Update on Mechanical Ventilatory Strategies Martin Keszler Neoreviews 2013;14;e237 DOI: 10.1542/neo.

14-5-e237

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/14/5/e237

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Article

respiratory disorders

Update on Mechanical Ventilatory Strategies

Martin Keszler, MD*

Educational Gaps
With a large number of modalities of mechanical ventilation to choose from and paucity of good clinical studies, clinicians face the difcult task of selecting the best tools to utilize and the optimal strategies to employ in order to minimize ventilator-associated lung injury.

Author Disclosure Dr Keszler disclosed he has been a consultant to and received research support and lecture honoraria from Draeger Medical, Inc; that he is on the advisory board and speaker bureau of Ikaria, Inc; and that he is a consultant and on the advisory board for Discovery Laboratories, Inc. and has received research support from the company. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Abstract
Mechanical ventilation is essential for survival of many extremely premature infants, but all forms of positive pressure ventilation are to some degree injurious to the lungs. A variety of sophisticated devices are used to provide respiratory support, yet substantial uncertainty remains regarding the optimal ways in which these tools can be used to minimize ventilator-associated lung injury. A good understanding of the unique aspects of respiratory physiology of extremely preterm infants is key to obtaining the greatest benet from modern ventilator technology. Early lung volume recruitment with adequate end-expiratory pressure, avoidance of volutrauma during the immediate postnatal period, and noninvasive respiratory support as the initial strategy are now accepted as important factors in minimizing lung injury. Volume-targeted ventilation combined with optimal lung volume strategies to ensure that the tidal volume is evenly distributed throughout an open lung seems to be the best approach to lower the incidence of bronchopulmonary dysplasia.

Objectives

After completing this article, readers should be able to:

1. Understand the unique aspects of neonatal respiratory physiology and the complexity of patientventilator interactions during synchronized mechanical ventilation. 2. Know the key factors involved in ventilator-associated lung injury and the ventilation strategies designed to minimize them. 3. Understand the importance and principles of the open lung concept. 4. Be familiar with the basic operating principles of various modes of volume-targeted ventilation, their advantages, and indications for use.

Introduction
Mechanical ventilation (MV) remains an essential tool in NICUs, especially in extremely low gestational age (GA) neonates. In a large cohort analysis of extremely preterm infants, 89% were mechanically ventilated during the rst day after birth, and nearly 95% of survivors were ventilated at some point during their hospital stay. (1) The Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) trial found that 83% of infants assigned to noninvasive support required intubation at some point during their hospitalization. (2) A recent study focusing on infants less than 28 weeks GA documented a 74% rate of intubation. (3) The Continuous Positive Airway Pressure or Intubation (COIN) trial, which included only 25- to 28-week GA infants who breathed at birth, reported that 46% of infants assigned to noninvasive support ultimately required endotracheal intubation and MV. (4) These studies demonstrate that MV remains an indispensable tool in NICUs, even in the era of noninvasive respiratory support. However, although MV may be life-saving, it

*Department of Pediatrics, Warren Alpert Medical School of Brown University, and Director of Neonatal Respiratory Services, Women and Infants Hospital, Providence, RI.

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is associated with signicant complications, including ventilator-associated lung injury (VALI) and neurodevelopmental impairment. With improved survival of preterm infants, focus has shifted from reducing mortality to reducing the persistently high incidence of chronic lung disease and neurodevelopmental impairment. Although high-frequency ventilation was once seen as the answer to this need, inconsistent results and continued concerns about the hazards of inadvertent hyperventilation have limited its acceptance as rst-line therapy in infants who have uncomplicated respiratory distress syndrome. Instead, the focus has shifted to avoiding intubation and MV in the rst place; use of noninvasive respiratory support has become generally accepted as the best way to reduce VALI. Surfactant is now increasingly administered without prolonged MV, thus potentially preserving the well-documented benets of surfactant replacement therapy while avoiding the risks associated with MV. Administration of nebulized surfactant during nasal continuous positive airway pressure (CPAP) is a potentially attractive approach that is currently under investigation. Nasal ventilation may augment an immature infants inadequate respiratory effort without the complications associated with endotracheal intubation. This approach may reduce the incidence of ventilator-associated pneumonia and thus avoid the contribution of postnatal

inammatory response to the development of bronchopulmonary dysplasia (BPD). One of the consequences of the shift in clinical practice away from invasive ventilation is that fewer infants now receive MV, and this reduction has led to decreased levels of experience for trainees and practitioners. Infants who now receive MV tend to be smaller and more immature than those ventilated 10 or 15 years ago and may remain ventilated for extended periods for reasons not related to their lung disease. Data from clinical trials conducted many years ago may therefore not be applicable to the extremely immature infants who now constitute the majority of ventilated infants. In the closing years of the 20th century, a new generation of microprocessor-based ventilators with advanced features enabling effective synchronized ventilation became widely available. However, it is essential to recognize that better technology alone will not improve outcomes; unless used with care and with optimal ventilation strategies, these machines cannot materially affect outcomes. The goal of this review was to discuss the unique challenges of ventilating extremely low GA neonates, review the basic modes of synchronized ventilation, describe the various approaches of volume-targeted ventilation (VTV), and emphasize key aspects of lung-protective ventilation strategies with conventional MV.

Basic Ventilator Terminology Abbreviations

A/C: BPD: CPAP: ETT: FIO2: GA: MMV: MV: NAVA: PRVC: PEEP: PIP: PSV: SIMV: VALI: VCV: VG: VT: VTV: assist/control bronchopulmonary dysplasia continuous positive airway pressure endotracheal tube fraction of inspired oxygen gestational age mandatory minute ventilation mechanical ventilation neurally adjusted ventilatory assist pressure-regulated volume control positive end-expiratory pressure peak ination pressure pressure support ventilation synchronized intermittent mandatory ventilation ventilator-associated lung injury volume-controlled ventilation volume guarantee tidal volume volume-targeted ventilation

