Carbon Dioxide Elimination

The primary purpose of ventilation is to eliminate carbon dioxide, which is accomplished by delivering tidal volume (V_t) breaths at a designated rate. The product (V_t × rate) determines the minute volume ventilation (). Although CO₂ elimination is proportional to , it is, in fact, directly related to the volume of gas ventilating the alveoli because part of the resides in the conducting airways or in nonperfused alveoli. As such, the portion of the ventilation that does not participate in CO₂ exchange is termed the dead space (V_d).¹⁵ In a patient with healthy lungs, this dead space is fixed or ‘anatomic’, and consists of about one-third of the tidal volume (i.e., V_d/V_t = 0.33). In a setting of respiratory insufficiency, the proportion of dead space (V_d/V_t) may be augmented by the presence of nonperfused alveoli and a reduction in V_t. Furthermore, dead space can unwittingly be increased through the presence of extensions of the trachea such as the endotracheal tube, a pneumotachometer to measure tidal volume, an end-tidal CO₂ monitor, or an extension of the ventilator tubing beyond the ‘Y.’

Tidal volume is a function of the applied ventilator pressure and the volume/pressure relationship (compliance), which describes the ability of the lung and chest wall to distend. At the functional residual capacity (FRC), the static point of end expiration, the tendency for the lung to collapse (elastic recoil) is in balance with the forces that promote chest wall expansion.¹⁵ As each breath develops, the elastic recoil of both the lung and chest wall work in concert to oppose lung inflation. Therefore, pulmonary compliance is a function of both the lung elastic recoil (lung compliance) and that of the rib cage and diaphragm (chest wall compliance).

The compliance can be determined in a dynamic or static mode. Figure 7-2 demonstrates the dynamic volume/pressure relationship for a normal patient. Note that application of 25 cmH₂O of inflating pressure (ΔP) above static FRC at positive end-expiratory pressure (PEEP) of 5 cmH₂O generates a V_t of 40 mL/kg. The lung, at an inflating pressure of 30 cmH₂O when compared with ambient (transpulmonary) pressure, is considered to be at total lung capacity (TLC) (Table 7-1). Note that the loop observed during both inspiration and expiration is curvilinear. This is due to the resistance that is present in the airways and describes the work required to overcome air flow resistance. As a result, at any given point of active flow, the measured pressure in the airways is higher during inspiration and lower during expiration than at the same volume under zero-flow conditions. Pulmonary compliance measurements, as well as alveolar pressure measurements, can be effectively performed only when no flow is present in the airways (zero flow), which occurs at FRC and TLC. The change observed is a volume of 40 mL/kg and pressure of 25 cmH₂O or 1.6 mL/kg/cmH₂O. This is termed effective compliance because it is calculated only between the two arbitrary points of end inspiration and end expiration.

As can be seen from Figure 7-3, the volume/pressure relationship is not linear over the range of most inflating pressures when a static compliance curve is developed. Such static compliance assessments are most commonly performed via a large syringe in which aliquots of 1–2 mL/kg of oxygen, up to a total of 15–20 mL/kg, are instilled sequentially with 3 to 5-second pauses. At the end of each pause, zero-flow pressures are measured. By plotting the data, a static compliance curve can be generated. This curve demonstrates how the calculated compliance can change depending on the arbitrary points used for assessment of the effective compliance (C_eff).¹⁶

Alternatively, the pulmonary pressure/volume relationship can be assessed by administration of a slow constant flow of gas into the lungs with simultaneous determination of airway pressure.17,18 A curve may be fitted to the data points to determine the optimal compliance and FRC.¹⁹ The compliance will change as the FRC or end-expiratory lung volume (EELV) increases or decreases. For instance, as can be seen in Figure 7-3, at low FRC (point A), atelectasis is present. A given ΔP will not optimally inflate alveoli. Likewise, at a high FRC (point C), because of air trapping or application of high PEEP, the lung is already distended. Application of the same ΔP will result only in over distention and potential lung injury with little benefit in terms of added V_t. Thus, optimal compliance is provided when the pressure/volume range is on the linear portion of the static compliance curve (point B). Clinically, the compliance at a variety of FRC or PEEP values can be monitored to establish optimal FRC.²⁰

Finally, it is important to recognize that a portion of the V_t generated by the ventilator is actually compression of gas within both the ventilator tubing and the airways. The ratio of gas compressed in the ventilator tubing to that entering the lungs is a function of the compliance of the ventilator tubing and the lung. The compliance of the ventilator tubing is 0.3–4.5 mL/cmH₂O.²¹ A change in pressure of 15 cmH₂O in a 3 kg newborn with respiratory insufficiency and a pulmonary compliance of 0.4 mL/cmH₂O/kg would result in a lung V_t of 18 mL and an impressive ventilator tubing/gas compression volume of 15 mL if the tubing compliance were 1.0 mL/cmH₂O. The relative ventilator tubing/gas compression volume would not be as striking in an adult. The ventilator tubing compliance is characterized for all current ventilators and should be factored when considering V_t data. The software in many ventilators corrects for ventilator tubing compliance when displaying V_t values.

