Assisted Ventilation of the Newborn

This article reviews assisted ventilation of the newborn, highlighting the concepts of pulmonary mechanics, gas exchange, respiration control, and lung injury that can be used to optimize respiratory support and the use of mechanical ventilation in newborn infants. Sound application of these concepts is necessary to improve survival, while reducing the adverse effects of mechanical ventilation.

Over the past 30-40 years, the availability of ventilatory support has led to a substantial improvement in the survival rate for preterm infants. Conventional frequency ventilation is being used on smaller and sicker infants for longer durations.

The primary objective of assisted ventilation is to support breathing until the patient's respiratory efforts are sufficient. Ventilation may be required during immediate care of the infant who is in respiratory failure due to birth depression, encephalopathy,  apnea, shock, or pulmonary disease. Improved survival rates as a result of advances in neonatal care have led to an increased number of infants at risk for chronic lung disease.

Although the etiology of lung injury is multifactorial, animal and clinical data indicate that lung injury is affected, in large part, by the ventilatory strategies used. Optimal ventilatory strategies provide the best possible gas exchange, while minimizing lung injury or other adverse effects. The use of evidence-based ventilatory strategies, strategies to prevent lung injury, and alternative modes of ventilation should yield further improvements in neonatal outcomes.

Newborns are vulnerable to impaired gas exchange because of their relatively high metabolic rate, propensity for decreased functional residual capacity (FRC), decreased lung compliance, increased resistance, and potential for right-to-left shunts through the ductus arteriosus, foramen ovale, or both. Thus, impaired gas exchange is common in newborns. Hypercapnia and hypoxemia frequently coexist, though some disorders may affect gas exchange differentially.

Hypercapnia

Hypercapnia is usually caused by severe ventilation/perfusion (V/Q) mismatch or hypoventilation. Optimal V/Q matching occurs when the ratio of the volume of gas to the volume of blood entering the lungs approximates 1. Intra-pulmonary veno-arterial shunting of blood commonly occurs through lung segments with alveolar hypoventilation. The resulting V/Q mismatch is probably the most important mechanism of impaired gas exchange among infants with respiratory failure due to lung disease, including respiratory distress syndrome (RDS). Hypoventilation is frequently seen in infants with apnea of prematurity.

The effect of assisted ventilation on hypercapnia depends on the mechanism of gas-exchange impairment. Hypercapnia secondary to severe V/Q mismatch may be treatable with conventional frequency ventilation, mid-frequency ventilation, or high-frequency ventilation (HFV). Hypercapnia secondary to hypoventilation is usually easily managed with conventional frequency ventilation.

Carbon dioxide normally diffuses readily from the blood into the alveoli. Elimination of carbon dioxide from the alveoli is directly proportional to alveolar minute ventilation (see the image below), which is determined by the product of tidal volume (minus dead-space ventilation) and frequency as follows:

Alveolar minute ventilation = (tidal volume – dead space) × frequency

Relations between ventilator-controlled variables (shaded circles) and pulmonary mechanics (unshaded circles) that determine minute ventilation during pressure-limited time-cycled ventilation. Relations between circles joined by solid lines are described by simple mathematical equations. Dashed lines represent relations that cannot be calculated precisely without considering other variable such as pulmonary mechanics. Thus, simple mathematical equations determine time constant of lungs, pressure gradient, and inspiratory time. In turn, these determine delivered tidal volume, which, when multiplied by the respiratory frequency, provides minute ventilation. Alveolar ventilation can be calculated from product of tidal volume and frequency when dead space is subtracted from former. Image adapted from Chatburn RL, Lough MD.

Tidal volume is the volume of gas inhaled (or exhaled) with each breath; frequency is the number of breaths per minute; and dead space is the part of the tidal volume not involved in gas exchange (eg, the volume of the conducting airways) and is relatively constant. Thus, increases in either tidal volume or frequency increase alveolar ventilation and decrease the arterial partial pressure of carbon dioxide (Pa CO2).

Because dead-space ventilation is constant, changes in tidal volume appear to be more effective in altering carbon dioxide elimination compared with changes in frequency. For example, a 50% increase in tidal volume (eg, 6-9 mL/kg) with a constant dead space (eg, 3 mL/kg) doubles alveolar ventilation (3-6 mL/kg × frequency). In contrast, a 50% increase in frequency increases alveolar ventilation by 50% because dead-space ventilation (dead space × frequency) increases when frequency is increased.

Although increases in minute ventilation achieved via larger tidal volumes are more effective in increasing alveolar ventilation, the use of relatively small tidal volumes and high frequencies is usually preferred to minimize volutrauma. The optimal frequency for mechanical ventilation may be defined as the frequency at which alveolar ventilation is maximized. A simple mathematical model can be used to calculate this theoretical optimal frequency based on the time constant of the respiratory system. At optimal frequency, alveolar ventilation is likely to be higher than required, thus enabling a reduction in peak inspiratory and delta pressures.[1]

Hypoxemia

Hypoxemia is usually the result of V/Q mismatch or right-to-left shunting, though diffusion abnormalities and hypoventilation (eg, apnea) may also decrease oxygenation. V/Q mismatch is a major cause of hypoxemia in infants with RDS and other causes of respiratory failure. V/Q mismatch is usually caused by poor ventilation of alveoli relative to their perfusion. Shunting can be intracardiac (eg, congenital cyanotic heart disease or patent foramen ovale), extracardiac (eg, intra-pulmonary or via a patent ductus arteriosus), or both.

Diffusion abnormalities typical of interstitial lung disease and other diseases that affect the alveolar-capillary interface are not major mechanisms of severe hypoxemia in neonates. Hypoventilation usually causes mild hypoxemia unless severe hypercapnia develops.

During mechanical ventilation, oxygenation (see the image below) is largely determined by the fraction of inspired oxygen (FiIO2) and the mean airway pressure (MAP).

Determinants of oxygenation during pressure-limited time-cycled ventilation. Shaded circles represent ventilator-controlled variables. Solid lines represent simple mathematical relations that determine mean airway pressure and oxygenation, whereas dashed lines represent relations that cannot be quantified in simple mathematical way. Image adapted from Carlo WA, Greenough A, Chatburn RL.

MAP is the average airway pressure during the respiratory cycle and can be calculated by dividing the area under the airway pressure curve by the duration of the cycle. The formula includes the constant determined by the flow rate and the rate of rise of the airway pressure curve (K), peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), inspiratory time (TI), and expiratory time (TE), as follows:

Table. MAP (Open Table in a new window)

This equation indicates that MAP increases with increasing PIP, PEEP, ratio of TI to TI + TE, and flow (which increases K by creating a squarer waveform).

