Respir Care Clin 8 (2002) 247260

High-frequency mechanical ventilation Principles and practices in the era of lung-protective ventilation strategies
Je M. Singh, MDa, Thomas E. Stewart, MDa,b,*
a

Department of Medicine and the Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, M5G 1X5, Canada b Intensive Care Unit, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada

Mechanical ventilation is the cornerstone of care for patients in respiratory failure. Conventional positive-pressure mechanical ventilation (CMV) at near-physiologic tidal volumes has become the most popular form because of its simplicity and widespread availability. Recent evidence, however, suggests that mechanical ventilation itself both potentiates and causes lung injury in patients with severe respiratory disease. This observation has prompted a search for safer ventilation strategies that provide optimal ventilatory support while minimizing the potential for causing lung injury. The term high-frequency ventilation (HFV) refers to mechanical ventilation modes that use high respiratory rates and small tidal volumes-often smaller than anatomic dead space. First developed in the 1960s, HFV was the subject of considerable research. Despite theoretical advantages that support the use of HFV in patients with injured lungs, initial clinical studies failed to demonstrate a signicant advantage over CMV [13]. Subsequently, interest in HFV waned. Recently, there has been renewed interest in some forms of HFV, particularly high-frequency oscillatory ventilation (HFO). This renewed interest has been fueled by the belief that HFO may be well suited for a lung-protective ventilation strategy. Early clinical studies that have evaluated HFO in this regard have been promising. This review provides an overview of HFV, its mechanical properties, and the rationale that supports its use in this era of lung-protective mechanical ventilation.
* Corresponding author. E-mail address: tom.stewart@utoronto.ca (T.E. Stewart). 1078-5337/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 7 8 - 5 3 3 7 ( 0 2 ) 0 0 0 0 7 - 2

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Principles Before the 1950s, negative-pressure ventilation was the ventilation mode of choice. Not until the polio epidemic of the 1950s did a lack of negativepressure ventilators (so-called iron lungs) prompt the development of positive-pressure mechanical ventilators. These new ventilators quickly became the standard of care for patients in respiratory failure. In the 40 years that followed, positive-pressure ventilation was applied typically with a volume- or pressure-cycled mode and often used high-driving pressures to inate lungs to physiologic or supraphysiologic volumes. The observation that sucient ventilation in dogs occurred with tidal volumes of less than anatomic dead space was made in 1915 [4]. Over 50 years passed, however, before this concept was applied to mechanical ventilation in humans [5]. Nonetheless, the original observation did stimulate research into the physiology of gas exchange using high frequencies and low tidal volumes.

Theories of gas transport The adequate ventilation that was achieved by using small volumes in animal models implied that gas exchange during positive-pressure ventilation is complex and may be only partially dependent on bulk ow. There are physiologic data that support the role of several mechanisms of gas transport during HFV.

Bulk ow If a suciently large volume of gas is inspired, the leading edge of the gas front may reach the proximal airways and a few proximal alveoli [6]. At tidal volumes greater than one-half of the anatomic dead space, this may be a contributing mechanism of gas transport and may account for the sudden decrease in ventilation eciency in high-frequency modes when the tidal volumes decrease below this volume [7].

Pendelluft The rate at which a lung unit is lled with fresh gas when inated by a given driving pressure is determined by its mechanical properties, as expressed by its time constant. Heterogeneity of time constants between lung units has long been recognized [8]. Because of this heterogeneity, some lung units experience more rapid lling than others during a given inspiration. After inspiration, gas is redistributed from fast- to slow-lling units, with redistribution in the opposite direction at end-expiration. This mechanism may enhance alveolar gas exchange, particularly of peripheral lung units, and may help gas mixing within the airways [9].