Typical ventilator rate requirements in patients with healthy lungs range from 10 breaths/min in an adult to 30 breaths/min in a newborn. The V_t is maintained at 5–10 mL/kg, resulting in a of about 100 mL/kg/min in adults and 150 mL/kg/min in newborns. In healthy lungs, these settings should provide sufficient ventilation to maintain normal PaCO₂ levels of approximately 40 mmHg, and should generate peak inspiratory pressures between 15–20 cmH₂O above an applied PEEP of 5 cmH₂O. Clinical assessment by observing chest wall movement, auscultation, and evaluation of gas exchange determines the appropriate V_t in a given patient.

Oxygenation

In contrast to CO₂ determination, oxygenation is determined by the fraction of inspired oxygen (FiO₂) and the degree of lung distention or alveolar recruitment, determined by the level of PEEP and the mean airway pressure (P_aw) during each ventilator cycle. If CO₂ was not a competing gas at the alveolar level, oxygen within the pulmonary capillary blood would simply be replaced by that provided at the airway, as long as alveolar distention was maintained. Such apneic oxygenation has been used in conjunction with extracorporeal carbon dioxide removal (ECCO₂R) or arteriovenous CO₂ removal (AVCO₂R), in which oxygen is delivered at the carina, whereas lung distention is maintained through application of PEEP.22,23 Under normal circumstances, however, alveolar ventilation serves to remove CO₂ from the alveolus and to replenish the PO₂, thereby maintaining the alveolar/pulmonary capillary blood oxygen gradient.

Rather than depending on the degree of alveolar ventilation, oxygenation predominantly is a function of the appropriate matching of pulmonary blood flow to inflated alveoli (ventilation/perfusion [] matching).¹⁵ In normal lungs, the PEEP should be maintained at 5 cmH₂O, a pressure that allows maintenance of alveolar inflation at end expiration, balancing the lung/chest wall recoil. An FiO₂ of 0.50 should be administered initially. However, one should be able to wean the FiO₂ rapidly in a patient with healthy lungs and normal matching. Areas of ventilation but no perfusion (high ), such as in the setting of pulmonary embolus, do not contribute to oxygenation. Therefore, hypoxemia supervenes in this situation once the average residence time of blood in the remaining perfused pulmonary capillaries exceeds that necessary for complete oxygenation. Normal residence time is threefold that required for full oxygenation of pulmonary capillary blood.

However, the common pathophysiology observed in the setting of respiratory insufficiency is that of minimal or no ventilation, with persistent perfusion (low ), resulting in right-to-left shunting and hypoxemia. Patients with the acute respiratory distress syndrome (ARDS) have collapse of the posterior, or dependent, regions of the lungs when supine.24,25 As the majority of blood flow is distributed to these dependent regions, one can easily imagine the limited oxygen transfer and large shunt secondary to mismatch and the resulting hypoxemia that occurs in patients with ARDS. Attempts to inflate the alveoli in these regions, such as with the application of increased PEEP, can reduce mismatch and enhance oxygenation.

Just as partial pressure of CO₂ in the pulmonary artery (PaCO₂) is used to evaluate ventilation, partial pressure of oxygen in pulmonary arterial blood (PaO₂) and arterial oxygen saturation (SaO₂) levels are the measures most frequently used to evaluate oxygenation. Lung oxygenation capabilities are also frequently assessed as a function of the difference between the ideal alveolar and the measured systemic arterial oxygen levels (A–a gradient), the ratio of the PaO₂ to the FiO₂ (P/F ratio), the physiologic shunt (), and the oxygen index (OI).

where FiO₂ is the fraction of inspired oxygen, P_B is the barometric pressure, PH₂O is the partial pressure of water, and RQ is the respiratory quotient or the ratio of CO₂ production (VCO₂) to oxygen consumption (VO₂).

where C_vO₂, C_aO₂, and C_iO₂ are the oxygen contents of venous, arterial, and expected pulmonary capillary blood, respectively.