The mechanism by which increases in MAP generally improve oxygenation appears to involve increased lung volume and improved V/Q matching. Although a direct relation between MAP and oxygenation is observed, some exceptions are found. For the same change in MAP, increases in PIP and PEEP enhance oxygenation more than changes in the ratio of TI to TE (I:E ratio).

Increasing the TI reduces the TE, which may impair oxygenation owing to gas trapping. Selection of the optimal TI and TE is based on the time constant, which is short in diseases that cause decreased lung compliance and longer in infants with normal lung compliance.

PEEP levels outside of the ideal range may result in alveolar overdistension or loss of recruitment.[2]  Increases in PEEP are not as effective once optimal inflation is reached and may not improve oxygenation at all. In fact, excessive MAP may also cause overdistension of alveoli and gas trapping leading to decreased venous return, right-to-left shunting of blood in the lungs, and impairment of gas exchange.

Thus, if a very high MAP is transmitted to the intrathoracic structures, as may occur when lung compliance is near normal or improving, cardiac output may decrease. In such a scenario, even with adequate oxygen delivery to the alveoli, systemic oxygen transport (arterial oxygen content × cardiac output) may decrease.

Unlike other causes of hypoxemia, shunting is usually unresponsive to oxygen supplementation. Hypoxemia due to V/Q mismatch can be difficult to manage but may be resolved if an increase in airway pressure reexpands atelectatic alveoli. Hypoxemia due to impaired diffusion or hypoventilation usually responds readily to oxygen supplementation and assisted ventilation.

Blood oxygen content largely depends on the oxygen saturation and the hemoglobin level. Accordingly, it is common practice to give packed red blood cells (RBCs) to infants with anemia (hemoglobin level < 10-12 mg/dL) who are receiving assisted ventilation. Oxygen delivery also depends on oxygen unloading at the tissue level, which is strongly determined by the oxygen dissociation curve. Acidosis, fever, increases in 2,3-diphosphoglycerate, and adult hemoglobin levels reduce oxygen affinity to hemoglobin and, thus, favor oxygen delivery to the tissues.

The interaction between the ventilator and the infant largely depends on the mechanical properties of the respiratory system.

Pressure gradient

A pressure gradient between the airway opening and the alveoli must be present to drive the flow of gases during both inspiration and expiration. The necessary pressure gradient can be calculated from the following equation:

Pressure = volume compliance + resistance × flow

Compliance

Compliance describes the elasticity or distensibility of the respiratory structures (eg, alveoli, chest wall, and pulmonary parenchyma) and is calculated from the change in volume per unit change in pressure as follows:

Compliance = Δvolume/Δpressure

Thus, the higher the compliance, the larger the delivered volume per unit change in pressure. Normally, the chest wall is compliant in newborns and does not impose a substantial elastic load as compared with the lungs. The range of total respiratory system compliance (lungs + chest wall) in newborns with healthy lungs is 0.003-0.006 L/cm H2 O, whereas compliance in babies with respiratory distress syndrome (RDS) may be as low as 0.0005-0.001 L/cm H2 O.

Resistance

Resistance describes the inherent capacity of the air conducting system (eg, airways, endotracheal tube [ETT]) and tissues) to oppose airflow. It is expressed as the change in pressure per unit change in flow as follows:

Resistance = Δpressure/Δflow

Airway resistance depends on the following 4 variables:

• Radii of the airways (total cross-sectional area)

• Lengths of the airways

• Flow rate

• Density and viscosity of gas

Unless bronchospasm, mucosal edema, or interstitial edema decrease their lumina, distal airways normally contribute less than proximal airways to airway resistance because of their larger cross-sectional area. Small ETTs that may contribute significantly to airway resistance are also important, especially when high flow rates that may lead to turbulent flow are used. The range of values for total airway plus tissue respiratory resistance for healthy newborns is 20-40 cm H2 O/L/s; in intubated newborns, this range is 50-150 cm H2 O/L/s.

Time constant

Compliance and resistance can be used to describe the time necessary for an instantaneous or step change in airway pressure to equilibrate throughout the lungs. The time constant of the respiratory system is a measure of the time necessary for the alveolar pressure to reach 63% of the change in airway pressure, which can be calculated as follows:

Time constant = resistance × compliance

Thus, the time constant of the respiratory system is proportional to compliance and resistance. For example, the lungs of a healthy newborn with a compliance of 0.004 L/cm H2 O and a resistance of 30 cm H2 O/L/s have a time constant of 0.12 seconds. When a longer time is allowed for equilibration, a higher percentage of airway pressure equilibrates throughout the lungs. The longer the duration of the inspiratory (or expiratory) time allowed for equilibration, the higher the percentage of equilibration.

For practical purposes, delivery of pressure and volume is complete (95-99%) after 3-5 time constants. Similarly, exhalation is completed after 3-5 time constants. A time constant of 0.12 seconds indicates a need for an inspiratory or expiratory phase of 0.36-0.6 seconds. In contrast, lungs with decreased compliance (eg, in RDS) have shorter time constants. Lungs with shorter time constants complete inflation and deflation faster than normal lungs and achieve optimal frequency at high ventilator rates. Conversely, infants with bronchopulmonary dysplasia have a relatively long time constant that may need a longer TI and TE and achieve optimal frequency at lower ventilator rates.

The clinical application of the concept of time constant is clear: Inspiratory times that are too short lead to incomplete delivery of tidal volume and lower mean arterial pressure (MAP), resulting in hypercapnia and hypoxemia (see the image below).

Effects of incomplete inspiration (A) or incomplete expiration (B) on gas exchange. Incomplete inspiration leads to decreases in tidal volume and mean airway pressure. Hypercapnia and hypoxemia may result. Incomplete expiration may lead to decreases in compliance and tidal volume and increase in mean airway pressure. Hypercapnia with decrease in arterial oxygen tension may result. However, gas trapping and its resulting increase in mean airway pressure may decrease venous return, decreasing cardiac output and impairing oxygen delivery. Image adapted from Carlo WA, Greenough A, Chatburn RL.

Similarly, insufficient expiratory time may lead to increases in FRC, inadvertent PEEP, and gas trapping. For practical purposes, an I:E ratio of 1:2 may decrease the risk of gas trapping.