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Asymmetric velocity proles Schroter and Sudlow [10] rst demonstrated that inspiratory velocity proles in bifurcating systems were more skewed during inspiration than during expiration [10]. After repeated cycles of inspiration and expiration, a central current delivers gas distally and the gas at the periphery of the airways returns proximally. Taylor dispersion The aforementioned asymmetric velocity prole of inspired air creates a radial concentration gradient in the airway and, thus, turbulent eddies. These eddies, which augment the mixing of gas in the airways, are produced by the combined eect of convective ow and diusion [11,12]. Cardiogenic mixing and diusion As in conventional modes of ventilation, the mechanical agitation of lung units adjacent to the beating heart and the molecular diusion along concentration gradients near the alveolocapillary membrane may play important roles in gas transport. The mechanisms of gas exchange during HFV are undoubtedly complex, and many or all of the aforementioned mechanisms may contribute to gas exchange in a patient at any given moment. Perhaps most important to the clinician is that adequate ventilation can be achieved with judicious selection of patient and ventilation mode, despite the use of very low tidal volumes. Modes of high-frequency ventilation As HFV has advanced, dierent classes of this type of ventilation have emerged. They dier in the mechanism with which driving pressure and, hence, tidal volume are generated. HFV also can be classied according to the exhalation phase; most classes of HFV depend on the passive recoil of the respiratory system for exhalation. HFO, however, develops a negative pressure gradient to create an active expiration phase. The unique characteristics, limitations, and potential complications of some of the most popular modes of HFV are outlined in the following sections. Passive exhalation High-frequency jet ventilation (HFJV) was developed in 1967 and subsequently gained some popularity. HFJV delivers tidal volumes of 25 cm3/kg at a rate of 100 to 200 breaths per minute. A system of valves controls the gas stream, which is delivered at high pressure through a narrow-bore cannula into the proximal endotracheal tube and is conditioned with aerosolized saline. The small-bore gas cannula reduces visual obstruction in the airway, a characteristic that has led to HFJVs popularity in rigid bronchoscopy. Because the high-velocity jet entrains air from the circuit, precisely controlling tidal volume is dicult. Additionally, gas warming and humidication

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can be problematic in HFJV because the gas jet both expands and cools as it exits the high-pressure cannula. Suboptimal gas conditioning and high gasow rates have been implicated in the damage to the trachea and proximal airways that has been observed with HFJV [1317]. Expiration in HFJV is passive and depends on the elastic recoil of the respiratory system. Thus, at high respiratory frequencies, the clinician must be wary of gas trapping with its associated lung injury and hemodynamic complications. High-frequency positive-pressure ventilation was developed to provide adequate mechanical ventilation in circumstances during which minimal movement of the upper airway is desired, such as laryngeal surgery. Small tidal volumes of gas are delivered at rates between 60 and 100 breaths per minute. As with HFJV, expiration is passive, and the risk of gas trapping increases as the respiratory time decreases at higher respiratory rates. Active exhalation First reported in a letter in 1972 by Lunkenheimer et al. [18,19], HFO utilizes a reciprocating diaphragm to create oscillations in the air column. This generates a driving pressure that results in gas exchange and ventilation (Fig. 1). As the diaphragm drives pressure waves in both directions, inspiration and expiration are active. This may reduce the potential for gas trapping, particularly at high mean airway pressures, thereby allowing for tighter control of lung volumes. In HFO, mean airway pressure is determined by controlling the ow of fresh gas through the circuit, known as bias ow. The result is the eective uncoupling of oxygenation and ventilation, whereby (1) mean airway pressure is adjusted to control lung volume and oxygenation, and (2) the rate

Fig. 1. Schematic diagram of an HFO ventilator and circuit (Adapted from Hess D, Mason BR, High-frequency ventilation: design and equipment issues. Respir Care Clin North Am 2001; 7:57798.)

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and the displacement of the oscillating diaphragm are varied to achieve adequate ventilation. During HFO, the airway pressures are thought to oscillate at pressures close to the mean airway pressure (Fig. 2), which avoids large pressure swings and therefore may help reduce iatrogenic lung injury. Additionally, HFO provides considerable advantages over other forms of HFV in gas conditioning. The lack of gas entrainment and the strict control of bias ow in HFO permit optimal warming and humidication of inspired gas. Tracheal damage similar to that seen in HFJV, however, has been reported and must be monitored closely [13,15]. Rationale Recently, a lung-protective ventilation strategy designed to minimize ventilator-induced lung injury (VILI), was demonstrated to reduce mortality in patients with acute respiratory distress syndrome (ARDS) [20,21]. The proven benets of lung-protective ventilation have spurred renewed interest in HFV, particularly HFO. The advantages of HFO with respect to volume control and gas conditioning may make it well suited to lung-protective mechanical ventilation in an adult population. Understanding the rationale for using HFO in such a strategy requires some knowledge of the pathogenesis of VILI, which is reviewed briey in the following section. Current concepts of ventilator-induced lung injury Respiratory mechanics are altered signicantly in injured or diseased lungs. Respiratory-system compliance often is decreased, necessitating higher driving pressures to maintain adequate tidal volumes and ventilation. Moreover, disease pathology is not distributed uniformly throughout the lung. Consequently, there is regional heterogeneity in lung compliance [22,23]. Applying positive-pressure ventilation in this scenario can result in overination

Fig. 2. Diagram that compares pressure oscillations throughout the respiratory cycle between conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation (HFO). (Adapted from Ferguson ND, Stewart T. Use of high-frequency oscillatory ventilation in adults with acute lung injury. Respir Care Clin North Am 2002;18:98.)

