Assisted Ventilation of the Newborn

Updated: Jan 28, 2015
  • Author: Massimo Bellettato, MD; Chief Editor: Ted Rosenkrantz, MD  more...
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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 enhance conventional mechanical ventilation (CMV) so as to improve survival and reduce adverse effects. Sound application of these concepts is necessary to optimize mechanical ventilation.

See the video of assisted ventilation of the newborn, below.

Assisted ventilation of the newborn - Intubation and meconium aspiration. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.

Hypercapnia is usually caused by severe ventilation/perfusion (V/Q) mismatch or hypoventilation. Over the past 30-40 years, the availability of improved ventilatory support has led to a substantial proportion in the survival rate for preterm infants. CMV is being used on smaller and more ill 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 depressed or apneic or during prolonged periods of respiratory failure treatment. Improved survival rates due to advances in neonatal care have resulted in 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, with minimal or no lung injury or other adverse effects. The use of pathophysiology-based ventilatory strategies, strategies to prevent lung injury, and alternative modes of ventilation should yield further improvements in neonatal outcomes.


Impaired Gas Exchange

Newborns are vulnerable to impaired gas exchange because of their 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 may coexist, though some disorders may affect gas exchange differentially.


Optimal V/Q matching occurs when the ratio of the volume of gas to the volume of blood entering the lungs approximates 1. Pulmonary venoarterial shunts and alveolar hypoventilation result in V/Q mismatch, which is probably the most important mechanism of gas exchange impairment in infants with respiratory failure due to various causes, including respiratory distress syndrome (RDS). Hypoventilation is frequently seen in infants with apnea of prematurity.

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

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 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 than frequency changes are. 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.


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), extracardiac (eg, 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 CMV, oxygenation (see the image below) is largely determined by the fraction of inspired oxygen (FI O2) and the mean airway pressure (MAP).

Determinants of oxygenation during pressure-limite 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).

Increases in PEEP are not as effective once optimal inflation is reached and may not improve oxygenation at all. In fact, an excessive MAP may cause overdistention of alveoli, leading to air trapping and right-to-left shunting of blood in the lungs.

If a very high MAP is transmitted to the intrathoracic structures, as may occur when lung compliance is near normal, cardiac output may decrease; thus, even with adequate oxygenation of blood, 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 to oxygen supplementation and assisted ventilation.

Blood oxygen content largely depends on oxygen saturation and hemoglobin level. Accordingly, it is common practice to give packed red blood cells (RBCs) to infants with anemia (hemoglobin level < 7-10 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, increases in 2,3-diphosphoglycerate, and adult hemoglobin levels reduce oxygen affinity to hemoglobin and, thus, favor oxygen delivery to the tissues.


Pulmonary Mechanics

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 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 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. 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 do.

The clinical application of the concept of time constant is clear: Very short inspiratory times may lead to incomplete delivery of tidal volume, resulting in lower peak inspiratory pressure (PIP) and mean arterial pressure (MAP) and leading to hypercapnia and hypoxemia (see the image below).

Effects of incomplete inspiration (A) or incomplet 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 and inadvertent PEEP, which is evidence of gas trapping.

Gas trapping

A short expiratory time, a prolonged time constant, 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. 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 may suggest the presence of gas trapping include the following:

  • Use of a short expiratory time (eg, high ventilatory rates)

  • A prolonged time constant (eg, high resistance)

  • Lung overexpansion on radiography

  • Decreased thoracic movement despite high PIP

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

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.

Estimation of optimal inspiratory and expiratory t 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.


Physiologic Control of Breathing

For a better understanding of the interaction between the ventilator and the baby's respiratory system, it is a necessary to consider certain important physiologic aspects of the control of breathing. The respiratory drive is servocontrolled 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.


When arterial partial pressure of carbon dioxide (Pa CO2) changes, ventilation is largely adjusted by the activity of chemoreceptors in the brainstem. An increase in Pa CO2 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.


Particularly during neonatal life and infancy, it is important also to consider the role of mechanoreceptors in the regulation of breathing. 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 good 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 (continuous positive airway pressure [CPAP] or positive end-expiratory pressure [PEEP]) can prolong expiratory time and even decrease the respiratory rate because of the intercostal phrenic inhibitory and Hering-Breuer reflexes. During weaning from a ventilator, a high PEEP may decrease the spontaneous respiratory rate.