Gas trapping

An expiratory time that is too short or an inspiratory time that is too long, a high PEEP or MAP, or an elevated tidal volume can result in gas trapping. Gas trapping may decrease compliance and impair cardiac output. Gas trapping during mechanical ventilation may manifest as decreased tidal volume, CO2 retention, or lung hyperexpansion seen on a chest radiograph. Although arterial partial pressure of oxygen (Pa O2) may be adequate during gas trapping, venous return to the heart and cardiac output may be impaired; thus, oxygen delivery can be decreased.

Clinical situations that increase the risk of gas trapping include the following:

• Use of an expiratory time that does not allow complete exhalation based on pulmonary graphics (eg, high ventilatory rates in infants with normal compliance or increased resistance)

• Use of an inspiratory time that is too long based on pulmonary graphics (eg, TI greater than 0.4 seconds in an infant with RDS)

• Use of high PEEP and/or MAP, particularly among infants with low compliance (eg, infants with RDS)

Clinical signs that may suggest the presence of gas trapping include the following:

• Decreased thoracic movement and worsening hypercapnia despite high PIP

• Impaired cardiovascular function (ie, increased central venous pressure, decreased systemic blood pressure, metabolic acidosis, peripheral edema, decreased urinary output)

• Worsening hypoxemia despite high MAP

• Lung overexpansion on radiography

Values of compliance and resistance differ throughout inspiration and expiration; thus, a single time constant cannot be assumed. Furthermore, with heterogeneous lung diseases such as bronchopulmonary dysplasia (BPD), different lung regions may have different time constants because of varying compliances and resistances, and these differences partly account for the coexistence of atelectasis and hyperexpansion.

Chest wall motion

A technique to estimate the time constant that may be helpful in everyday clinical practice is the use of chest wall motion as a semiquantitative estimate of tidal volume. At the bedside, chest wall motion can be measured with appropriately placed heart rate/respiration leads such as are used for routine clinical monitoring (see the image below). Careful visual assessment of chest wall motion can also suffice with the goal of achieving chest rise similar to that of a spontaneously breathing infant.

Estimation of optimal inspiratory and expiratory times on basis of chest wall motion. Image adapted from Ambalavanan N, Carlo WA.

The shape of the inspiratory and expiratory phases can be analyzed. A rapid rise in inspiratory chest wall motion (or volume) with a plateau indicates complete inspiration. A rise without a plateau indicates incomplete inspiration. In this situation, prolongation of the inspiratory time results in more inspiratory chest wall motion and tidal volume delivery. An inspiratory plateau indicates that inspiratory time may be too long; shortening inspiratory time does not decrease inspiratory chest wall motion or tidal volume delivery and does not eliminate the plateau.

A short expiratory time leads to gas trapping. If gas trapping results from a short expiratory time, lengthening expiration improves ventilation. However, a very prolonged expiratory time does not improve ventilation. Indeed, in the absence of gas trapping, shortening expiratory time allows the provision of more breaths per minute, which improves ventilation.

In the absence of a large leak, the pulmonary graphics displayed on the ventilator can also be reviewed at the bedside to determine if the inspiratory and expiratory phases are completing. If the inspiratory phase is completing, the flow will return to baseline just before the expiratory phase begins, with no step-off visible. If the expiratory phase is completing, the flow will return to baseline before the next cycle begins and no step-off will be visible. Many ventilators can also display flow cycle loops that can be analyzed at the bedside to ensure flows return to zero between the inspiratory and expiratory phases of the respiratory cycle.

For a better understanding of the interaction between the ventilator and the baby's respiratory system, it is necessary to consider certain important physiologic aspects of the control of breathing. The respiratory drive is servo-controlled by the brain. This serves to minimize variations in arterial blood gas values and pH despite physiologic changes in the efficiency of gas exchange and moment-to-moment differences in oxygen consumption and carbon dioxide production.

Ventilation is maintained by intrinsic fine adjustments in tidal volume and respiratory rate that minimize the work of breathing. These adjustments are accomplished by motor neurons in the central nervous system (CNS) that receive input largely from chemoreceptors and mechanoreceptors to regulate inspiratory and expiratory muscles. These 2 components of respiratory control provide feedback to the brain that allows continuous adjustment of ventilation. Mechanical ventilation results in changes in chemoreceptor and mechanoreceptor stimulation.

Chemoreceptors

When arterial partial pressure of carbon dioxide (Pa CO2) or pH changes, ventilation is largely adjusted by the activity of chemoreceptors in the brainstem. An increase in Pa CO2 or decrease in pH increases respiratory drive. Because the chemoreceptors most likely sense the hydrogen ion concentration (pH), metabolic acidosis and metabolic alkalosis have strong effects on respiratory drive that are somewhat independent of Pa CO2 values.

Most changes in ventilation and respiratory drive produced by arterial partial pressure of oxygen (Pa O2) changes depend on the peripheral chemoreceptors, which include the carotid bodies and, to a lesser extent, the aortic bodies. In newborns, acute hypoxia produces a transient increase in ventilation that disappears quickly. Moderate or profound respiratory depression can be observed after a couple of minutes of hypoxia, and this decline in respiratory drive is an important cause of hypoventilation, apnea, or both.

Mechanoreceptors

Mechanoreceptors play an important role in the regulation of breathing during neonatal life and infancy. Stretch receptors in airway smooth muscles respond to tidal volume changes. For example, immediately after inflation, a brief period of decreased or absent respiratory effort can be detected. This is called the Hering-Breuer inflation reflex; it is usually observed in newborns during conventional ventilation, when a large enough tidal volume is delivered.

The presence of the Hering-Breuer inflation reflex is a clinical indication that a relatively large tidal volume is delivered, and the reflex is absent if the ventilator tidal volume is very small (eg, if the endotracheal tube [ETT] becomes plugged). The Hering-Breuer reflex is also time-related (eg, a longer inspiration tends to stimulate the reflex more). Thus, for the same tidal volume, a breath with a longer inspiratory time elicits a stronger Hering-Breuer reflex and a longer respiratory pause.

At slow ventilator rates, large tidal volumes stimulate augmented inspirations (Head's paradoxical reflex). This reflex demonstrates improved lung compliance, and its occurrence is increased by methylxanthine administration. This reflex may be one of the mechanisms through which methylxanthines facilitate weaning from mechanical ventilation.