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of more healthy lung units while injuring areas of lung collapse. Animals that are subjected to mechanical ventilation at extreme airway pressures and volumes demonstrate severe alterations in lung permeability and histologic damage similar to that observed in human ARDS patients [2426]. Although the exact pathogenesis of VILI remains controversial, several contributory mechanisms have been elucidated. Current models of injury include volutrauma, atelectrauma, and oxygen toxicity. Recently, these mechanical and chemical insults have been reported to activate inammatory cascades, resulting in further lung injury and contributing to multisystem organ failure. This process has been termed biotrauma. The static pressure-volume curve (P-V curve) of the total respiratory system may be useful to help understand concepts of VILI. Within the P-V curve, two points often can be identied: the lower inection point (LIP) and the upper inection point (UIP) (Fig. 3). Some have argued that LIP may represent the point in inspiration when lung units begin to open (recruitment); hence, some authors have advocated setting PEEP above this level to avoid atelectasis [21,27]. The LIP represents the pressure at which most lung units open, not the pressure at which all lung units open. Considerable heterogeneity may exist in lung-opening pressures. Recent animal and human data have demonstrated that lung recruitment in injured lungs (ARDS) is progressive and continuous over the P-V curve regardless of inection points, possibly clouding the clinical use of LIP measurements [28]. The UIP may represent the point at which most of the lung is overdistended and prone to injury; thus, some have suggested that peak pressure should be maintained below this level to reduce the potentially deleterious eects [29].

Fig. 3. An example of a P-V curve that depicts the total respiratory system in an ARDS patient. Note the lower and upper inection points on the inspiratory limb and the zones of potential atelectrauma and volutrauma.

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Volutrauma High-volume ventilation may overdistend both normal and diseased alveoli and thereby produce lung injury. Some have suggested that ventilatorinduced pulmonary edema may not be caused by high airway pressures but by the large lung volumes with which they are associated. One animal study found that rats ventilated with high tidal volumes and high pressures rapidly developed pulmonary edema and ultrastructural abnormalities. When the rats were ventilated with high pressures but with tidal volumes that were limited by mechanical strapping, they did not develop pulmonary edema [24]. Moreover, pulmonary edema has been observed to develop rapidly in rats ventilated to high tidal volumes by negative-pressure mechanical ventilation [24]. Because these ndings have been reproduced in other animal models, [30,31] the accepted theory has become that alveolar distention from large ventilatory volumes, not the associated high airway pressure, is the key contributor to ventilator-induced pulmonary edema. Accordingly, the term barotrauma has been replaced with the term volutrauma. To reduce the risk of regional lung-unit overdistention, some have suggested that lung-protective CMV should incorporate low tidal volumes (68 mL/kg) and moderate peak airway pressures. Recently, the clinical benet of lower-tidal-volume ventilation in the context of ARDS was supported by a large multicenter trial by the National Institutes of Health ARDS network [20]. In this landmark study, a lung-protective strategy of lower tidal volumes (<6 mL/kg) and plateau pressures (<30 cm H2O) was compared in a prospective, randomized fashion with a higher-tidal-volume strategy. The observed reduction in absolute mortality was 9%. Aside from the benet of low-tidal-volume CMV, there may be theoretical advantages to HFV. One study found that 80% of ARDS patients who were ventilated with CMV had plateau pressures above that which corresponded to UIP on their P-V curves. As mentioned previously, this introduced the possibility of the overdistention of compliant lung units [29]. Although this study used tidal volumes larger than those that have been proven benecial in ARDS [20], plateau pressures were maintained below UIP only at small tidal volumes (5.5 mL/kg). These observations imply that even lung-protective strategies based on CMV may cause volutrauma-type injury to the lung. The theoretical advantage to the HFV modes lies in the small tidal volumes and small pressure swings, both of which reduce the risk of regional lung-unit distention and volutrauma.