The rapid evolution of ventilator technology with increasing availability of a variety of complex modes of respiratory support has led to a great deal of confusion in terminology. Because different manufacturers employ catchy proprietary nomenclature to describe similar modes of ventilation, communication between users of different devices has become increasingly difcult. Pragmatic considerations led to the adoption of the universal ventilator designed to ventilate the entire spectrum of patients from the 150-kg adult to the 400-g extremely low GA neonate, as the industry standard. It is not clear that all of these devices function as effectively at the lowest end of the patient spectrum, as they are primarily designed for the much larger adult market. These devices offer a variety of modes, the safety and efcacy of which have never been evaluated in newborn infants. Detailed discussion of the terminology is beyond the scope of this article, but to ensure clarity of understanding, the basic terminology for modes that are commonly used in newborn infants is reviewed. Basic modes of MV may be classied according to 3 characteristics:

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1. How is the ination initiated? 2. How is gas ow controlled during the ination? 3. How is the ination terminated? Inations can be initiated at a xed rate without regard to patient inspiratory effort. This mode is known as controlled MV and is used in patients who are heavily sedated or paralyzed. In awake patients, assistedalso known as synchronized or patient-triggeredventilation modes are used where inations are triggered by the patients inspiratory effort. The primary control variable for gas ow during the ination is either pressure (pressure-controlled/pressurelimited ventilation) or tidal volume (VT; volume-controlled ventilation [VCV]). Ination termination occurs when a set ination time has elapsed (time-cycled), when ination ow decelerates to a certain percent of peak ow (ow-cycled), or when a set VT is delivered (volume-cycled) (Fig 1). In addition to the basic modes, a variety of hybrid modes now exist that combine features of several of the basic types, as will be discussed in subsequent paragraphs.

simply small adults. To optimally utilize the complex devices at our disposal, we need to be aware of the many unique aspects of a newborn infants respiratory physiology.

Lung Mechanics
Small infants who have poorly compliant lungs have very short time constants and normally have rapid respiratory rates with very short inspiratory times to match their lung mechanics. They have limited muscle strength and cannot develop strong inspiratory ow or pressure. This situation imposes great technological challenges on device design, especially in terms of triggering ventilator inations, ination termination, and VT measurement. Suboptimal trigger devices may lead to excessive trigger delay with asynchrony, failure to trigger or terminate ination, and errors in VT measurement or delivery.

Uncuffed Endotracheal Tubes

Uncuffed endotracheal tubes (ETT) have traditionally been used in newborn infants because of concern about pressure necrosis of the tracheal mucosa and the small size of the tubes that makes inatable cuffs difcult to incorporate. For this reason, some degree of leak around the ETT is present in most infants, especially after prolonged ventilation, because the larynx and trachea progressively dilate from the cyclic stretch of thousands of inations per day. Leak is greater during ination, because the pressure gradient driving the leak is greater and because the airways distend with the higher ination pressure. Therefore, it is important to measure both inspiratory and expiratory VT, with the latter more closely approximating the volume of gas that had entered the lungs. The leak varies from moment to moment because the ETT is inserted only a short distance beyond the larynx and thus the leak will change with any change in the infants head position or a slight tension on the ETT.

Unique Challenges in MV of Newborn Infants

Individuals involved in the care of critically ill newborn infants should be keenly aware that newborns are not simply small children, any more than children are

Measurement of VT
The importance of accurate VT measurement in any sort of VCV/VTV of extremely small infants is obvious, considering that infants weighing 400 to 1,000 g require VT in the range of 2 to 5 mL. Unfortunately, most ventilators measure ow and volume at the junction of the ventilator circuit and the ventilator. This approach is convenient and avoids extra wires and the added instrumental dead space of a ow sensor. However, in neonates, this remote placement results in major inaccuracy of VT measurement because when the VT is measured at the ventilator end
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Figure 1. Basis of classication of ventilation modes: How is the ination initiated, how is the gas ow controlled during ination, and how is the breath terminated? A/C[assist control; PSV[pressure support ventilation; SIMV[ synchronized intermittent mandatory ventilation; TCPL[timecycled, pressure-limited ventilation; VCV[volume-controlled ventilation.

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of the circuit, the value does not account for compression of gas in the circuit, distention of the circuit, or leak around the ETT. The loss of volume in the circuit is proportional to the volume and compliance of the ventilator circuit and humidier, relative to the volume and compliance of the patients lungs. In large subjects with cuffed ETT, the volume measured at the ventilator correlates reasonably well with the actual VT entering the lungs, and the volume loss to compression of gas in the circuit can be automatically corrected. In tiny infants whose lungs are very small and noncompliant, the loss of volume to the circuit is much larger and not easily corrected, especially in the presence of a signicant ETT leak.

lungs, because the VT measurement does not account for compression of gas in the circuit/humidier and distention of the compliant circuit. Furthermore, the variable leak around uncuffed ETT makes accurate control of delivered VT very difcult with traditional volume-controlled modes. One study did demonstrate the feasibility of VCV in small preterm infants when special measures are taken to compensate for these problems. (5) In that study, the set VT was manually adjusted at frequent intervals to achieve a target exhaled VT measured by using an optional proximal ow sensor at the airway opening.

Pressure-Controlled Ventilation
Intermittent positive pressure ventilation using timecycled, pressure-limited ventilators remains the most widely used mode of neonatal ventilation. This practice evolved as a direct consequence of the difculties with traditional VCV described earlier. The basic design of these devices is similar to a T-piece circuit with continuous ow of gas and a valve that directs gas ow into the patient or allows it to continue around the circuit. A pressure-limiting valve controls the maximum pressure in the circuit during ination (peak ination pressure [PIP]) and another maintains a set level of positive pressure during the expiratory phase (positive end-expiratory pressure [PEEP]). The basic settings include ination and exhalation time (which together determine the ventilator rate), PIP, PEEP, circuit ow, and fraction of inspired oxygen (FIO2). During ination, the expiratory valve closes, the circuit is pressurized, and gas ows into the patient in proportion to the PIP and compliance of the lungs. Once the pressure within the patient circuit reaches the PIP, additional gas escapes through the pressure-limiting valve. When the ination time has elapsed, the expiratory valve opens, allowing circuit pressure to fall rapidly to the level of PEEP. The valve remains open with circuit pressure at the PEEP level with fresh gas owing in the circuit available for spontaneous breathing, until the end of the expiratory time, at which point the valve closes again and the cycle repeats. Modern ventilators are more advanced and use low circuit gas ows during the expiratory phase, generating additional ow to meet the patients demand as needed during spontaneous breathing or mechanical ination, but functionally they differ very little from the traditional devices. These pressure-limited ventilators overcome the difculties associated with VCV and are simple to use. Their chief disadvantage is that VT delivery is not directly controlled; the VT is a dependent variable that changes as a function of ination pressure and (sometimes rapidly) changing lung compliance.