Mechanoreceptors also are altered by changes in functional residual capacity (FRC). An increase in FRC leads to a longer expiratory time because the next inspiratory effort is delayed. High continuous distending pressure can prolong expiratory time and even decrease the respiratory rate because of the intercostal phrenic inhibitory and Hering-Breuer reflexes. Therefore, during weaning from a ventilator, a high PEEP may decrease the spontaneous respiratory rate and impede weaning. After weaning from a ventilator, continuous positive airway pressure (CPAP) using higher PEEP may maintain FRC better compared with lower PEEP and reduce the need for mechanical ventilation.[3]

Other components of the mechanoreceptor system are the juxtamedullary (J) receptors. These receptors are located in the interstitium of the alveolar wall and are stimulated by interstitial edema and fibrosis, as well as by pulmonary capillary engorgement (eg, congestive heart failure). Stimulation of the J receptors increases respiratory rate and may explain the rapid shallow breathing frequently observed in patients with these conditions.

Another reflex that affects breathing is the baroreflex. Arterial hypertension can lead to reflex hypoventilation, apnea, or both through aortic and carotid sinus baroreceptors. Conversely, a decrease in blood pressure may result in hyperventilation.

Continuous positive airway pressure

Continuous positive airway pressure (CPAP) has been an important tool in the treatment of newborns with respiratory distress syndrome (RDS). The mechanisms by which CPAP produces its beneficial effects include increased alveolar volumes, alveolar recruitment and stability, and redistribution of lung water, resulting in an improvement in ventilation/perfusion (V/Q) matching. However, high CPAP levels before intubation for surfactant may increase the risk of pulmonary air leaks.

The use of CPAP instead of assisted ventilation may be a strategy for minimizing ventilator-associated lung injury. Meta-analyses of randomized controlled trials suggest that early prophylactic CPAP decreases mortality and the need for ventilator support. Early CPAP use among very preterm infants in the delivery room may allow lung inflation to be maintained, while preventing volutrauma due to alveolar overdistension from mechanical ventilation, atelectasis, or both.[4]

When RDS is anticipated based on the degree of prematurity or when RDS is diagnosed, administration of CPAP decreases oxygen requirements and the need for mechanical ventilation. However, the incidence of air leaks is increased among infants who receive CPAP.

CPAP facilitates successful extubation following mechanical ventilation.[5]  CPAP reduces extubation failure among preterm infants in clinical trials and is now used routinely following extubation. Nasal intermittent positive pressure ventilation (NIPPV) may provide limited ventilatory support in preterm infants and may reduce the risk of extubation failure in preterm infants.[6]  NIPPV can be provided as continuous mandatory breaths or be synchronized with infant breaths. A comparison study found that in preterm babies with RDS, bilevel nasal CPAP has advantages over nasal CPAP.[7] Lista et al reported that babies treated with bilevel nasal CPAP had better respiratory outcomes, earlier discharge, and the same changes in cytokine levels.

Synchronizing ventilatory support during nasal intermittent mandatory ventilation can be achieved with newer ventilators that detect inspiratory flow or volume as a trigger. Because the leakage varies, using a fixed flow level to trigger inspiration is difficult. Nasal intermittent mandatory ventilation is commonly used in neonatal intensive care units (ICUs).[8] Although isolated gastrointestinal (GI) problems have been reported, no significant increase in GI side effects have been noted. Synchronized NIPPV may reduce the risk of extubation compared with nasal CPAP.[9]  Noninvasive high-frequency oscillatory ventilation is a relatively newer modality that may improve CO2 removal compared with nasal CPAP.[10]  Noninvasive neurally adjusted ventilatory assist is another relatively new modality of patient-triggered NIPPV that requires further study.

Sustained inflation followed by early CPAP has been studied as a potentially less injurious way of recruiting the lung in very premature neonates at birth. However, randomized controlled trials have not shown a benefit of this strategy compared with routine care using early CPAP with intermittent positive pressure ventilation in the delivery room.[11]

Meta-analyses of randomized controlled trials suggest that early nasal CPAP with a wait-and-see approach for intubation and surfactant reduces the rate of death or bronchopulmonary dysplasia (BPD) when compared with intubation and prophylactic surfactant.[12, 13] Although the CPAP group had a higher incidence of pneumothorax, fewer infants received oxygen at 28 days and the infants had fewer days of ventilation.

Only limited data are available regarding the practical aspects of CPAP delivery, including the best way of providing the positive airway pressure (ie, bubble CPAP, infant flow driver CPAP, or ventilator CPAP), optimal pressures, need for intermittent breaths, and patient interfaces. Mask interfaces may be superior to prong interfaces for CPAP delivery.[14]  In addition, there is evidence that delivery of CPAP through narrow bore tubing increases resistance, resulting in a significant reduction in the delivered PEEP.[15]  Higher PEEP may reduce the risk of extubation failure,[3] but the optimal PEEP before intubation for surfactant is not clear. Success with CPAP is likely to be center-dependent.

The optimal method and timing of weaning infants from CPAP are unclear. The 2 most common weaning methods are (1) reducing pressure gradually until off and (2) reducing the time spent on CPAP each day by cycling. In randomized controlled trials, gradual weaning of pressures followed by abrupt cessation was associated with significantly greater weaning success compared with cycling off CPAP in preterm infants.[16, 17, 18] Extending CPAP for 2 additional weeks may increase FRC in preterm infants, but the clinical effects of extended CPAP are unclear.[19]

Conventional frequency ventilation

The ventilator, the blood gas values, the mechanical characteristics of the respiratory system, and the infant's spontaneous respiratory efforts are interrelated in a complex fashion. Although attention is often focused on the effect of ventilator setting changes on blood gases, these changes may also alter pulmonary mechanics either acutely (eg, changes in positive end-expiratory pressure [PEEP] affect compliance) or chronically (eg, high tidal volumes causing lung injury). They may also affect spontaneous breathing (eg, high PEEP decreases respiratory rate).

An understanding of the basic pathophysiology of the underlying respiratory disorder is therefore essential to optimize the ventilatory strategy. The aim should be to achieve adequate gas exchange without injuring the lungs; the ultimate goal is a healthy child without chronic lung disease.

A review of the major ventilatory parameters that can be adjusted on a pressure-limited time-cycled ventilator (the type of ventilator most commonly used for conventional frequency ventilation) is useful. These concepts are also applicable to volume ventilators.