Atelectrauma Animal studies have demonstrated that ventilation at low lung volumes induces injury to the alveolar wall because of the shear stresses generated by the repeated opening and closing of alveoli during the respiratory cycle [32]. This shearing injury occurs when atelectatic lung regions are forced open repetitively and then allowed to collapse on expiration. If expiratory

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volumes are low, lung units collapse at end-expiration and set the stage for atelectrauma. A recent animal study demonstrated that healthy lungs tolerated these injurious forces for short periods without histologic damage [33]. In the context of surfactant dysfunction or deciency similar to that seen in ARDS, however, severe histologic damage was observed after only brief ventilation [34,35]. In an attempt to reduce the potential damage from such injury, some clinicians have advocated the use of PEEP to maintain pressures above the alveolar closing pressure. This strategy is thought to maintain lung volume and to prevent lung-unit collapse at end-exhalation. One study that targeted PEEP levels above LIP on the static P-V curve demonstrated increased survival at 28 days; however, this was a relatively small study (n 53) and had a mortality rate in the control group that was higher than normally expected [21]. Despite data indicating that the application of high PEEP level is benecial, the optimal level of PEEP for reducing ventilator-associated lung injury remains elusive. Oxygen toxicity Exposure to high concentrations of fractional inspired oxygen was one of the rst mechanisms to be linked to VILI. This phenomenon has been well studied and is accepted widely. In addition to VILI, oxygen toxicity may potentiate lung injury through absorption atelectasis, secondary hypoventilation, and systemic vasoconstriction [36]. Despite these observations, the exact oxygen level that results in toxicity has not been determined. Similarly, the relative contribution of volutrauma, atelectrauma, and oxygen toxicity to lung damage are unknown. Biotrauma Mortality in ARDS has been reported to be between 35% to 65%. Most deaths, however, do not result from respiratory failure but from progressive multiple-organ dysfunction [37]. Inammatory mediators released in the lungs because of primary lung disease or secondary injury may contribute to widespread systemic inammation and multiple-organ dysfunction [38,39]. Several early trials have observed that lung-protective ventilation strategies are associated with lower levels of systemic inammatory mediators [20,40,41,42]. Although promising, the implications of this in terms of clinical outcomes require conrmation from future clinical trials. Ventilation and the open lung The stabilizing properties of surfactant create hysteresis in the breathing, or ventilated, lung. This is manifested by two limbs (ination and deation) on the static P-V curve. Ideally, one should attempt to inate the lung so that cyclic ventilation occurs on the deation limb of its P-V curve at which lung volumes are higher at a given pressure [4346]. The idea behind open-lung

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ventilation is to maintain the lung on its deation limb (Fig. 4). Theoretically, such a strategy improves lung volumes and increases the number of aerated alveoli. Consequently, this has a positive eect on oxygenation and increases respiratory-system compliance, which often allows for ventilation at lower driving pressures. Lung recruitment and lung-volume maintenance is particularly important in HFO. Because small tidal volumes are used, one cannot rely on pressure or volume swings during the respiratory cycle to open atelectatic lung units [43]. Initial studies of HFO did not include aggressive volume recruitment [1]. The omission of recruitment maneuvers in early applications of HFO may be partially responsible for the lack of benet reported in early studies of HFO. Subsequently, several studies have investigated the role and safety of lungvolume recruitment in the application of HFO. These techniques have demonstrable benet in improving lung volume, compliance, oxygenation, and histologic markers of lung injury [4750]. Methods of recruitment that have been found to be eective in these studies have included (1) setting the mean airway pressure above the opening pressure of the lung, and (2) more aggressive intervention such as intermittent-volume recruitment maneuvers. These maneuvers have been found to be safe, causing minimal hemodynamic eects in animal studies and in neonatal and adult human studies [5153]. After lung units are recruited, the goal is to maintain lung volumes with high mean airway pressures. In CMV, this usually is accomplished by applying PEEP at the expense of higher peak airway pressures and reduced ventilation. Because of its small tidal volumes, HFO can maintain a higher mean airway pressure while protecting compliant lung units from

Fig. 4. An example of a P-V curve that depicts the theoretical goal of lung-protective ventilation on the total respiratory system in an ARDS patient: (1) Lung-volume recruitment maneuver may shift respiratory-system mechanics to the expiratory limb of P-V curve, and (2) lung volume is maintained with HFO via high mean airway pressures with low-magnitude pressure swings throughout the respiratory cycle.

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overdistention. This allows end-expiratory pressures to be maintained above the closing pressure of most alveoli, thus improving recruitment of lung units and reducing atelectrauma.