Pressure-Limited Ventilation Versus VCV

Volume-Controlled Ventilation
VCV delivers a constant, preset VT with each ination. In theory, these volume ventilators allow the operator to select VT and rate, thereby directly controlling minute ventilation. The ventilator delivers the preset VT into the circuit, generating whatever pressure is needed, up to a safety popoff, which is generally set at 40 cm H2O. A maximum ination time is also set as an additional safety measure. Ination ends when the set VT has been delivered or when the maximum ination time has elapsed. The latter ensures that with very stiff lungs, the ventilator does not maintain ination for a prolonged period trying to deliver the set VT. Figure 2 contrasts the salient features of pressure and volume ventilation. The major limitation of volume-controlled ventilators is that what they really control is the volume injected into the ventilator circuit, not the VT that enters the patients

Figure 2. Key features of volume-controlled ventilation compared with pressure-limited ventilation.

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Basic Assisted Ventilation Modes

Synchronized Intermittent Mandatory Ventilation
Synchronized intermittent mandatory ventilation (SIMV) is a time-cycled, pressure-limited mode that provides a set number of mechanical inations synchronized with the infants spontaneous respiratory effort, if present. Spontaneous breaths in excess of the set rate are not supported, resulting in uneven VT and potentially a high work of breathing during weaning. This issue is especially important in extremely small infants who have narrow ETT in whom the high airway resistance, along with the infants limited muscle strength and the mechanical disadvantage of the infants excessively compliant chest wall, result in small, ineffective VT with a high dead space:VT ratio. Thus, the very small VT results in re-breathing of dead space gas and contributes little to effective alveolar ventilation (alveolar ventilation minute ventilation deadspace ventilation). To maintain adequate alveolar minute ventilation with the limited number of mechanical inations provided by the ventilator in SIMV mode, these inations must use relatively large VT.

Pressure Support Ventilation

Pressure support ventilation (PSV) is a ow-cycled, rather than time-cycled, pressure-limited mode that supports every spontaneous breath similar to the way A/C does. With ow cycling, ination is terminated when ination ow declines to a preset threshold, usually 10% to 20% of peak ow. This feature eliminates ination hold (prolonged ination time, which keeps the lungs at peak ination) and thus provides more optimal synchrony. PSV is often used to support spontaneous breathing between low-rate SIMV to overcome the problems associated with inadequate spontaneous respiratory effort and high ETT resistance. Alternately, in some devices, PSV can be used as a standalone technique, much like A/C.

Trigger Technology
An effective trigger device must be sensitive enough to be activated by a small preterm infant, avoid autotriggering, and must have a very rapid response time to match the short ination times and rapid respiratory rates of small preterm infants. The situation is further complicated by the ubiquitous and variable leak of gas around uncuffed ETT. Common types of triggering devices used in clinical care and their relative advantages are listed in the Table. Evidence supports ow-triggering with a ow sensor at the ETT adaptor as the best compromise that is widely available at present. (6) An emerging technology, which is currently available only on the Servo-i ventilator (Maquet Medical Systems, Wayne, NJ), uses the electrical activity of the diaphragm, as assessed by transesophageal electromyography to trigger ination. This method is attractive because it has a short trigger delay, does not require a ow sensor, and is not affected by ETT leakage. (7) However, it cannot currently be used independent of the neurally adjusted ventilatory assist (NAVA) mode, which has not been adequately evaluated in small preterm infants who have immature respiratory control.

Assist/Control
Assist/control (A/C) is also a time-cycled, pressure-limited mode, in which every spontaneous breath is supported by the ventilator. This approach results in more uniform VT and lower work of breathing. A set rate of mandatory inations provides a minimum rate in case of apnea. A backup rate slightly below the infants spontaneous breathing rate should be chosen so as not to preempt spontaneous breaths. Because the infant controls the ventilator rate, support is gradually withdrawn by lowering the PIP, rather than the ventilator rate. This approach decreases the amount of support provided to each breath, allowing the infant to gradually take over the work of breathing. One reason for the apparent reluctance to adopt this mode seems to be this slightly less intuitive weaning strategy.
Table.

Available Modes of Triggering/Synchronization

Advantages No added dead-space Sensitivity, rapid response Rapid response, no added deadspace No added dead-space, very rapid response, not affected by leak Disadvantages Poor sensitivity, long trigger delay, high work of breathing Added dead space, leak may cause autotriggering Susceptible to artifact with incorrect position; limited availability Costly, somewhat invasive; limited availability

Method Pressure Airow Surface capsule Electrical activity of the diaphragm

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Although ow triggering has emerged as the method of choice, it is not free from drawbacks. Inline placement of the ow sensor adds w0.8 mL of dead space to the breathing circuit. This added instrumental dead space becomes a larger proportion of the VT as the infants size decreases. Autotriggering in the presence of a leak around the ETT can lead to cycling at an excessive rate, hypocapnia, or air-trapping. This is because leak ow during the expiratory phase will be misinterpreted as inspiratory effort. The problem can be corrected by decreasing trigger sensitivity, but because the leak ow is highly variable, frequent adjustments are needed. Moreover, with a less sensitive trigger, increased patient effort is needed and the trigger delay increases, both of which are highly undesirable. Most devices now allow a xed amount of leak compensation, but this does not account for the variability of the leak. One device, the Draeger Babylog (Draeger Medical, Inc, Telford, PA), offers an effective solution to this problem, using a proprietary technology to determine the leak ow throughout the respiratory cycle and electronically correcting the measured ow. This method effectively eliminates the leak-related problems, allowing the trigger sensitivity to remain high with rapid response time and minimal work to trigger the device.

