lung. All these changes result in progressive uncoupling of V/Q matching, as perfusion continues to favor the dependent lung [45]. This technique permits the isolation of one lung from the other and favors the ventilation of either one or both lungs separately. OLV is usually carried out using a double-lumen tube. It is well tolerated when the contralateral lung is collapsed and perfusion excluded. On initiation of OLV, the upper, nondependent lung with its favorable compliance becomes excluded from the ventilatory circuit and converts to true shunt. Ventilation now is restricted to the noncompliant lower lung [11]. Re-expansion of a collapsed lung should be carried out with caution and progressively to avoid alveolar and bronchiolar rupture and interstitial emphysema. High Frequency Ventilation (HFV) HFV has been proposed for several years to improve gas exchange and reduce lung barotrauma in intensive care therapy. Some modes have also been used during specific types of surgery [46], particularly in thoracic and tracheobronchial surgery [47]. The most common modalities are: High Frequency Positive Pressure Ventilation; High Frequency Jet Ventilation; High Frequency Oscillatory Ventilation. Difficulties in monitoring ventilating pressures, tidal volumes and end-tidal CO2 concentrations, in addition to the inherent risks of baro trauma associated with this technique, continue to hamper its widespread adoption [48]. Airway Pressure Release Ventilation (APRV)/BI-Level Positive Airway Pressure (BIPAP) APRV/BIPAP has recently been introduced into clinical anesthesia. It differs from other modes of positive pressure ventilation in that it applies a form of continuous positive airway pressure (CPAP), which is released periodically, augmenting CO 2 clearance. APRV/BIPAP ventilates by time-cycled switching between two pressure levels in a high flow or demand valve CPAP circuit, and therefore it allows unrestricted spontaneous breathing in any phase of the mechanical ventilator cycle [49]. APRV/BIPAP may deliver adaptive pressures to prevent

9 Mechanical Ventilation During General Anesthesia 9 the dynamic airway collapse which tends to occur with standard IPPV. This kind of ventilation has been shown to be beneficial in decreasing ventilation perfusion mismatch and improving oxygenation when compared with conventional intermittent positive pressure ventilation (with or without PEEP) during general anesthesia [50]. Lung Protective Ventilation Strategies A VCM can completely abolish atelectasis that develops after induction of general anesthesia [51]. After a lung inflation to a pressure of 40 cm H2O maintained for 15 seconds the atelectatic lung tissue is fully re-expanded. More recently, it has been shown that this maneuver needs to be maintained for only 7-8 s in order to re-expand all previously collapsed lung tissue [52]. PEEP is the primary means of maintaining alveolar recruitment and returning FRC towards awake values during controlled ventilation in the anesthetized patient. PEEP applied immediately after a VCM will completely prevent recurrence of atelectasis, even when FiO2 1 is used [53]. During induction of anesthesia, application of PEEP can prevent formation of atelectasis [54] and can increase the margin of safety before intubation. Application of PEEP in morbidly obese patients is also very effective for the prevention of atelectasis during induction [55]. Application of appropriate levels of PEEP can prevent the loss of FRC and homogeneity of ventilation in ventilated and paralyzed patients [56]. PEEP has effects on optimizing pulmonary blood flow as well as distribution of ventilation [57]. PEEP has been shown to improve respiratory function, as measured by lung volumes, respiratory system elastance, pressure volume curves, and intra-abdominal pressure, in paralyzed and anesthetized patients [58-61]. Excessive PEEP, of course, has potentially deleterious effects, including reduced cardiac output and pulmonary hyperinflation, so the lowest possible PEEP that prevents collapse should be used [62]. Allowing spontaneous breathing during mechanical ventilation, even as little as 10-20% of the total ventilation, improves gas exchange. This can be obtained with APRV/BIPAP [50]. By combining some of these techniques, it could be possible to prevent atelectasis formation during general anesthesia. Parenchymal and peripheral airways injury may be avoided by reducing tidal closure. This can be achieved by using a low TV and PEEP levels high enough to increase EELV above airway closure. Several recent studies investigated the effects of protective ventilation strategies during general anesthesia for different surgical procedures, showing that a low volume ventilation is associated with reduced incidence of complications and decreased inflammatory response [63-68]. Other authors [69], observed that mechanical ventilation with large TV (12 ml/kg) and no PEEP promoted pro-coagulant changes, whereas, with lung-protective lower TV and PEEP of 10 cmh2o, these pro-coagulant changes were prevented. During esophagectomy [70], a TV of 9 ml/kg during two-lung ventilation or 5 ml/kg during one-lung ventilation with PEEP of 5 cmh2o decreased pro-inflammatory systemic response,

10 10 Marco Luchetti improved lung function and allowed earlier extubation compared with conventional ventilatory strategy. In contrast, in other randomized studies including a heterogeneous group of surgical procedures, protective lung ventilation failed to show a decrease in intrapulmonary and systemic inflammation [71,72], and, in cardiac surgery, did not prevent pulmonary adverse effects [73,74]. Use of a low TV in patients with normal lungs, however, may favor the development of atelectasis: hence, use of low TV in the absence of recruitment or PEEP in anesthetized patients without lung injury is not generally recommended [75]. Conclusive Remarks Patients with normal lungs may also be at risk for ventilator-associated lung injury. Even though short-term ventilation with high volumes has not been found conclusively to be injurious, the hypothesis should be considered that the development of VILI may require a two hit mechanism: the high volume ventilation would provide the first hit and complications following anesthesia would produce the second hit, thereby inducing an acute lung injury in the postoperative period. The main objective of lung-protective mechanical ventilation strategies is to minimize regional end-inspiratory stretch, thereby decreasing alveolar damage and inflammation. Protective ventilation is not synonymous with simply low TV ventilation but also includes adequate PEEP, lower FiO2, and lower ventilatory pressures. In many patients with normal lungs the end-inspiratory stretch may be relatively low even with a TV of 10 ml/kg. In these patients, if the plateau pressure is low (< 15 cm H2O) and they are not breathing spontaneously, the use of lower TV is probably not indicated, as it may lead to atelectasis, especially if PEEP is low or not used at all. De-recruitment of lung tissue, impaired CO2 elimination, and dynamic hyperinflation potentially may complicate this approach. Lung de-recruitment may be more prevalent with low TV because of the loss of endinspiratory stretch in the setting of high FiO2. If plateau pressures are higher (> cm H2O), TV should be decreased to approximately 6 ml/kg. However, plateau pressures may be misleading sometimes. In patients with significant spontaneous breathing efforts, plateau pressures may be low, but the transalveolar pressures and lung overdistension may still be high because of large negative pleural pressures. Conversely, in patients who have decreased chest wall compliance (increased intra-abdominal pressure, obesity), plateau pressures may be high without there being pulmonary overdistension. Sufficient external PEEP should help to minimize de-recruitment and atelectasis, and maintain oxygenation. PEEP titration, however, may be difficult in the intraoperative setting, since the determination of inflection points and auto-peep requires in-line spirometry, as routine expiratory holds are not feasible intraoperatively. Finally, the use of lower TV could improve the hemodynamic tolerance of mechanical ventilation. By decreasing the need for fluids, this beneficial hemodynamic effect could contribute to the decreased incidence of secondary acute lung injury. To date, no studies have been performed addressing this issue. Prospective studies are required to further evaluate

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