where P_aw represents the mean airway pressure.¹⁵

The overall therapeutic goal of optimizing oxygenation parameters is to maintain oxygen delivery (DO₂) to the tissues. Three variables determine DO2: cardiac output (Q), hemoglobin concentration (Hgb), and arterial blood oxygen saturation (SaO₂). The product of these three variables determines DO₂ by the relation:

Note that the contribution of the PaO₂ to DO₂ is minimal and may be disregarded in most circumstances. If the hemoglobin concentration of the blood is normal (15 g/dL) and the hemoglobin is fully saturated with oxygen, the amount of oxygen bound to hemoglobin is 20.4 mL/dL (Fig. 7-4). In addition, approximately 0.3 mL of oxygen is physically dissolved in each deciliter of plasma, which makes the oxygen content of normal arterial blood equal to approximately 20.7 mL O₂/dL. Similar calculations reveal that the normal venous blood oxygen content is approximately 15 mL O₂/dL.

Typically, DO₂ is four to five times greater than the associated oxygen consumption (VO₂). As DO₂ increases or VO₂ decreases, more oxygen remains in the venous blood. The result is an increase in the oxygen hemoglobin saturation in the mixed venous pulmonary artery blood (). In contrast, if the DO₂ decreases or VO₂ increases, relatively more oxygen is extracted from the blood, and therefore less oxygen remains in the venous blood. A decrease in is the result. In general, the serves as an excellent monitor of oxygen kinetics because it specifically assesses the adequacy of DO₂ in relation to DO₂ (DO₂/VO₂ ratio) (Fig. 7-5).²⁶ Many pulmonary arterial catheters contain fiber optic bundles that provide continuous mixed venous oximetry data. Such data provides a means for assessing the adequacy of DO₂, rapid assessment of the response to interventions such as mechanical ventilation, and cost savings due to a diminished need for sequential blood gas monitoring.^26,27 If a pulmonary artery catheter is unavailable, the central venous oxygen saturation () may serve as a surrogate of the .²⁸

Four factors are manipulated in an attempt to improve the DO₂/VO₂ ratio: cardiac output, hemoglobin concentration, SaO₂, and VO₂. The result of various interventions designed to increase cardiac output, such as volume administration, infusion of inotropic agents, administration of afterload-reducing drugs, and correction of acid–base abnormalities, can be assessed by the effect on the . One of the most efficient ways to enhance DO₂ is to increase the oxygen-carrying capacity of the blood. For instance, an increase in hemoglobin from 7.5 g/dL to 15 g/dL will be associated with a twofold increase in DO₂ at constant cardiac output. However, blood viscosity is also increased with blood transfusion, which may result in a reduction in cardiac output.²⁹ The SaO₂ can often be enhanced through application of supplemental oxygen and mechanical ventilation.

Assessment of the ‘best PEEP’ identifies the level at which DO₂ and are optimal without compromising compliance.30,31 Evaluation of the best PEEP should be performed in any patient requiring an FiO₂ greater than 0.60 and may be determined by continuous monitoring of the as the PEEP is sequentially increased from 5 cmH₂O to 15 cmH₂O over a short period. The point at which the is maximal indicates optimal DO₂. The use of PEEP with mechanical ventilation is limited, however, by the adverse effects observed on cardiac output, the effect of barotrauma, and the risk for ventilator-induced lung injury with application of peak inspiratory pressures greater than 30–40 cmH₂O.32,33 Furthermore, oxygen consumption can be elevated secondary to sepsis, burns, agitation, seizures, hyperthermia, hyperthyroidism, and increased catecholamine production or infusion. A number of interventions may be applied to reduce VO₂, such as sedation and mechanical ventilation. Paralysis may enhance the effectiveness of mechanical ventilation while simultaneously reducing VO₂.^34,35 In the appropriate setting, hypothermia may be induced with an associated reduction of 7% in VO₂ with each 1°C decrease in core temperature.³⁶

The Mechanical Ventilator and Its Components

The ventilator must overcome the pressure generated by the elastic recoil of the lung at end inspiration plus the resistance to flow at the airway. To do so, most ventilators in the ICU are pneumatically powered by gas pressurized at 50 pounds per square inch (psi). Microprocessor controls allow accurate management of proportional solenoid-driven valves, which carefully control infusion of a blend of air or oxygen into the ventilator circuit while simultaneously opening and closing an expiratory valve.³⁷ Additional components of a ventilator include a bacterial filter, a pneumotachometer, a humidifier, a heater/thermostat, an oxygen analyzer, and a pressure manometer. A chamber for nebulizing drugs is usually incorporated into the inspiratory circuit. The V_t is not usually measured directly. Rather, flow is assessed as a function of time, thereby allowing calculation of V_t. The modes of ventilation are characterized by three variables that affect patient and ventilator synchrony or interaction: the parameter used to initiate or ‘trigger’ a breath, the parameter used to ‘limit’ the size of the breath, and the parameter used to terminate inspiration or ‘cycle’ the breath (Fig. 7-6).³⁸