Choice of Assisted Ventilation Modes

In the absence of large randomized trials to denitively prove the superiority of one mode, the relative merits of A/C and SIMV, the two most widely used modalities of synchronized ventilation, continue to be debated. Short-term clinical trials found that A/C, compared with SIMV, resulted in substantially smaller and less variable VT, less tachypnea, more rapid weaning from MV, and smaller uctuations in blood pressure. (8)(9)(10)(11) In very premature infants who have correspondingly small ETT, SIMV may not provide optimal support because of high airway resistance and work of breathing, but many clinicians still use it, especially for weaning from MV. This choice seems to be based largely on tradition but also on the supercially plausible assumption that fewer mechanical breaths are inherently less damaging. This belief ignores the fact that the slower rate is accomplished at the expense of larger VT, a factor that is more injurious than frequency. Furthermore, the concept that ventilator rate must be lowered before extubation is deeply ingrained, although contradicted by available data. (10) Many clinicians also mistakenly believe that assisting every breath prevents respiratory muscle training. This concern reects a lack of understanding of the complex patientventilator interaction during assisted ventilation.
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Figure 3. The tidal volume entering the lungs (vertical axis) is the result of the transpulmonary pressure: the combination of the negative pressure generated by the patients inspiratory effort and the positive ination pressure from the ventilator. Because the patient contributes to each ination, there is continuous respiratory muscle training. During weaning from assist control, the pressure generated by the ventilator is gradually reduced, allowing the patient to take over progressively more of the work of breathing.

As illustrated in Fig 3, the VT with synchronized ventilation is the result of the sum of the negative intrapleural pressure generated by the infant and the positive ination pressure generated by the ventilator. This transpulmonary pressure, together with the compliance of the respiratory system, determines the resulting VT. Thus, as ventilator ination pressure is decreased during weaning, the infant gradually takes over a greater proportion of the work of breathing and, in the process, achieves effective training of the respiratory muscles. Ultimately, the ventilator pressure is decreased to the point when it only overcomes the added resistance of the ETT and circuit, at which point the infant should be extubated.

Principles Underlying Lung-Protective Ventilation Strategies

Limitations of Pressure as a Primary Control Variable
Pressure-limited ventilation became the default mode in our NICUs because early attempts to use VCV proved to be impractical in small preterm infants. Pressure-limited

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ventilation remains the primary mode of ventilation in many centers because of its simplicity and immunity from the effects of large ETT leak. Better intrapulmonary gas distribution due to the decelerating gas ow pattern and the presumed benet of directly controlling PIP were also seen as advantages. The major drawback of pressure-limited ventilation is that VT varies with changes in lung compliance, which may occur rapidly in the immediate postnatal period with resorption of lung uid, optimization of lung volume, and administration of exogenous surfactant. When compliance improves, inadvertent hyperventilation and lung injury from excessively large VT (volutrauma) may occur, unless the ination pressure is quickly reduced. As few as six excessively large breaths can negate the benets of surfactant therapy. (12) Therefore, relying on manual adjustment of ination pressure may be ineffective in preventing lung injury. In one study, inadvertent hyperventilation to PaCO2 less than 25 mm Hg occurred in w30% of ventilated newborn infants during the rst day after birth, (13) indicating that hypocapnia continues to be a common problem despite increasing awareness of its dangers.

contribute to an increased risk of intraventricular hemorrhage. Low VT also leads to inefcient gas exchange due to the increased dead space: VT ratio; in time, it results in atelectasis with increased oxygen requirement, decreased lung compliance, and maldistribution of VT leading to regional volutrauma. Clearly, some form of VTV with relatively tight control of VT delivery during MV is a desirable goal and remains the main reason why VCV is still the standard of care in adult and pediatric respiratory support.

Importance of the Open Lung Strategy

Despite a substantial body of evidence accumulated over many years, the critical importance of distributing the VT evenly into an optimally aerated lung has not been widely appreciated. This concept requires special emphasis, because the benets of VTV cannot be realized without ensuring that this VT is distributed evenly throughout the lungs. The admonition of Burkhard Lachman more than 20 years ago to open the lung and keep it open (21) has been ignored by many during conventional MV despite its sound physiologic basis and strong experimental evidence in its favor. Adequate end-expiratory pressure may be more important than small VT. (22)(23) Furthermore, in the presence of atelectasis, the nondependent (ie, aerated) lung was the most injured area of the lungs.

Ventilator-Associated Lung Injury

Despite extensive evidence that excessive volume, not pressure, is the key determinant of VALI, baro-phobia remains widespread. It is important to recognize that high ination pressure causes lung injury only if it results in excessive VT. Dreyfuss et al (14) demonstrated 20 years ago that severe acute lung injury occurred in small animals ventilated with large VT, irrespective of whether that volume was generated by positive or negative ination pressure. In contrast, animals exposed to the same high ination pressure but in whom VT was limited to a physiologic volume by external binding of the chest and abdomen experienced much less acute lung injury. This landmark article and other similar preclinical studies clearly demonstrate that excessive VT, not pressure by itself, is responsible for lung injury. (15)(16) Together with increasing recognition of the well-documented dangers of inadvertent hyperventilation, (17)(18)(19) the appreciation of the key role of volutrauma in VALI constitutes a powerful argument in favor of adoption of VT as the primary control variable in MV. (20) Insufcient VT is also undesirable. With a xed ination pressure, insufcient VT may occur because of a decrease in lung compliance, increase in airway resistance, airway obstruction, air-trapping, or decreased spontaneous respiratory effort. Inadequate VT results in hypercapnia, increased work of breathing, increased oxygen consumption, agitation, fatigue, and atelectasis, and it could