Peak inspiratory pressure

Changes in peak inspiratory pressure (PIP) affect both Pa O2, by altering mean arterial pressure (MAP), and Pa CO2, by affecting tidal volume and thus alveolar ventilation. Therefore, an increase in PIP improves oxygenation and decreases Pa CO2. Use of a high PIP may increase the risk of volutrauma with resultant air leaks and BPD; thus, exercise caution when using high levels of PIP. The level of PIP required in an infant depends largely on the compliance of the respiratory system.

A useful clinical indicator of adequate PIP is a gentle chest rise with every breath; this should be little more than the chest expansion seen with spontaneous breathing. The absence of breath sounds may indicate inadequate PIP (or a blocked or displaced endotracheal tube [ETT], or even ventilator malfunction), but their presence is not helpful in determining optimal PIP. Adventitious sounds (eg, crackles) often indicate disorders of lung parenchyma associated with poor compliance (shortening the time constant); wheezes often indicate increased resistance (lengthening the time constant).

Always use the minimum effective PIP. Frequently change PIP in the presence of changing pulmonary mechanics (eg, after the administration of surfactant in the management of RDS). Babies with chronic lung disease often have nonhomogeneous lung disease, leading to varying compliance throughout different regions of the lung and, therefore, differing requirements for PIP. This partially accounts for the coexistence of atelectasis and hyperinflation in the same lung.

Positive end-expiratory pressure

Adequate PEEP helps prevent alveolar collapse, maintains lung volume at end-expiration, and improves V/Q matching. Increases in PEEP usually increase oxygenation associated with increases in MAP.

However, in infants with RDS, an excessive PEEP may not further improve oxygenation and may in fact decrease venous return, cardiac output, and oxygen transport. High levels of PEEP also may decrease pulmonary perfusion by increasing pulmonary vascular resistance. By reducing the difference between PIP and PEEP, an elevation of PEEP may decrease tidal volume and increase Pa CO2.

Although both PIP and PEEP increase MAP and may improve oxygenation, they usually have opposite effects on Pa CO2. Generally, older infants with chronic lung disease tolerate higher levels of PEEP without carbon dioxide retention and with improvements in oxygenation. PEEP also has a variable effect on lung compliance and may affect the PIP required. When using optimal PEEP levels, FRC should be maintained, compliance will be improved, and gas exchange, both carbon dioxide and oxygen, will be improved.

With RDS, compliance improves with low levels of PEEP, followed by declining compliance at higher levels of PEEP. A minimum PEEP of 4-5 cm H2 O is recommended, as endotracheal intubation eliminates the active maintenance of functional residual capacity (FRC) accomplished with vocal cord adduction and closure of the glottis.

Rate

Changes in frequency alter alveolar minute ventilation and thus Pa CO2. Increases in rate (and, therefore, increases in alveolar minute ventilation) decrease Pa CO2 proportionally; decreases in rate increase Pa CO2. Frequency changes alone (with a constant inspiratory-to-expiratory [I:E] ratio) usually do not alter MAP or substantially affect Pa O2. Any changes in the I:E ratio that accompany frequency adjustments may change the airway pressure waveform and thereby alter MAP and oxygenation.

Generally, a high-rate, low-tidal-volume strategy is preferred. However, if a very short expiratory time is used, expiration may be incomplete. Gas trapped in the lungs can increase FRC and over-distend the lungs, thereby decreasing lung compliance. Tidal volume may be insufficient if inspiratory time is reduced beyond a critical level, depending on the time constant. Thus, above a certain rate during pressure-limited ventilation, minute ventilation is not a linear function of frequency. Alveolar ventilation may fall with higher rates as tidal volume decreases and approaches the volume of the anatomic dead space.

Rates of 60-150 on conventional ventilators may be used in infants with short time constants such as RDS. This strategy is known as mid-frequency ventilation.[1]  This strategy may allow the use of smaller tidal volumes and PIPs, which could be lung protective.[20]  Rates of 60 or higher may decrease the risk of air leaks,[21]  although caution should be used to avoid inadvertent PEEP and gas trapping at high rates among infants with improving lung compliance.

High-frequency jet ventilators typically use rates of 360-480, whereas high-frequency oscillatory ventilators use frequencies of 8-15 Hz (480 to 900 cycles per second).

Inspiratory and expiratory times

The effects of changes in inspiratory and expiratory times on gas exchange are influenced strongly by the relations of these times to the inspiratory and expiratory time constants, respectively. An inspiratory time 3-5 times longer than the time constant of the respiratory system allows relatively complete inspiration. A long inspiratory time increases the risk of pneumothorax (eg, inspiratory times ≥ 0.5 seconds among infants with RDS).[5]

Shortening inspiratory time is advantageous during weaning. In a randomized trial, limitation of inspiratory time to 0.5 second, instead of 1 second, resulted in a significantly shorter duration of weaning. In contrast, patients with chronic lung disease may have a prolonged time constant. In these patients, a longer inspiratory time (closer to 0.8 second) may result in improved tidal volume and better carbon dioxide elimination. Inspiratory times as short as 0.2 second have been reported among preterm infants receiving mid-frequency ventilation. Inspiratory times of 0.02 second are commonly used during high-frequency jet ventilation.

Inspiratory-to-expiratory ratio

I:E ratios of 1:1 to 1:3 are commonly used in newborn care. The length of inspiratory and expiratory time is best selected by evaluating the flow signals on modern ventilators. If pulmonary graphics are not available, I:E ratios of ~1:2 are typically used during mid-frequency and high-frequency oscillatory ventilation (set at 0.33 on oscillator).

Decreasing the I:E ratio has been described in the treatment of air leaks such as pneumothorax and pulmonary interstitial emphysema.[22]  The major effect of an increase in the I:E ratio is an increased MAP and thus improved oxygenation. However, when corrected for MAP, changes in the I:E ratio are not as effective in increasing oxygenation as are changes in PIP or PEEP. A reversed (inverse) I:E ratio (ie, with the inspiratory time longer than the expiratory time) as high as 4:1 has been demonstrated to be effective in increasing Pa O2; however, adverse effects may occur. Trials of reversed I:E ratio or airway pressure release ventilation (APRV) using reversed I:E ratios in neonates have not shown long-term clinical benefits.

Although it is possible that reversing the I:E ratio might decrease the incidence of BPD, a large, well-controlled, randomized trial found that reversed I:E ratios only reduced the duration of a high FI O2 and PEEP exposure and did not yield any differences in morbidity or mortality. Changes in the I:E ratio usually do not alter tidal volume unless inspiratory and expiratory times become relatively too short. Thus, carbon dioxide elimination is usually not altered by changes in the I:E ratio.