Gas flow in most ventilators is triggered either by time (controlled breath) or by patient effort (assisted breath). Controlled ventilation modes are time triggered: the inspiratory phase is concluded once a desired volume, pressure, or flow is attained, but the expiratory time will be the difference between the inspiratory time and the preset respiratory cycle time. In the assist mode, the ventilator is pressure or flow triggered. With the former, a pressure generated by the patient of approximately −1 cmH₂O will trigger the initiation of a breath. The sensitivity of the triggering device can be adjusted so that patient work is minimized. Other ventilators detect the reduction in constant ventilator tubing gas flow that is associated with patient initiation of a breath. Detection of this decrease in flow results in initiation of a positive-pressure breath.

The magnitude of the breath is controlled or limited by one of three variables: pressure, volume, or flow. When a breath is volume, pressure, or flow ‘controlled,’ it indicates that inspiration concludes once the limiting variable is reached. Pressure-controlled or pressure-limited modes are the most popular for all age groups, although volume-control ventilation may be of advantage in preterm newborns.39,40 In the pressure modes, the respiratory rate, the inspiratory gas flow, the PEEP level, the inspiratory/expiratory (I/E) ratio, and the P_aw are determined. The ventilator infuses gas until the desired peak inspiratory pressure (PIP) is provided. Zero-flow conditions are realized at end inspiration during pressure-limited ventilation. Therefore, in this mode, PIP is frequently equivalent to end-inspiratory pressure (EIP) or plateau pressure.

In many ventilators, the gas flow rate is fixed, although some ventilators allow manipulation of the flow rate and therefore the rate of positive-pressure development. Those with rapid flow rates will provide rapid ascent of pressure to the preset maximum, where it will remain for the duration of the inspiratory phase. This ‘square wave’ pressure pattern results in decelerating flow during inspiration (Fig. 7-7). Airway pressure is ‘front loaded,’ which increases P_aw, alveolar volume, and oxygenation without increasing PIP.⁴¹ However, one of the biggest advantages of pressure-controlled or pressure-limited ventilation is the ability to avoid lung over-distention and barotrauma/volutrauma (discussed later). The disadvantage of pressure-controlled or pressure-limited ventilation is that delivered volume varies with airway resistance and pulmonary compliance, and may be reduced when short inspiratory times are applied (Fig. 7-8).⁴² For this reason, both V_t and must be monitored carefully.

Volume-controlled or volume-limited ventilation requires delineation of the V_t, respiratory rate, and inspiratory gas flow. Gas will be inspired until the preset V_t is attained. The volume will remain constant despite changes in pulmonary mechanics, although the resulting EIP and PIP may be altered. Flow-controlled or flow-limited ventilation is similar in many respects to volume-controlled or volume-limited ventilation. A flow pattern is predetermined, which effectively results in a fixed volume as the limiting component of inspiration.

The ventilator breath is concluded based on one of four variables: volume, time, pressure, or flow. With volume-cycled ventilation, inspiration is terminated when a prescribed volume is obtained. Likewise, with time-, pressure-, or flow-cycled ventilation, expiration begins after a certain period has passed, the airway pressure reaches a certain value, or when the flow has decreased to a predetermined level, respectively.

A factor that limits inspiration suggests that the chosen value limits the level of the variable during inspiration, but the inspiratory phase does not necessarily conclude once this value is attained. For instance, during ‘pressure-limited’ ventilation, gas flow continues until a given pressure limit is attained. However, the inspiratory phase may continue beyond that point. The limitation only controls the magnitude of the breath but does not always determine the length of the inspiratory phase. In contrast, during pressure-controlled ventilation, both gas flow and the inspiratory phase terminate once the preset pressure is reached because pressure is used to limit the magnitude of the breath and the gas flow.