Figure 4. In the presence of extensive atelectasis, as seen in

the right lower corner, there are two populations of alveoli with very different critical opening pressures. From LaPlaces law, we know that the already aerated alveoli have a lower critical opening pressure; therefore, the tidal volume will enter the already aerated portion of the lung, which becomes overexpanded with each ination, leading to volutrauma, while the atelectatic portion is also damaged by outpouring of protein-rich edema uid that inactivates surfactant. COP[critical opening pressure; FRC=functional residual capacity.
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(24) This phenomenon occurs because, in the presence of extensive atelectasis, even a normal, physiologic VT will result in overexpansion of the aerated portion of the lungs. These aerated alveoli are more compliant than the atelectatic portion of the lungs (LaPlaces law). Therefore, the gas will preferentially enter the already open alveoli and lead to overexpansion with subsequent volutrauma/biotrauma (Fig 4). Atelectasis results in accumulation of protein-rich uid leading to surfactant inactivation and release of inammatory mediators. Shear forces and uneven stress in areas in which atelectasis and overination coexist add to the damage. The repeated collapse and re-expansion of alveoli with low end-expiratory volume contribute further to VALI. Collectively, this process is known as atelectotrauma. The open lung concept (25) is central to minimizing VALI, regardless of other aspects of ventilation strategy. The importance of optimizing lung ination has long been recognized by users of high-frequency oscillatory ventilation (HFOV), in which the optimal lung volume strategy has become standard practice and is widely understood to be the key to its success. (26) There are a number of animal studies indicating that conventional ventilation with the open lung concept can achieve similar degrees of lung protection as HFOV, suggesting that optimizing lung volume, rather than frequency, is the key factor. (25)(27)(28) However, the clinical application of the open lung concept with conventional ventilation has not been extensively evaluated in clinical trials. (26) The failure to actively embrace the open lung concept may be based on the paucity of evidence from human trials of how to best achieve it. In clinical practice, lung volume recruitment seems to be best achieved by applying adequate PEEP, preferably very soon after birth. A number of studies indicate that an oxygen-guided bedside recruitment strategy during high-frequency ventilation is feasible. (29)(30)(31) There are limited data for a similar maneuver during conventional ventilation, (32) but this strategy has been successfully used by the group of Lista in Milan and others for some time. (33) The general strategy of optimizing lung volume relies on oxygenation as determined by using pulse oximetry as a proxy for ventilation/perfusion matching and thus lung volume. If FIO2 remains greater than 0.30, PEEP is increased in increments of 0.5 to 1 cm H2O every 5 to 10 minutes until FIO2 falls below 0.30, or until there is no further improvement in oxygenation with incremental PEEP change, or a maximum PEEP of 10 cm H2O is reached. Once lung recruitment is achieved, the lungs become more compliant, and PEEP needs to be reduced to
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a level just above the point when derecruitment (signaled by deteriorating oxygenation) begins to avoid overexpansion. It is important to understand that there is no single safe PEEP level. Optimal PEEP must be tailored to the degree of lung injury (ie, lung compliance). For infants who have healthy lungs and thus normal lung compliance, PEEP of 3 cm H2O is adequate and PEEP of 6 cm H2O may result in overexpansion of the lungs with circulatory impairment and elevated cerebral venous pressure. Conversely, atelectatic, poorly compliant lungs may require PEEP levels of 8 to 10 cm H2O or more to achieve adequate alveolar recruitment and improve the ventilation/perfusion ratio. Because we seldom ventilate infants who have healthy lungs, PEEP of less than 5 cm H2O should be used infrequently.

Importance of Optimizing Initial Respiratory Support

The immediate postnatal period when air breathing is initiated is a critical period that may determine the subsequent pulmonary outcome. There is a strong evidence base in support of initial respiratory support strategies aimed at facilitating lung uid clearance and helping the preterm infant who has insufcient chest wall rigidity to establish functional residual capacity in the delivery room. Positive pressure ventilation with high pressure and excessively large VT values must be avoided. The T-piece resuscitator is best suited for accomplishing this goal because of its ability to provide consistent, controlled ination pressure and consistent PEEP. Initial FIO2 should be between 0.30 and 0.40 for preterm infants and 0.21 for term infants. FIO2 should be promptly titrated to maintain target saturation according to published normograms. The use of sustained inations to rapidly establish normal functional residual capacity and optimal gas distribution may be benecial and is currently the focus of active investigation. Although physiologically attractive and supported by several preclinical and clinical studies, there is currently insufcient evidence to recommend sustained ination as standard practice.

General Principles of MV
Based on the principles outlined here, the following general guidelines of MV can be formulated. The overarching goal of MV is to support adequate gas exchange with a minimum of adverse effects on the infants lungs, hemodynamics, and brain. Longer duration of ventilation is associated with increased likelihood of chronic lung disease, late-onset sepsis, and neurodevelopmental impairment; therefore, extubation at the earliest possible time is desirable. Ventilation strategies should be individualized to

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address each patients specic condition, but the key objectives are to improve lung compliance, reduce oxygen requirement, prevent surfactant inactivation, and ensure even VT distribution by recruiting optimal lung volume and preventing atelectasis. The second key element of lung-protective ventilation strategies is to minimize volutrauma and hypocapnia, the preventable elements of lung and brain injury, by avoiding excessively large VT. This goal is best accomplished by the use of one of the volume-targeted modes available on the ventilators in common use in North America, following the guidelines outlined later in this review. Mild permissive hypercapnia and minimal FIO2 to achieve adequate oxygen saturation (88%93%) are generally considered appropriate. There is no evidence to support the routine use of sedation, and infants should therefore be allowed to breathe spontaneously. Routine suctioning should be avoided because it leads to derecruitment, transient hypoxemia, and perturbation of cerebral hemodynamics. When secretions are detected by auscultation or by perturbation of the ow waveform, gentle rapid suctioning without instillation of normal saline is indicated. The choice of SIMV or A/C is, to some extent, a matter of personal preference and practice style. There is little difference between the two methods in the acute phase of respiratory failure. In a patient who has little or no respiratory effort or is heavily sedated and/or paralyzed, we are really providing simple intermittent mandatory ventilation, regardless of the ventilator mode selection. The differences between SIMV and A/C or PSV become more pronounced during weaning and are especially important in the smallest infants who have narrow ETT. Prolonged ventilation with low SIMV rates should be avoided in these infants because it imposes an undesirably high work of breathing. To a signicant degree, this problem may be overcome by adding PSV to the spontaneous breaths during SIMV. (34) Although this approach is effective, it adds complexity and does not seem to have any advantage over PSV used alone, as long as atelectasis is avoided by using an adequate level of PEEP.

primary control variable, the ination pressure will fall as lung compliance and patient inspiratory effort improve, resulting in real-time weaning of pressure, as opposed to intermittent manual lowering of pressure in response to blood gases. This method avoids excessive VT and achieves a shorter duration of MV. A recent meta-analysis that included a combination of several different modalities of VTV documented a number of advantages of VTV compared with pressure-limited ventilation: VTV signicantly reduced the combined outcome of death or BPD, as well as the risk of pneumothorax, and it signicantly shortened the duration of MV. (35) Another more inclusive meta-analysis also documented decreased risk of severe intraventricular hemorrhage or periventricular leukomalacia. (36) Although very supportive, these meta-analyses do not provide the denitive evidence of the superiority of VTV because the studies included in the analyses were small and diverse and many of the key outcomes reported in the meta-analysis were not prospectively collected or dened. In some of the studies, other variables beyond volume versus pressure targeting also differed. All the included studies focused on short-term physiologic outcomes, and none included BPD as a primary outcome. Except for one follow-up study based on a parental questionnaire, no long-term pulmonary or developmental outcomes have been reported.