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.


Ventilatory Approaches

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 may lead to adverse effects.

The use of CPAP instead of assisted ventilation may be a strategy for minimizing ventilator-associated lung injury. Several retrospective studies suggest that the decreased need for ventilator support with the use of CPAP may allow lung inflation to be maintained but may prevent volutrauma due to alveolar overdistention, atelectasis, or both. However, 3 multicenter randomized controlled trials including a total of 459 preterm infants reported that prophylactic CPAP did not decrease the incidence or severity of RDS or its complications. [1]

Once the diagnosis of RDS is established, administration of CPAP decreases oxygen requirements, decreases the need for mechanical ventilation, and may reduce mortality. However, the incidence of air leaks is increased among infants who receive CPAP.

The optimal time to start CPAP may depend on the severity of RDS. Early CPAP (ie, when arterial partial pressure of oxygen [Pa O2] is less than 50 mm Hg on a fraction of inspired oxygen [FI O2] of 0.40 or more) decreases the subsequent need for mechanical ventilation and duration of ventilatory assistance in newborns with RDS.

Initiate CPAP in newborns with RDS when Pa O2 is less than 50 mm Hg on an FI O2 of 0.40 or more. Studies performed to determine whether CPAP facilitates successful extubation have not yielded consistent results. CPAP and nasal intermittent mandatory ventilation (compared with nasal CPAP) reduce extubation failure in small trials and can be an alternative to reintubation.

Synchronizing ventilatory support during nasal intermittent mandatory ventilation can be difficult with newer ventilators that rely on inspiratory flow to trigger the ventilator in relation to inspiratory leak through the nasal prongs. Because the leakage varies, using a fixed flow level to trigger inspiration is difficult. Nasal intermittent mandatory ventilation is used in about 50% of English neonatal intensive care units (ICUs). [2] Although isolated gastrointestinal (GI) problems have been reported, no significant increase in GI side effects have been noted.

A combination of a sustained inflation and early CPAP may be an effective and potentially less injurious way of recruiting the lung in very premature neonates at birth. This attempt to avoid intubation and mechanical ventilation may reduce lung injury and bronchopulmonary disease (BPD) in preterm infants. Sustained inflation and early nasal CPAP at birth seems justified in extremely preterm infants at risk for RDS, providing that early surfactant rescue is given if required.

In a large randomized, controlled study of infants born at 25-28 weeks’ gestation, early nasal CPAP did not significantly reduce the rate of death or BPD when compared with intubation. [3] Although the CPAP group had a higher incidence of pneumothorax (9% vs 3%), fewer infants received oxygen at 28 days (51% vs 63%), 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. Success with CPAP is likely to be center-dependent.

The optimal method of weaning infants from CPAP is unclear. The 2 most common weaning methods are (1) reducing pressure and (2) reducing the time spent on CPAP each day. In a randomized trial, weaning by pressure was shown to be associated with significantly greater weaning success in infants born at 23-31 weeks' gestation. [4]

A comparison study found that in preterm babies with RDS, bilevel nasal CPAP has advantages over nasal CPAP. [5] Lista et al reported that babies treated with bilevel nasal CPAP had better respiratory outcomes, earlier discharge, and the same changes in cytokine levels.

A study to investigate if postresuscitation care (PRC) is indicated for all infants who receive positive pressure ventilation (PPV) at birth concludes that neonates who receive PPV at birth for as little as one minute still need close monitoring as part of their postresuscitation care. [6, 7]

Conventional mechanical 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 (by predisposing to 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 mechanical ventilation [CMV]) 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 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 (requiring higher PIP); wheezes often indicate increased resistance (affecting 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.

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, in that endotracheal intubation eliminates the active maintenance of functional residual capacity (FRC) accomplished with vocal cord adduction and closure of the glottis.


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 inspiratory time 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, decreasing lung compliance. Tidal volume falls as 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.

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. 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-to-expiratory ratio

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.

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 very low FI O2 is reached because a higher incidence of air leaks has been observed if the patient is not weaned from distending pressures earlier.


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.