Modes of Ventilation (Table 7-2)

Management of the Mechanical Ventilator

IMV and SIMV may suffice for patients with normal lungs, such as when needed after an operation.⁹⁶ If the patient is spontaneously breathing and is to be ventilated for more than a brief period, a flow- or pressure-triggered assist mode, pressure support, or PAV will result in maximal support and minimal work of breathing.^48,49 Ventilator modes that allow adjustment of specific details of pressure, flow, and volume are required in the patient with severe respiratory failure. With all these modes, the ventilator rate, V_t or PIP, PEEP, and either inspiratory time alone or I/E ratio (if ventilation is pressure limited) must be assigned. Other secondary controls such as the flow rate, the flow pattern, the trigger sensitivity for assisted breaths, the inspiratory hold, the termination sensitivity, and the safety pressure limit also are set on individual ventilators. The normal is 100–150 mL/kg/min. The FiO₂ is usually initiated at 0.50 and decreased based on pulse oximetry. All efforts should be made to maintain the FiO₂ less than 0.60 to avoid alveolar nitrogen depletion and the development of atelectasis.97,98 Oxygen toxicity likely is a result of this phenomenon, although free oxygen radical formation may play a role when an FiO₂ greater than 0.40 is applied for prolonged periods.⁹⁹ A short inspiratory phase with a low I/E ratio favors the expiratory phase and CO₂ elimination, whereas longer I/E ratios enhance oxygenation. In the normal lung, I/E ratios of 1 : 3 and inspiratory time of 0.5 to 1 second are typical.

Strategies in Respiratory Failure

Adjunctive Maneuvers

Another means for enhancing oxygenation is through administration of diuretics and the associated reduction of left atrial and pulmonary capillary hydrostatic pressure.¹⁴⁰ Diuresis results in a decrease in lung interstitial edema. In addition, reduction of lung edema decreases compression of the underlying dependent lung.¹⁴¹ Collapsed dependent lung regions are thereby recruited. Although this treatment approach has not been proved in randomized clinical trials, reduction in total body fluid in adult patients with ARDS appears to be associated with an increase in survival.¹⁴² One must be cognizant of the risks of hypoperfusion and organ system failure, especially renal insufficiency, if overly aggressive diuresis is performed. Overall, however, a strategy of fluid restriction and diuresis should be pursued in the setting of ARDS, while monitoring organ perfusion and renal function.¹⁴³ In a randomized trial, a conservative fluid management strategy improved the oxygenation index, the lung injury score, the ventilator-free days, and the number of days spent out of the ICU while the prevalence of shock and use of dialysis did not increase.¹⁴⁴ Although the study was limited to 60 days, the results further support keeping a patient with acute lung injury in a state of fluid balance.

Applying noninjurious PIPs and enhancing PEEP levels limits the ΔP (the amplitude between the PIP and the PEEP) and V_t, and compromises CO₂ elimination. Therefore, the concept of permissive hypercapnia, which was discussed previously, is integral to the successful application of lung-protective strategies. PaCO₂ levels greater than 100 mmHg have been allowed with this approach, although most practitioners prefer to maintain the PaCO₂ at less than 60–70 mmHg.¹¹⁵ Bicarbonate or tris-hydroxymethyl-aminomethane (THAM) can be used to induce a metabolic alkalosis to maintain the pH at greater than 7.20. Few significant physiologic effects are observed with elevated PaCO₂ levels as long as the pH is maintained at reasonable levels.¹⁴⁵ If adequate CO₂ elimination cannot be achieved while limiting EIP to noninjurious levels, then initiation of extracorporeal life support (ECLS) should be considered.

The one situation in which it may be acceptable to increase EIP to levels greater than 35 cmH₂O (30 cmH₂O in the infant and newborn) is in the patient with reduced chest wall compliance and relatively normal pulmonary compliance. As pulmonary compliance is a combination of lung compliance and chest wall compliance, a decrease in chest wall compliance, such as due to abdominal distention, obesity, or chest wall edema, can markedly reduce pulmonary compliance despite reasonable lung compliance. This situation is analogous to studies discussed previously in which the lungs remain uninjured despite application of high airway pressures because the chest is strapped to prevent lung over distention.¹⁰⁵ This is a frequent problem in secondary respiratory failure due to trauma, sepsis, and other disease processes observed among surgical patients, including tightly placed dressings. A cautious increase in EIP in such patients may be warranted. Finally, a simple intervention, such as raising the head of the bed, may have marked effects on FRC and gas exchange in such patients.