Fraction of inspired oxygen

Changes in FI O2 alter alveolar oxygen pressure and thus oxygenation. Because FI O2 and MAP both determine oxygenation, they can be balanced as follows:

• During increasing support, first increase FI O2 to approximately 0.6-0.7, when additional increases in MAP are warranted

• During weaning, first decrease FI O2 to approximately 0.4-0.7 before reducing MAP; maintenance of an appropriate MAP may allow a substantial reduction in FI O2

Reduce MAP before a relatively low FI O2 (0.21-0.3) is reached because a higher incidence of air leaks has been observed if the patient is not weaned from distending pressures earlier. In addition, if an infant is being ventilated using a low FiO2, it suggests that the infant may be receiving excessive tidal volumes, which may increase the risk of bronchopulmonary dysplasia.

Flow

Although changes in flow have not been well studied in infants, they probably impact arterial blood gas values minimally as long as a sufficient flow rate is employed. Flow rates of 5-12 L/min are sufficient in most newborns, depending on the mechanical ventilator and ETT being used. To maintain an adequate tidal volume, high flow rates are needed when inspiratory time is shortened.

Respiratory distress syndrome

Respiratory distress syndrome (RDS) is characterized by low compliance and low functional residual capacity (FRC). An optimal ventilation strategy may include the lowest peak inspiratory pressure (PIP) and tidal volume at whatever frequency that will be effective using an I:E of approximately 1:2, modest positive end-expiratory pressure (PEEP; 4-5 cm H2 O), permissive hypercapnia (arterial partial pressure of carbon dioxide [Pa CO2] 45-60 mm Hg while maintaining a pH of 7.20 or higher), and aggressive weaning.

Chronic lung disease

Bronchopulmonary disease (BPD) usually has heterogeneous time constants among lung areas. Resistance may be increased markedly, and frequent exacerbations may occur. A higher PEEP (5-6 cm H2 O) is often used, and longer inspiratory and expiratory times with low rates are preferred using an I:E of 1:2. Hypercarbia with compensated respiratory acidosis, while maintaining a pH 7.20 or higher,[23]  is often tolerated to prevent lung injury secondary to aggressive mechanical ventilation.

Persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn may be primary or associated with aspiration syndrome, prolonged intrauterine hypoxia, congenital diaphragmatic hernia, pulmonary hypoplasia, or other causes. Ventilatory treatment of infants is often controversial and may vary widely from one center to another.

In general, adjust the fraction of inspired oxygen (FI O2) to maintain pre- and post-ductal oxygen saturations of 94-100% among term infants and pre-ductal oxygen saturations of 91-95% among preterm infants at risk of developing retinopathy of prematurity to minimize hypoxia-mediated pulmonary vasoconstriction. Adjust ventilatory rates and pressures to maintain an arterial pH of 7.35-7.45 (sometimes a higher pH may of 7.45-7.55 may be targeted with bicarbonate infusion). However, in specific situations such as pulmonary hypoplasia, pH controlled permissive hypercapnia may be tolerated to minimize lung injury.

Take care to keep Pa CO2 from falling below 30 mm Hg; extremely low Pa CO2 values can cause cerebral vasoconstriction and subsequent neurologic injury. Addition of inhaled nitric oxide to mechanical ventilation reduces the need for extracorporeal membrane oxygenation (ECMO). Nitric oxide may be considered if unable to maintain oxygen saturations using mechanical ventilation and FiO2 = 1.0 or if the oxygenation index is 15-20 or higher.[24]  High-frequency ventilation is often used to increase mean airway pressure, while avoiding high tidal volumes and PIPs that may cause lung injury or air leaks.

Newborn infants with persistent pulmonary hypertension of the newborn may benefit from surfactant to reduce the risk of ECMO, irrespective of the underlying cause. Close attention should be given to maintaining mean arterial blood pressure using inotropes as needed to reduce the right to left shunt. Infants with persistent pulmonary hypertension of the newborn may benefit from intravenous calcium bolus targeting ionized calcium levels of 1.2 or higher.

Other medications that have been used to treat persistent pulmonary hypertension of the newborn acutely but lack data from large randomized controlled trials in newborn infants are milrinone, sildenafil, and endothelin receptor antagonists.[25]

There is substantial evidence to suggest that lung injury is partially dependent on the particular ventilatory strategies used. Ventilator-associated lung injury has traditionally been believed to result from the use of high pressures (hence the term barotrauma). However, laboratory-based and clinical research has raised questions about this purported mechanism.

Experimentally, investigators have used high and low volumes and pressures in an attempt to determine whether volume or pressure is the major culprit responsible for lung injury in the immature animal. These studies consistently demonstrate that markers of lung injury (pulmonary edema, epithelial injury, and hyaline membrane formation) are present with the use of high volumes and low pressures but not with the use of low volumes and high pressures. Thus, many investigators and clinicians prefer the term volutrauma to the more classic term barotrauma.

Lung injury is also caused by repeated collapse (atelectasis) and reopening of the alveoli, which occurs with very low end-expiratory pressures. The heterogeneity of lung tissue involvement in many respiratory diseases predisposes some parts of the lung to volutrauma. Oxidant injury may be another serious cause of lung injury. Immature and developing lungs are particularly susceptible to acquired injury.

Permissive hypercapnia

Permissive hypercapnia, or controlled mechanical hypoventilation, is a strategy for the treatment of patients receiving ventilatory assistance. When using this strategy, prioritize the prevention or limitation of overventilation rather than the maintenance of normal blood gases and the high alveolar ventilation that is frequently used. Respiratory acidosis and alveolar hypoventilation may be an acceptable price for the prevention of pulmonary volutrauma.

Experimental data show that therapeutic hypercapnia reduces lung and brain injury and attenuates hypoxic brain injury in newborn rats.[26] In preterm lambs, hypercapnia is associated with improved compliance and lung volume.

A multicenter trial of 841 adult patients with acute respiratory distress syndrome (ARDS) revealed that low tidal volume combined with pH controlled (7.15 or higher) permissive hypercapnia yielded a large reduction in mortality (from 40% to 31%) in the gentle ventilation group.[27]

Several trials in preterm infants have attempted to minimize lung injury by tolerating hypercapnia and reducing tidal volume and minute ventilation. A small pilot randomized trial revealed that permissive hypercapnia (target P a CO2, 45-55 mm Hg) during the first 4 days in infants who weighed 601-1250 g resulted in greater number of infants weaned from mechanical ventilation.[28] A second small trial did not confirm the potential benefits of permissive hypercapnia.[29]

A multicenter trial of infants weighing less than 1000 g reported that permissive hypercapnia (target P a CO2, >50 mm Hg) during the first 10 days of life led to a trend toward reduced bronchopulmonary disease (BPD) or death at a postconceptional age (PCA) of 36 weeks (68% vs 63%).[23] Furthermore, permissive hypercapnia reduced the severity of BPD, as evidenced by a decreased need for ventilator support (from 16% to 1%) at 36 weeks' PCA.