Practices There are compelling animal data to support the application of HFO in ARDS. Comparative studies of HFO and CMV in surfactant-decient adult rabbits or premature primates have demonstrated improved gas exchange, reduced lung injury, and lower levels of inammatory mediators [54]. The successful application of HFO, however, seems to require the recruitment of adequate lung volume and high mean airway pressures to prevent derecruitment of lung units. In the neonatal and pediatric populations, HFO has been studied most extensively; several clinical trials have evaluated HFO for the management of acute respiratory failure. The earliest randomized clinical trial in neonates who had respiratory failure showed that HFO did not reveal an oxygenation advantage and was associated with higher rates of major complications compared with CMV [1]. When this study was conducted, however, two therapies that are now known to be eective were not used: exogenous surfactant and HFO applied with mean airway pressures high enough to maintain lung volume. Additionally, methodologic aws in these early studies may have obscured potential benets [55]. A subsequent study in preterm infants found that HFO applied with a higher mean airway pressure had demonstrable benets over conventional ventilation. Infants on HFO experienced improved gas exchange and a lower incidence of air-leak syndrome [56]. Other studies have found that the use of HFO in respiratory failure is associated with improved oxygenation and a lower incidence of chronic lung disease [57,58]. A decreased incidence of barotrauma, air-leak syndrome, and supplemental oxygen use at 30 days all have been reported as well [59]. Not all studies, however, have demonstrated as clear an advantage as these [60]. Although many similarities exist between infant and adult ARDS, signicant dierences (eg, the absence of primary surfactant deciency in adults) make the extrapolation of these results to the adult population impossible. Most clinical experience with HFO in adult ARDS patients has been limited to rescue therapy. Fort et al. [61] published a case series of adults who had severe oxygenation failure on CMV who then were switched to HFO with a volume-recruitment strategy. A decrease in oxygenation index and concentrations of fractional inspired oxygen was observed without adverse hemodynamic eects. Although the mortality rate in this group of patients was high (53%), it was not entirely unexpected given the severity of the respiratory failure and that HFO was used as a salvage therapy. The investigators concluded that HFO with volume recruitment maneuvers was safe and eective in adult patients who had failed to respond to CMV. A more

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recent prospective clinical study that evaluated HFO as a rescue therapy in ARDS patients who had severe hypoxemic respiratory failure also demonstrated safety and benecial eects on oxygenation and ventilation [62]. By design, the patients mean airway pressures were signicantly higher while on HFO compared with CMV. There were no signicant changes in systemic blood pressure with the initiation or maintenance of HFO. Similar to the results published by Fort et al. [61], Mehta et al. [62] found that the number of days of CMV before HFO was higher in nonsurviving patients, suggesting that early initiation of HFO may be benecial. These studies conrm the ecacy and safety of ventilating ARDS patients with HFO, even though the lack of a comparison CMV population prevents further interpretation with respect to the potential benet of HFO over CMV. In an as-yet-unpublished randomized prospective trial, HFO applied with an open-lung approach (high mean airway pressures) was compared with CMV in 148 adults ARDS patients (Stephen Derdak, personal communication, 2001). Those ventilated with HFO were found to have improved oxygenation compared with those treated with CMV. HFO was well tolerated without any observed adverse eects on blood pressure or cardiac output. Although the study was not designed to demonstrate a survival advantage, it did nd an absolute reduction in mortality of 15% at 30 days of follow-up; however, it was not statistically signicant. Unfortunately, the clinical interpretation of these positive results is clouded by the fact that HFO was not compared with what today is considered the best low-tidal-volume CMV strategy-the one used in the trial performed by the Acute Respiratory Disease Syndrome Network [20]. Any benet of HFO compared with a proven CMV strategy must be conrmed in future clinical studies. Summary The term high-frequency ventilation is used to describe a heterogeneous group of ventilation modes that are characterized by high respiratory frequencies and low tidal volumes. The increasing understanding of the pathogenesis of VILI, including concepts such as volutrauma and atelectrauma, has led to a renewed interest in the role of HFV in lung-protective ventilation strategies. Inherent to many modes of HFV are low tidal volumes and small pressure swings during the respiratory cycle, which allow for higher mean airway pressures than those safely achieved with CMV. This has the potential to reduce lung injury by limiting volutrauma, whereas maintaining bigger lung volumes at end-expiration may reduce atelectrauma. Of the various forms of HFV, HFO is the only mode with an active expiration phase. This characteristic, combined with superior gas conditioning, may make HFO a promising ventilatory strategy for adults. Although a signicant amount of data exists in the literature to support the application of HFO in infants and children who have acute respiratory failure, clinical data on the use of HFO in adults is only now emerging. Early studies of

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applying HFO in ARDS patients have demonstrated its safety and benet in terms of oxygenation. Additionally, limited data exist on the comparison between HFO and CMV in this patient population; however, encouraging preliminary results have been reported. The optimum strategy for the application of HFV, including the timing of HFV initiation, remains unclear.

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