Weaning From Mechanical Ventilation

Once a patient is spontaneously breathing and able to protect the airway, consideration is given to weaning from ventilator support. Weaning in the majority of children should take 2 days or less.⁵⁷ The Fi O₂ should be decreased to less than 0.40 before extubation. Simultaneously, PEEP should be lowered to 5 cmH₂O. The pressure support mode of ventilation is an efficient means for weaning because the preset inspiratory pressure can be gradually decreased while partial support is provided for each breath.¹⁴⁶ Adequate gas exchange with a pressure support of 7–10 cmH₂O above PEEP in adults and newborns is predictive of successful extubation.¹⁴⁷ Another study in adults demonstrated that simple transition from full ventilator support to a ‘T-piece,’ in which oxygen flow-by is provided, is as effective at weaning as is gradual reduction in rate during IMV or pressure during PSV.¹⁴⁸ In all circumstances, brief trials of spontaneous breathing before extubation should be performed with flow-by oxygen and CPAP. Prophylactic dexamethasone administration does not appear to increase the odds of a successful extubation in infants, except in ‘high risk’ patients who receive multiple doses starting at least four hours before extubation.^149,150 Parameters during a T-piece trial that indicate readiness for extubation include the following: (1) maintenance of the pretrial respiratory and heart rates; (2) inspiratory force greater than 20 cmH₂O; (3) less than 100 mL/kg/min; and (4) SaO₂ greater than 95%. If the patient’s status is unclear, transcutaneous CO₂ monitoring, along with arterial blood gas analysis (PaCO₂ < 40 mmHg; PaO₂ > 60 mmHg), may help in determining whether extubation is appropriate. The weaning trial should be brief, and under no circumstances should it last longer than one hour. In most cases, the patient who tolerates spontaneous breathing through an endotracheal tube for only a few minutes will demonstrate enhanced capabilities once the tube is removed.

Frequent causes of failed extubation include persistent pulmonary parenchymal disease, interstitial fibrosis, and reduced breathing endurance. PSV is ideal for use in the difficult-to-wean patient because it allows gradual application of spontaneous support to enhance respiratory strength and conditioning (Box 7-2).¹⁴⁶ Enteral and parenteral nutrition should be adjusted to maintain the total caloric intake to no more than 10% above the estimated caloric needs of the patient. Excess calories will be converted to fat, with a high respiratory quotient and increased CO₂ production. Nutritional support high in glucose will have a similar effect.¹⁵⁰ Manipulation of feedings along with treatment of sepsis may reduce VCO₂ and enhance weaning. Pulmonary edema should be treated with diuretics. Some patients will benefit from a tracheostomy to avoid ongoing upper airway contamination, to decrease dead space and airway resistance, and to provide airway access for evacuation of secretions during the weaning process. In addition, the issue of ‘extubating’ the patient is removed by tracheostomy. Spontaneous breathing trials, therefore, are easy to perform, and the transition from the mechanical ventilator is a much smoother and efficient process.¹⁵¹ In older patients, the tracheostomy can be performed percutaneously in the ICU.¹⁵² Long-term complications are fairly minimal in older patients. However, in newborns and infants, the rate of development of stenoses and granulation tissue may be significant.^153,154

High-Frequency Ventilation

The concept of high-frequency jet ventilation (HFJV) was developed in the early 1970s to provide gas exchange during procedures performed on the trachea. HFJV uses small bursts of gas through a small ‘jet port’ in the endotracheal tube typically at a rate of 420 breaths/min, with the range being 240–660 breaths/min.¹⁵⁵ The expiratory phase is passive.¹⁵⁶ The V_t is adjusted by controlling the PIP, which is usually initiated at 90% of conventional PIP. CO₂ removal is most affected by the ΔP. Therefore, an increase in the PIP or a decrease in the PEEP will result in enhanced CO₂ elimination. Adjusting the P_aw, PEEP, and FiO₂ alters oxygenation. HFJV is typically superimposed on background conventional V_t mechanical ventilation.

The utilization of HFJV has decreased in favor of HFOV, which uses a piston pump-driven diaphragm and delivers small volumes at frequencies between 3–15 Hz.¹⁵⁵ Both inspiration and expiration are active. Oxygenation is manipulated by adjusting P_aw, which controls lung inflation similar to the role of PEEP in conventional mechanical ventilation. CO₂ elimination is controlled by adjusting the tidal volume, also known as the amplitude or power. In short, only four variables are adjusted during HFOV:

Gas exchange during HFOV is thought to occur by convection involving those alveoli located close to airways. For the remaining alveoli, gas exchange occurs by streaming, a phenomenon in which inspiratory gas, which has a parabolic profile, tends to flow down the center of the airways whereas the expiratory flow, which has a square profile, takes place at the periphery (Fig. 7-13).¹⁵⁷ Other effects may also play a role: (1) pendelluft, in which gas exchange takes place between lung units with different time constants, as some are filling while others are emptying; (2) the movement of the heart itself may enhance mixing of gases in distal airways; (3) Taylor dispersion, in which convective flow and diffusion together function to enhance distribution of gas; and (4) local diffusion.¹⁵⁸