Hypercapnia was well tolerated and no apparent side effects were reported in a study of infants with persistent pulmonary hypertension who were managed with P a CO2 values of up to 60 mm Hg. In nonrandomized studies, infants with congenital diaphragmatic hernia also appear to benefit from permissive hypercapnia.[30, 31]

A retrospective study of 849 infants who weighted 1250 g or less revealed that severe hypocapnia, severe hypercapnia, and wide fluctuations in arterial partial pressure of carbon dioxide (P a CO2) were associated with an increased risk of hemorrhage.[32] The potential higher risk of impaired cerebral blood flow autoregulation and intracranial hemorrhage in neonates with hypercapnia has not been shown in randomized controlled trials.[28, 33] Although hypercapnic acidosis increases cerebral oxygen delivery, the carbon dioxide–induced alterations in cerebral blood flow appear to be reversible.

Higher levels of permissive hypercapnia (60-75 mmHg) without pH control in the first week after birth were associated with a higher risk of necrotizing entercolitis, but this has not been seen in other trials of pH controlled permissive hypercapnia.[34]  The optimal pH control and P a CO2 goal for permissive hypercapnia in clinical practice has not been determined, and it is not known whether the optimal goal varies with postnatal age.

Low-tidal-volume ventilation

Strategies for mechanical ventilation in infants should focus on prevention of overdistention, use of relatively small tidal volumes, maintenance of adequate functional residual capacity (FRC), and use of sufficient inspiratory and expiratory times for optimal frequency.

Because high maximal lung volume appears to correlate best with lung injury, selection of an appropriate peak inspiratory pressure (PIP) and FRC (or operating lung volume) is critical for the prevention of lung injury during pressure-limited ventilation. With the recognition that large tidal volumes lead to lung injury, relatively small tidal volumes are now recommended.

Studies in healthy infants report tidal volume ranges of 5-8 mL/kg, whereas infants with RDS have tidal volumes of 3-6 mL/kg. In infants with severe pulmonary disease, ventilation with the smallest possible tidal volumes may be preferable because lung heterogeneity and unexpanded alveoli lead to overdistention and injury of the most compliant alveoli if a normal tidal volume is used. Maintenance of an adequate FRC is also necessary.

Technological advances have resulted in better ventilators and more effective ventilatory strategies. Patient-triggered ventilation (PTV), synchronized intermittent mandatory ventilation (SIMV), volume-targeted ventilation, and other newer ventilator modes are increasingly used in newborns. High-frequency ventilation (HFV) is another mode of ventilation that may reduce lung injury and may improve pulmonary outcomes, though available studies fail to demonstrate consistent benefits.

Patient-triggered ventilation

The ventilators most frequently used in the past among newborns were time-triggered at a preset frequency rather than patient-triggered; however, because of the available bias flow, they also allowed the patient to take spontaneous breaths.

In contrast, PTV (also referred to as assist-control ventilation) uses spontaneous respiratory effort to trigger each breath on the ventilator. During PTV, changes in airway flow or pressure, chest wall or abdominal movements, or esophageal pressure, or diaphragmatic electrical signals (as used in neurally adjusted ventilatory assist [NAVA]) are used as an indicator of the onset of the inspiratory effort. Once the ventilator detects inspiratory effort, it delivers a ventilator breath at predetermined settings (for peak inspiratory pressure [PIP], inspiratory duration, and flow).

Although PTV has been observed to yield improved oxygenation, it may occasionally have to be discontinued in some very immature infants because of weak respiratory efforts. A backup (control) rate is commonly used to reduce this problem. Despite the short-term benefit noted, large randomized, controlled trials report that PTV does not improve long-term outcomes in infants with respiratory distress syndrome (RDS), though it may reduce the cost of care.[35, 36] Trials of NAVA that are focused on longer term clinical benefits in term and preterm infants are needed.

A meta-analysis of randomized trials demonstrated no significant differences between the aforementioned ventilation modes with respect to the rates of bronchopulmonary disease (BPD), severe intracranial hemorrhage, air leaks, or death.[37] PTV was associated with a shorter duration of ventilation, but only in infants recovering from respiratory distress, not in infants in the acute stages of distress.

Synchronized intermittent mandatory ventilation

SIMV achieves synchrony between the patient and the ventilator breaths. Synchrony is typically achieved with the use of flow or volume sensors positioned in the endotracheal tube or ventilator that detect early inspiratory effort. Synchrony easily occurs in most newborns because strong respiratory reflexes during early life elicit relaxation of respiratory muscles at the end of lung inflation. Furthermore, inspiratory efforts usually start when lung volume is decreased at the end of exhalation.

Synchrony may be achieved by nearly matching the ventilator frequency to the spontaneous respiratory rate or by simply ventilating at relatively high rates (60-120 breaths/min) as used in mid-frequency ventilation. Triggering systems can be used to achieve synchronization when synchrony does not occur with these maneuvers. SIMV is as effective as continuous mandatory ventilation (CMV); however, no major benefits were observed in a large randomized, controlled trial.

Proportional assist ventilation

Unless they are flow-cycled, both PTV and SIMV are designed to synchronize only the onset of inspiratory support. In contrast, proportional assist ventilation (PAV) is designed to match the onset and duration of both inspiratory and expiratory support. Ventilatory support is provided in proportion to the volume or flow of the spontaneous breath. Thus, the ventilator can selectively decrease the elastic or resistive work of breathing. The magnitude of the support can be adjusted according to the patient's needs.

In comparison with CMV and PTV, PAV may reduce ventilatory pressures while maintaining or improving gas exchange and may have advantages when used as for weaning. Randomized clinical trials are needed to determine whether PAV has any major advantages over  common ventilator modes.

Volume-targeted ventilation

Volume-targeted ventilators self-adjust in an attempt to maintain the tidal volume set by the clinician. This approach may be effective in maintaining tidal volume despite changes in respiratory mechanics. Modern neonatal ventilators, which have very sensitive and accurate flow sensors, make adjustments to PIP or inflation time from one inflation to the next in an effort to deliver the set volume. Although little information is available regarding the optimal tidal volume for preterm infants, the typical volume target is 4-6 mL/kg.