Volume Guarantee
VG is a mode that is available on the Draeger Babylog 8000 and the newer VN 500 (Draeger Medical, Inc), as well as the Leoni Plus (Heinen Lwenstein GmbH, Bad Ems, Germany), which is not available in the United States. More recently, a version of this mode has been implemented on the Avea ventilator (CareFusion, San Diego, CA). The VG mode, as implemented on the Draeger device, has been studied more thoroughly than other modes of VTV. (37) Specic clinical guidelines for VG have been published. (38)(39) VG has been shown to be more effective when used with A/C than with SIMV. (40) The choice of appropriate VT depends on the infants size and basic synchronization mode. One size does not t all. The smallest infants require a larger VT on a per-kilogram basis, due to the proportionally larger impact of xed instrumental dead space of the ow sensor. (41) Infants less than 600 g need a VT of 5.5 to 6 mL/kg, whereas those greater than 600 g will likely achieve adequate ventilation with a VT of 4.5 to 5.5 mL/kg. These values were established for A/C; SIMV requires slightly larger values for the same alveolar minute ventilation because fewer breaths are supported and volume-targeted. When starting with VG, the ination
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Volume-Targeted Ventilation
There are important differences in how volume targeting is achieved with various devices, and their relative efcacy has not been established. The ability to achieve more stable VT and a reduction in hypocapnia has only been demonstrated with volume guarantee (VG), not with the other modalities of VTV. However, the primary benet of VTV probably rests in the ability to regulate VT, regardless of how that goal is achieved. When VT is the

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pressure limit should initially be set 3 to 5 cm H2O above the level estimated to be sufcient to achieve a normal VT. If the target VT cannot be reached with this setting, increase the pressure limit until the desired VT is generated. It is important to make sure the ETT is not kinked, malpositioned in the mainstem bronchus or obstructed on the carina. Signicant volutrauma and/or air leak could result from failure to recognize single-lung intubation. If changing from pressure-limited ventilation, the pressure limit should be increased by 3 to 5 cm H2O from baseline to allow the microprocessor to adjust working pressure as needed. Pressure limit is subsequently adjusted to be w20% above the current working pressure and adjusted periodically as lung compliance improves and working pressure comes down. If the ventilator is unable to reach the target VT with the set ination pressure limit, an alarm will sound. This alarm serves as an early warning system that should prompt an evaluation of the reason for this change. Subsequent adjustments of VT should be guided by arterial blood gas measurement. Over time, with development of BPD, which results in more heterogeneous ination and air trapping, a modestly higher VT is required even with permissive hypercapnia. (42) In the VN 500 ventilator, the leak-compensated VT value should be selected in the ventilator default setting to minimize artifacts caused by ETT leakage. The Babylog 8000 uses the uncorrected VT measurement, which begins to progressively underestimate the true VT with increasing ETT leak, potentially resulting in inadvertent hypocapnia. This commonly occurs if a preterm infant remains intubated for more than 2 weeks, because of stretching of the larynx, and may require reintubation with a larger ETT. As long as the pH is low enough for the infant to have a respiratory drive, weaning occurs automatically, in real time, and requires fewer blood gas measurements. VT should normally not be weaned to less than 4 mL/kg to avoid shifting all the work of breathing to the infant. When the infant is able to maintain good gas exchange with low ination pressure, extubation should be attempted.

compliance compensation decreases with lower infant weights and often results in wide swings of apparent VT among children weighing 750 to 1,000 g. Therefore, the compliance compensation feature is generally not used in small preterm infants. Substantial loss of VT to compression of gas in the circuit occurs; the set VT must account for this and typically must be two to three times larger than the target VT at the airway opening. If the infant is being switched from a pressure-limited mode, a common approach to setting the initial volume target is to set the target volume either: (1) to match the inspiratory volumes generated by pressure-limited ventilation; or (2) to generate pressures similar to those being used in pressure-limited ventilation. If the infant is being begun de novo on PRVC, the usual method of choosing the target VT is the same as that used with VCV (as discussed in the following text). If a proximal ow sensor is available, it should be used to directly measure the exhaled VT and adjust the set value to achieve an exhaled VT of w5 mL/kg. Similar to other VTV modalities, the pressure needed to achieve the target VT comes down automatically, as lung compliance and patient effort improve. The target VT should not be reduced below 4 mL/kg exhaled volume at the airway opening for the same reasons as described in the previous section on VG.

Volume Ventilation Plus

Volume Ventilation Plus (Puritan Bennett 840, Covidien, Manseld, MA ) is a complex mode that combines two different dual-mode, volume-targeted breath types: Volume Control Plus for delivery of mandatory breaths in A/C and SIMV, and Volume Support for delivery of spontaneous breaths in the spontaneous breathing mode. The ventilator adjusts ination pressure to target ination VT. Because VT is not routinely measured at the ETT, it is functionally similar to VC and PRVC modes described earlier. Thus, the selection of volume setting reects the proximal VT and must allow for the loss of volume to compression in the ventilator circuit. Proximal ow sensor use is recommended where available with the same aforementioned targets. As noted earlier, avoidance of inadvertent mainstem bronchus intubation is essential.