HFOV should be applied to the newborn and child for whom conventional ventilation is failing, because of either parameters of oxygenation or CO₂ elimination. The advantage of HFOV lies in the alveolar distention and recruitment that is provided while limiting exposure to potentially injurious high ventilator pressures.¹⁵⁹ Thus, the approach during HFOV should be to apply a mean airway pressure that will effectively recruit alveoli and maintain oxygenation while limiting the ΔP to that which will provide chest wall movement and adequate CO₂ elimination. CO₂ elimination at lower PIPs may be a specific advantage in patients with air leak, especially those with bronchopleural fistulas.¹⁶⁰ Once again, the effect on DO₂, rather than simply PaO₂, should be considered.

Although some studies with HFOV in preterm newborns have suggested that the incidence of BPD is similar to that found with conventional ventilation, other trials have found an increase in the rescue rate and a reduction in BPD with HFOV.161–165 One multicenter, randomized trial found that 56% of preterm newborns managed with HFOV were alive without the need for supplemental oxygen at 36 weeks postmenstrual age as compared with 47% of those receiving conventional ventilation (P = 0.046).¹⁶⁶ In an additional pilot study, those preterm infants managed with HFOV were extubated earlier and had decreased supplemental oxygen requirements.¹⁶⁷ In addition, improved neurodevelopmental outcomes were also seen after early intervention with HFOV, especially when used in conjunction with surfactant.¹⁶⁸ Thus, although mixed, the data would suggest a reduction in pulmonary morbidity with the use of HFOV when compared with conventional ventilation.

In term newborns and children with respiratory insufficiency, studies suggest that the rescue rate and survival in those treated with HFOV is significantly increased when compared with conventional mechanical ventilation.169–171 In a randomized controlled trial of HFOV and inspired (inhaled) nitrous oxide (iNO) in pediatric ARDS, HFOV with or without iNO resulted in greater improvement in the PaO₂/FiO₂ ratio than did conventional mechanical ventilation.¹⁷² However, in contrast, one randomized controlled trial in term newborns failed to identify a significant difference in outcome between these treatment modalities.¹⁷³ In fact, a Cochrane Database review of randomized clinical trials comparing the use of HFOV versus conventional ventilation failed to show any clear advantage in the elective use of HFOV as a primary modality in the treatment of premature infants with acute pulmonary dysfunction.¹⁷⁴

Inhaled Nitric Oxide Administration

Nitric oxide is an endogenous mediator that serves to stimulate guanylate cyclase in the endothelial cell to produce cyclic guanosine monophosphate (cGMP), which results in relaxation of vascular smooth muscle (Fig. 7-14).¹⁷⁵ NO is rapidly scavenged by heme moieties. Therefore, iNO serves as a selective vasodilator of the pulmonary circulation, but is inactivated before reaching the systemic circulation. Diluted in nitrogen and then mixed with blended oxygen and air, iNO is administered in doses of 1–80 parts per million (ppm).

Pediatric patients with respiratory failure demonstrate increases in PaO₂ with iNO at 20 ppm.¹⁷⁶ Unfortunately, a prospective, randomized, controlled trial investigating the effects of iNO therapy in children with respiratory failure revealed that although pulmonary vascular resistance and systemic oxygenation were acutely improved at one hour by administration of 10 ppm iNO, a sustained improvement at 24 hours could not be identified.¹⁷⁷

Other studies have shown more promising results with iNO. In one study, only 40% of the iNO-treated term infants with pulmonary hypertension required ECLS when compared with 71% of controls.¹⁷⁸ These results were corroborated in another study by demonstrating a reduction in the need for ECLS in control newborns (ECLS, 64%) when compared with iNO-treated newborns (ECLS, 38%; P = 0.001).¹⁷⁹ The incidence of chronic lung disease was also decreased in newborns managed with iNO (7% vs 20%). Similar results were noted for infants with persistent pulmonary hypertension of the newborn (PPHN) who were on HFOV. In another study, the need for ECLS was decreased from 55% in the control HFOV group to 14% in the combined iNO and HFOV group (P = 0.007).¹⁸⁰ In a clinical trial conducted by the Neonatal Inhaled Nitric Oxide Study (NINOS) Group, neonates born at 34 weeks or older gestational age with hypoxic respiratory failure were randomized to receive 20 ppm iNO or 100% oxygen as a control.¹⁸¹ If a complete response, defined as an increase in PaO₂ of more than 20 mmHg within 30 minutes after gas initiation, was not observed, then iNO at 80 ppm was administered. Sixty-four per cent of the control group and 46% of the iNO group died within 120 days or were treated with ECLS (P = 0.006). No difference in death was found between the two groups (iNO, 14% vs control, 17%), but significantly fewer neonates in the iNO group required ECLS (39% vs 54%). Follow-up at age 18 to 24 months failed to demonstrate a difference in the incidence of cerebral palsy, rate of sensorineural hearing loss, and mental developmental index scores between the control and iNO patients.¹⁸² Other studies have similarly failed to identify a difference in pulmonary, neurologic, cognitive, or behavioral outcomes between survivors managed with iNO and those in the conventional group.¹⁸³