Pathophysiology-Based Ventilatory Strategies

Respiratory distress syndrome

Respiratory distress syndrome (RDS) is characterized by low compliance and low functional residual capacity (FRC). An optimal conventional ventilation strategy may include conservative indications for conventional ventilation, the lowest peak inspiratory pressure (PIP) and tidal volume that will be effective, 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), judicious use of sedation or paralysis, 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 (4-6 cm H2 O) is often used, and longer inspiratory and expiratory times with low rates are preferred. Hypercarbia with compensated respiratory acidosis 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, 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 the arterial partial pressure of oxygen (Pa O2) at 80-100 mm Hg to minimize hypoxia-mediated pulmonary vasoconstriction; adjust ventilatory rates and pressures to maintain an arterial pH of 7.45-7.55 (sometimes combined with bicarbonate infusion).

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.


Ventilatory Strategies for Preventing Lung Injury

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.

The increased risk of impaired cerebral blood flow autoregulation and intracranial hemorrhage in neonates with hypercapnia is concerning. However, hypercapnic acidosis increases cerebral oxygen delivery, and the carbon dioxide – induced alterations in cerebral blood flow appear to be reversible.

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. [8] The randomized, controlled trials of permissive hypercapnia in neonates have not reported an increase in intracranial hemorrhage. [9]

Hypercapnia may play a role in the development of retinopathy of prematurity (ROP) through retinal vessel vasodilation, increased oxygenation, and subsequent formation of oxygen-derived free radicals. However, randomized trials in neonates that tested for the presence of ROP or long-term visual outcomes reported no differences between control groups and hypercapnia groups. [10]

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. [11] In preterm lambs, hypercapnia is associated with improved compliance and lung volume.

A multicenter trial of 841 adult patients with acute respiratory distress syndrome (RDS) revealed that low tidal volume and hypercapnia yielded a large reduction in mortality (from 40% to 31%) in the gentle ventilation group.

Three 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. [9] A second small trial did not confirm the potential benefits of permissive hypercapnia.

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%). 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. [12, 13]

A gentle ventilator strategy consisting of small tidal volumes, higher rates, and permissive hypercapnia may reduce BPD in very premature infants. However, extreme hypercapnia may be associated with an increased risk of intracranial hemorrhage. [14] Thus, avoiding large fluctuations in P a CO 2 values may be imperative. The optimal P a CO 2 goal in clinical practice has not been determined.

Low-tidal-volume ventilation

Strategies for conventional mechanical ventilation (CMV) 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.

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 small 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.


Strategies Based on Alternative Modes of Ventilation

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 newborns are time-triggered at a preset frequency; however, because of the available bias flow, they also allow the patient to take spontaneous breaths.

In contrast, PTV (also referred to as assist-control ventilation) uses spontaneous respiratory effort to trigger the ventilator. During PTV, changes in airway flow or pressure, chest wall or abdominal movements, or esophageal pressure 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, 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 may be 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. [15, 16]

A meta-analysis of randomized trials demonstrated no significant differences between ventilation modes with respect to the rates of bronchopulmonary disease (BPD), severe intracranial hemorrhage, air leaks, or death. [17] 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 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). Triggering systems can be used to achieve synchronization when synchrony does not occur with these maneuvers. SIMV is as effective as conventional mechanical 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 CMV.

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 no differences in mortality between volume-targeted and pressure-limited groups but found some clinically important benefits of volume-targeting, including reductions in the duration of intermittent positive pressure ventilation and the incidence of pneumothorax, and severe intraventricular hemorrhage. [18]

In one randomized study, volume targeting plus SIMV was more effective than SIMV alone in maintaining a desirable arterial partial pressure of carbon dioxide (Pa CO2) in infants born at more than 25 weeks' gestation. [19]

Volume-targeted ventilation may be particularly helpful in patients with heterogeneous lung disease because the differing time constants throughout the lung parenchyma when pressure-limited ventilation is used may result in suboptimal tidal volume delivery. Low volume-targeted levels increase the work of breathing during volume-targeted ventilation. During weaning, a volume-targeted level of 6 mL/kg could be used in place of a lower level to avoid an increase in the work of breathing. [20]

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.

The various forms of HFV have been extensively used in newborns. High-frequency positive-pressure ventilators use standard ventilators modified with low-compliance tubing and connectors. Thus, an adequate tidal volume may be delivered despite very short inspiratory times.

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. [21, 22, 23, 24, 25] Although the trial results have been heterogeneous, meta-analysis reveals no clear evidence that HFV is superior to conventional 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. [26] 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 CMV 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. [27] HFOV and CMV 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.


Benefits and Drawbacks of Specific Ventilatory Strategies

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