Pressure-Regulated Volume Control

The pressure-regulated volume control (PRVC) mode on the Servo-i ventilator uses the VT of the previous breath, measured at the ventilator end of the circuit, to regulate the ination pressure needed to achieve the desired VT. The compliance (tubing) compensation function is only effective when there is no signicant ETT leak, and even then, it is only an approximation of the true exhaled VT. In addition, the reliability of the
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Volume-Targeted Ventilation
VTV as implemented on the Hamilton G5 (Hamilton Medical, Reno, NV) is a mode similar to VG that adjusts the ination pressure in response to any deviation of measured VT from the target value. This relatively new mode has no published literature on its effectiveness, but it seems to have functionality similar to standard VG, and therefore similar guidelines should be applied to its use.

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Volume Limit
Some pressure-limited ventilators, such as the Bear Cub 750 and the older-generation Avea (CareFusion), use a simple volume limit function that merely terminates inspiration when the maximum allowed VT is delivered, which may result in very short ination times. These have now been supplanted by more sophisticated algorithms in the newer generation of ventilators.

Volume-Controlled Ventilation
The volume control mode on all devices directly controls the volume of gas delivered to the ventilator circuit (also known as Vdel), not the volume of gas delivered to the patient. Substantial loss of volume to compression of gas in the circuit occurs; the set volume (Vdel) must account for this loss and typically must be two to three times larger than the target exhaled VT at the airway opening. A common approach to the use of VC is to adjust Vdel settings until clinically adequate chest excursion and air entry are achieved, and then make further adjustments based on blood gas measurements. An alternative and preferred approach is to measure exhaled VT by using a ow sensor at the airway opening, which is then used to adjust the set Vdel needed to achieve an appropriate exhaled VT. As discussed earlier, the same caution needs to be exercised to avoid inadvertent mainstem bronchus intubation. Each ventilator functions differently, and it is critical that users become familiar with the specic features of their device. Readers are referred to user manuals of their respective devices for further guidance. A ventilator is only a tool in the hands of the clinician; a tool that can be used well or not. Yet, we talk of ventilator-induced lung injury as though the machines were to blame for the undesirable outcome. Perhaps the term physicianinduced lung injury is more appropriate, for we are the ones that select the ventilator settings.

uncuffed ETT. Specically, the common problem of periodic breathing would be accentuated by the ventilator with less support being generated during hypopnea and excessive assist provided when the infant becomes agitated. Because the system by necessity responds to inspiratory ow and volume, a large leak around the ETT would be interpreted as a large inspiration and given correspondingly high level of ination pressure, potentially leading to dangerously large VT. Only limited clinical data regarding this technique are available in preterm infants, and it remains experimental.

Neurally Adjusted Ventilator Assist

NAVA is a potentially attractive approach that uses the patients own respiratory control to drive the ventilator. (44) The device detects electrical activity of the diaphragm by using bipolar electrodes mounted on a modied nasogastric feeding tube positioned at the level of the diaphragm to trigger and modulate inspiration. Based on an arbitrary NAVA number, which represents the gain applied to the electrical signal from the diaphragm, the ventilator automatically adjusts the level of support in proportion to the inspiratory effort. NAVA is still an unproven therapy in newborn infants, but the concept is attractive because the system is not affected by leak around the ETT. However, like PAV, NAVA is a positive feedback system that assumes that the respiratory control center is mature, which is not a valid assumption in the preterm infant. Incorporating minimal and maximal support levels may overcome this limitation, but this approach has yet to be fully validated.

Airway Pressure Release Ventilation

Airway pressure release ventilation is a technique designed to achieve lung volume recruitment and relies on patients spontaneous breathing to achieve the bulk of minute ventilation. The technique consists of maintaining a relatively high ination pressure for the bulk of a respiratory cycle with periodic release of this pressure for brief periods. (45) This alternating pattern of low and high pressure can be thought of as extreme inverse ratio ventilation. It also bears some similarity to the various forms of biphasic CPAP. Airway pressure release ventilation is usually used as a rescue technique, and unlike biphasic CPAP, the upper pressure level P high is maintained for majority of the cycle T high. The pressure to which the lungs are released is called P low, and the release time is called T low. The technique has primarily been used in adult patients who have acute lung injury, where there may be some short-term benets in terms of oxygenation. No clear survival advantage or
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Novel Techniques of Assisted Ventilation

Proportional Assist Ventilation
Proportional assist ventilation is a technique that is not currently available in North America. It is based on the principle of elastic and resistive unloading of the respiratory system, designed to overcome the added workload imposed by poor lung compliance and high airway and instrumental resistance. (43) The device uses a positive feedback algorithm to generate ination pressure in proportion to patient effort. This approach assumes a mature respiratory control center and a closed, leak-free system, neither of which is true in the preterm infant with

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reduction in complications has been demonstrated. There is insufcient evidence to assess the utility of this technique in newborn infants, with only a handful of case reports available and no controlled trials. There should seldom be a need for such rescue techniques if lungprotective ventilation strategies are used from the outset.

that closed loop systems will begin to be adapted to neonatal care in the future to facilitate weaning and extubation. In the meantime, unit protocols designed to facilitate weaning from MV may be the best available approach. (49)

Conclusions
A variety of new modalities and techniques have become available for the treatment of respiratory failure in the past decade. Our understanding of how to optimally use these devices, while continuing to improve, lags behind the pace of technological innovation. Moreover, improvements in outcomes such as BPD are increasingly difcult to demonstrate, as each incremental improvement gets us closer to what may be an irreducible minimum. Early establishment of optimal lung volume, careful avoidance of high ination pressures in the delivery room, and appropriate titration of FIO2 may be key to minimizing lung injury. Avoidance of MV by means of early CPAP with or without surfactant administration may still be the most effective way to reduce the risk of chronic lung disease. For infants who do require MV, the combination of VTV, combined with the open lung strategy, seems to offer the best chance of reducing the risk of chronic lung disease.