A meta-analysis of trials in preterm infants reported a lower rate of bronchopulmonary dysplasia or death with the use of volume-targeted compared with pressure-limited ventilation. There were also other clinically important benefits of volume-targeting, including reductions in the duration of ventilation, the incidence of pneumothorax, hypocapnia, and severe intraventricular hemorrhage or periventricular leukomalacia.[38, 39]

Volume-targeted ventilation may also be helpful in patients with heterogeneous lung disease because the differing time constants may result in suboptimal tidal volume delivery when pressure-limited ventilation is used. Conversely, in patients with large areas of atelectasis, targeting tidal volumes may result in delivery of relatively larger tidal volumes to the remaining non-atelectatic areas of the lung, resulting in volutrauma.

Tracheal gas insufflation

The added dead space provided by the endotracheal tube (ETT) and the ventilator circuit connected to the machine contribute to the anatomic dead space, reducing alveolar minute ventilation and leading to decreased carbon dioxide elimination. In smaller infants or infants with increasingly severe pulmonary disease, dead space becomes the largest proportion of the tidal volume.

With tracheal gas insufflation (TGS), gas delivered to the distal part of the ETT during exhalation washes out this dead space and the accompanying carbon dioxide. TGS results in a decrease in Pa CO2, PIP, or both. If TGS is proved safe and effective, it may be useful in reducing tidal volume and the accompanying volutrauma, particularly in very premature infants and infants with greatly decreased lung compliance.

High-frequency ventilation

HFV may improve blood gas values because in addition to the gas transport by convection, other mechanisms of gas exchange (variable velocity profiles of gas during inspiration and exhalation, gas exchange between parallel lung units, and increased turbulence and diffusion) may become active at high frequencies.

High-frequency jet ventilation (HFJV) is characterized by the delivery of gases from a high-pressure source through a small-bore injector cannula. The fast flow of gas from the cannula may produce areas of relative negative pressure that entrain gases from their surroundings.

High-frequency flow interruption (HFFI) also delivers small tidal volumes by interrupting the flow of the pressure source; however, unlike HFJV, HFFI does not use an injector cannula.

High-frequency oscillatory ventilation (HFOV) delivers very small volumes (even smaller than the dead space) at extremely high frequencies. HFOV is unique in that exhalation is generated actively, whereas in other forms of HFV, exhalation is passive.

HFOV, HFFI, and HFJV have been evaluated in many randomized controlled trials, including trials of more than 3000 preterm infants.[22, 40, 41, 42, 43] Although the trial results have been heterogeneous, meta-analysis reveals no clear evidence that HFV is superior to conventional frequency ventilation as the initial mode of ventilatory support. There may be a small reduction in the rate of chronic lung disease with HFOV, but the effect is inconsistent across trials and, overall, of borderline significance.[44]  Trends toward reductions in mortality and BPD have been reported, despite a significant increase in air leaks with HFOV.

In addition, trends toward increasing rates of grade 3 and 4 intraventricular hemorrhage and of periventricular leukomalacia have been seen; however, a subgroup meta-analysis of all trials using optimized respiratory care, including high use of antenatal steroids, surfactant replacement, lung volume recruitment, and a high rate of conventional ventilation, yielded inconsistent results.

The heterogeneity of the results of trials comparing HFV with conventional frequency ventilation in preterm infants may be due to differences in ventilatory strategies. Long-term outcome studies do not show HFV to have any significant advantages over conventional ventilation. The use of HFJV in preterm infants with pulmonary interstitial emphysema has led to more frequent and faster resolution of pulmonary interstitial emphysema but not to reductions in mortality or other adverse outcomes.

In the United Kingdom Oscillation Study (UKOS), a randomized trial involving a population of infants born at less than 28 weeks' gestation, the initial mode of ventilation had no impact on respiratory or neurodevelopmental morbidity at age 2 years.[45] HFOV and conventional frequency ventilation appeared to be equally effective for the early treatment of RDS. Follow-up assessments of UKOS survivors demonstrated no significant differences in lung function results or in respiratory outcome at 2 years of corrected age.

The benefits of using continuous positive airway pressure (CPAP) or high positive end-expiratory pressure (PEEP) in infants with respiratory distress syndrome (RDS) are as follows:

• Increased alveolar volume and functional residual capacity (FRC)

• Alveolar recruitment

• Alveolar stability

• Redistribution of lung water

• Improved ventilation/perfusion (V/Q) matching

The drawbacks of using CPAP or high PEEP in infants with RDS are as follows:

• Increased risk of air leaks

• Overdistention

• Carbon dioxide retention

• Cardiovascular impairment

• Decreased compliance

• Possible increase in pulmonary vascular resistance

The benefits of using a high rate and low tidal volume (low peak inspiratory pressure [PIP]) are as follows:

• Decreased air leaks

• Decreased volutrauma

• Decreased cardiovascular adverse effects

• Decreased risk of pulmonary edema

The drawbacks of using a high rate and low tidal volume (low PIP) are as follows:

• Gas trapping or inadvertent PEEP

• Generalized atelectasis

• Maldistribution of gas

• Increased resistance

The benefits of using a high inspiratory-to-expiratory (I:E) ratio or long inspiratory time are as follows:

• Increased oxygenation

• Potentially improved gas distribution in lungs with atelectasis

The drawbacks of using a high I:E ratio or long inspiratory time are as follows:

• Gas trapping and inadvertent PEEP

• Increased risk of volutrauma and air leaks

• Impaired venous return

• Increased pulmonary vascular resistance

The benefits of permissive hypercapnia in neonates are as follows:

• Decreased volutrauma and lung injury

• Decreased duration of mechanical ventilation

• Reduced alveolar ventilation

• Reduced side effects of hypocapnia

• Increased oxygen unloading

The drawbacks of permissive hypercapnia in neonates are as follows:

• Cerebral vasodilation

• Hypoxemia

• Hyperkalemia

• Decreased oxygen uptake by hemoglobin

• Increased pulmonary vascular resistance

The benefits of using a short inspiratory time are as follows:

• Faster weaning

• Decreased risk of pneumothorax

• Possibility of using a higher ventilator rate

The drawbacks of using a short inspiratory time are as follows:

• Insufficient tidal volume

• Potential need for high flow rates