An associated, but separate, trial demonstrated no difference in mortality and a significant increase in the need for ECLS when neonates with congenital disphragmatic hernia (CDH) were treated with 20 or 80 ppm of iNO versus 100% oxygen as control.¹⁸⁴ It should be noted, however, that some investigators have suggested that the efficacy of iNO in patients with CDH may be more substantial after surfactant administration or at the point at which recurrent pulmonary hypertension occurs.¹⁸⁵ iNO administration also may be helpful in the moribund CDH patient until ECLS can be initiated.

Some concern has been expressed for the development of intracranial hemorrhage in premature newborns treated with iNO. More than a 25% increase in the arterial/alveolar oxygen ratio (PaO₂/PAO₂) was observed in ten of 11 premature newborns, with a mean gestational age of 29.8 weeks and severe RDS, in response to administration of 1–20 ppm iNO.¹⁸⁶ However, in seven of these 11 newborns, intracranial hemorrhage developed during their hospitalization. Also, a meta-analysis of the three completed studies evaluating the efficacy of iNO in premature newborns suggested no significant difference in survival, incidence of chronic lung disease, or rate of development of intracranial hemorrhage between iNO and controls.¹⁸⁷

NO is associated with the production of potentially toxic metabolites. When combined with O₂, iNO produces peroxynitrates, which can be damaging to epithelial cells and also can inhibit surfactant function.188,189 Nitrogen dioxide, which is toxic, can be produced, and hemoglobin can be oxidized to methemoglobin. Additional concerns exist about the immunosuppressive effects and the potential for platelet dysfunction.

Surfactant Replacement Therapy

The use of exogenous surfactant has been responsible for a 30–40% reduction in the odds of death among very low birth weight newborns with RDS.190,191 In addition, in those premature neonates with birth weight more than 1250 g, mortality in a controlled, randomized, blinded study decreased from 7% to 4%.¹⁹²

A randomized, prospective, controlled trial in term newborns with respiratory insufficiency demonstrated that the need for extracorporeal membrane oxygenation (ECMO) was significantly reduced in those managed with surfactant when compared with placebo.¹⁹³ The benefit of surfactant was greatest in those with a lower oxygenation index (<23). Another randomized controlled study demonstrated the utility of surfactant in term newborns with the meconium aspiration syndrome.¹⁹⁴ The OI minimally decreased following the initial dose, but markedly decreased with the second and third surfactant doses from a baseline of 23.7 to 5.9 (Fig. 7-15). After three doses of surfactant, PPHN had resolved in all but one of the infants in the study group versus none in the control group. The incidence of air leaks and need for ECLS were markedly reduced in the surfactant group compared with the control infants. The neurodevelopmental outcome, however, was not affected by timing of surfactant administration. Therefore, gas exchange after intubation can be initially evaluated before surfactant is given, if needed.¹⁹⁵ The incidence of air leaks, chronic lung disease, and time on the ventilator seem to improve though when early surfactant administration with extubation to nasal CPAP was used.¹⁹⁶

Studies have concluded that surfactant phospholipid concentration, synthesis, and kinetics are not significantly deranged in infants with CDH compared with controls, although surfactant protein A concentrations may be reduced in CDH newborns on ECMO.197–199 Animal and human studies have suggested that surfactant administration before the first breath is associated with enhancement in PaO₂ and pulmonary mechanics.^200,201 However, among CDH patients on ECLS, no difference was noted in terms of lung compliance, time to extubation, period of oxygen requirement, and the total number of hospital days.¹⁹⁷

In summary, multiple approaches to preserve lung function should be used in patients with severe lung injury or RDS, including limiting lung volumes, recruitment maneuvers, prone positioning, APRV, high-frequency oscillation, nitric oxide, surfactant, and early ECMO use in nonresponders.202,203

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