Closed Loop Systems

A variety of closed loop forms of intelligent ventilation have been implemented on ventilators designed for adult use. VG and PRVC were the rst examples of this sort of servo-regulation, but they modulate only a single variable, the ination pressure, to target a xed VT . Other examples include mandatory minute ventilation (MMV, Draeger V500, Draeger Medical, Inc), which is potentially useful for infants who have inconsistent respiratory effort. MMV is a modication of SIMV with PSV and will maintain a low rate of mandatory inations as long as the patients spontaneous effort, augmented by PSV, is adequate to meet the preset MMV target and increase the SIMV rate in a proactive fashion if the projected MV is falling short. (46) Although conceptually attractive, the utility of this approach has not been clearly demonstrated; similar goals can be achieved with the use of volume-targeted modes and PSV. Adaptive Support Ventilation (Hamilton Medical) may be thought of as an internal electronic ventilator protocol that offers continuous measurement of lung mechanics to adjust ventilation parameters to optimize support. (47) This mode recognizes spontaneous respiratory activity and automatically switches the patient between mandatory pressure-controlled inations and spontaneous pressuresupported breaths. The clinician determines the desired minute ventilation, and the algorithm determines the optimal respiratory rate/VT combination according to the patients respiratory mechanics. There is no information to judge the safety and efcacy of this mode in newborn infants. SmartCare is another automated weaning system available on the adult Draeger V500 (Draeger Medical, Inc). (48) The program implements a continuous weaning protocol by using a pressure support mode by adjusting the level of support based on measurements of respiratory rate, VT, and end-tidal carbon dioxide measurement. SmartCare maintains the patients at a minimal level of support that is tolerated and automatically initiates a spontaneous breathing test when patients meet predened criteria. None of these systems, with the possible exception of MMV, is ready for implementation in newborn infants because of the many unique aspects of neonatal respiratory physiology and pathophysiology. It is likely, however,
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American Board of Pediatrics Neonatal-Perinatal Content Specications

Plan the ventilatory therapy for infants with respiratory failure of different etiologies. Know the indications for and techniques of positive pressure ventilation (PPV). Know the effects and risks of PPV.

Editors Note
For additional reading on this subject, please see the following articles in NeoReviews: Lan WC, Bhutani V. Core concepts: neonatal tidal volume: physiologic, technologic, and clinical considerations. NeoReviews. 2011;12 (11):e652e660 and Mammel M, King N. Picking your next ventilator. NeoReviews. 2010;11(9):e484e494.

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NeoReviews Quiz New minimum performance level requirements

Per the 2010 revision of the American Medical Association (AMA) Physicians Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certied for AMA PRA Category 1 CreditTM. In order to successfully complete 2013 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. In NeoReviews, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A family practice resident is rotating through the NICU and notes that she is very familiar with ventilator management in adults. What is an aspect of mechanical ventilation that is unique to neonates? A. Neonates have very long time constants and long inspiratory times to match their lung mechanics. B. Due to their very small airways, preterm infants will exhibit virtually no leak around the endotracheal tube, even with uncuffed tubes. C. There are minimal differences between ventilating critically ill adults and infants; the main difference is adjusting the tidal volume according to weight, with other parameters being similar. D. When inspiratory and expiratory tidal volumes are measured, the inspiratory volume will usually better approximate actual volume of gas entering the lungs, as that will have been specied exactly by the ventilator. E. The leak around the endotracheal tube may vary from moment to moment depending on the positioning of the infants head or changes in tension on the tube. 2. A 28-week-gestational-age male with respiratory distress syndrome is being treated with synchronized intermittent mandatory ventilation (SIMV), set at a rate of 32/minute. Which of the following is true? A. This mode will deliver a consistent tidal volume for at least 32 breaths per minute. B. Spontaneous breaths in excess of 32 times per minute will not be supported by the ventilator. C. If the infant is breathing spontaneously at a high respiratory rate, the spontaneous breaths will usually have higher tidal volume than supported breaths. D. As the ventilator is synchronized, if the infant is breathing at a rate of 20/minute, the ventilator will provide an average of 20 breaths per minute. E. As the ventilator provides a consistent and high pressure, there is no need to be concerned about dead space when using this mode in premature infants.
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respiratory disorders mechanical ventilatory strategies

3. A 28-week-gestational-age female is being supported on a mechanical ventilator with a time-cycled, pressure-limited mode in which every spontaneous breath is supported by the ventilator, with a backup rate. What mode of ventilation is this? A. Synchronized intermittent mandatory ventilation. B. Pressure limitvolume guaranteed ventilation. C. Assist/Control. D. Intermittent mandatory ventilation with time-cycle support. E. This type of ventilation is not available for neonates. 4. A 24-week-gestational-age male is receiving mechanical ventilation using pressure-limited ventilation. Which of the following is most correct in terms of potential limitations and adverse consequences of pressure-limited ventilation? A. Tidal volume can vary with changes in lung compliance, particularly after surfactant administration, resulting in inadvertently large tidal volume delivery and lung injury. B. As high pressures are more worrisome than high volumes in regard to lung injury, monitoring of pressure is more important in order to avoid chronic lung disease. C. With pressure-limited ventilation, this infant is primarily at risk for hypocapnia, and not hypercapnia, as ventilation will almost always be very effective with this mode. D. A difculty of pressure-limited ventilation is the lack of ability to directly control peak inspiratory pressure. E. Long-term lung injury caused by excessive tidal volumes is usually caused over the course of several weeks of pressure-limited ventilation. 5. You are caring for a 1-day-old 31-week-gestational-age female with respiratory distress syndrome, who has received one dose of surfactant. The infant is on volume targeted ventilation (VTV). Which of the following is true regarding VTV? A. Meta-analyses have shown that while VTV reduces need for surfactant therapy, there is no difference in the outcomes of death, pneumothorax, or duration of ventilation. B. An advantage of VTV is that the key measurement of 5 ml/kg target tidal volume is the same for all infants regardless of size or other parameters, making it easier to remember the correct setting. C. If the ventilator appears to be delivering 5 ml/kg effectively with relatively low pressures (peak inspiratory pressure of 12-15), this is a sign that the lungs are equally well aerated. D. With tidal volume as the primary control variable, ination pressure will fall as lung compliance improves and result in weaning of pressure. E. Volume guarantee is a mode that will work with synchronized intermittent mandatory ventilation, but not with assist/control mode.

NeoReviews Vol.14 No.5 May 2013 e251

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Update on Mechanical Ventilatory Strategies Martin Keszler Neoreviews 2013;14;e237 DOI: 10.1542/neo.14-5-e237

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