Dornase alfa

Improvement in the ratio of PaO^sub 2^ to the fraction of inspired oxygen and treatment of pulmonary infections in donors have been cited as important goals for improving lungs before implantation and restoring marginal lungs to the donor pool. Likewise, improving donor PaO^sub 2^ is often critical for other organs during donor care. The common physiological mechanisms responsible for hypoxemia are ventilation/perfusion mismatching, abnormal oxygen diffusion, and hypoventilation. These mechanisms are discussed and treatment options are considered. (Progress in Transplantation. 2005;15:141-148)

Orens et al1 have published a consensus report from the Pulmonary Council of the International Society for Heart and Lung Transplantation. That report is an excellent review of donor characteristics that may influence the selection of donor lungs and their function after transplantation. The criteria reviewed in that report are shown in Table 1. Orens et al express concern about the "quality" of available research and the need for additional appropriately designed investigations. Current practice standards during organ procurement are often based on recommendations from retrospective observational studies of small numbers of donors. Some characteristics of donors are not amenable to change (eg, the donor's sex, size, ABO blood type, age, cause of death, smoking history), some characteristics may influence ongoing donor care (eg, smoking history, prior asthma, findings on chest radiographs, duration of mechanical ventilation), and other characteristics may be modified during donor care (arterial blood gas levels, chest radiographic changes, ischemia time, bacterial infection). Conclusions from Orens et al1 are summarized in Table 2 and suggest that treatment of a low ratio of PaO^sub 2^ to fraction of inspired oxygen (FIO^sub 2^) (PaO^sub 2^:FIO^sub 2^) may allow more lungs to be accepted and may better support subsequent lung function in the recipient. Treatment of hypoxemia is a common challenge for procurement coordinators even when donor lungs are not being considered. Our intention in this discussion, therefore, is to review common pathways that cause donor hypoxemia and treatment to improve the PaO^sub 2^.

Conditions that may affect the donor lung (eg, inflammation, infection, edema, or contusion) produce hypoxemia through 1 or a combination of only 3 mechanisms: abnormal coordination of gas and blood flow in the lung (ventilation/perfusion [V/Q] mismatching), alterations in the normal diffusion pathway for oxygen, and hypercarbia. True anatomic shunting of blood from the right ventricle to the left ventricle in congenital or acquired structural cardiac defects, delivery of less than 21% oxygen, or treatment at high altitude may also cause hypoxemia, but these situations rarely or never apply to donor care and are not discussed further here.2

V/Q Matching and Mismatching

V/Q mismatching occurs in many pathological pulmonary conditions and is the most common cause of hypoxemia. To understand and treat this condition, it is important to review factors that control the normal distributions of pulmonary blood flow (perfusion) and gas flow (ventilation) and lead to normal V/Q matching.3,4

Distribution of Blood Flow (Perfusion)

Blood flow throughout the lung is strongly influenced by gravity. This constant force, exerted in a uniform direction, identifies 2 general zones of physiological importance, the gravitationally dependent region and the nondependent region. With the donor supine, greater amounts of blood flow are preferentially distributed along the chest's gravitationally dependent zones, the anatomically posterior areas of the upper and lower lobes of the lung. Changes in the body position of the donor change the gravitationally dependent/nondependent zones. For example, when the donor is turned to his or her left side, the left lung becomes gravitationally dependent and the right lung is nondependent. Of course blood flows to all areas of both lungs, but measurements such as blood flow per gram of lung tissue show greater blood flow to the dependent zones, confirming the importance of gravity in the distribution of perfusion.3

Distribution of Ventilation (Gas Flow)

During normal spontaneous breathing, several factors such as the distribution of perfusion and improved airway compliance in gravitationally dependent zones direct inspiratory gas flow preferentially to these dependent areas, optimizing V/Q matching. However, these influences are overwhelmed when spontaneous breathing ceases in apneic donors. During apnea, the contractions of the thoracic muscles and diaphragm that create the subatmospheric (negative) intrathoracic inspiratory pressure that pulls air into the lungs are lost. Instead, the weight of pulmonary and chest structures becomes the predominant factor in determining the distribution of ventilation.

With the donor supine, the sum of the weight of the lung and thoracic tissue is greatest along the posterior, most gravitationally dependent, plane of the chest. The weight is least along the more anterior planes where less tissue and blood mass are distributed (Figure). This compressive weight also changes as the donor's body position might be changed. For example, if the donor is on his or her left side, more weight is directed downward on the gravitationally dependent part of the left side of the thoracic cage than on the uppermost section of the right side of the thorax, where there is now less tissue and blood weight.

Because of donor apnea, the weight of the lungs and thoracic cage is no longer lifted during spontaneous inhalation and must, instead, be moved by the force of gas pushing into the lung from the ventilator. As gas enters the lung, its "path of least resistance" is toward the lung units least compressed by the weight of external thoracic mass and lung. This direction and hence the larger portion of gas flow is toward the gravitationally nondependent areas, away from the gravitationally dependent regions where the greatest amount of blood flow continues. Therefore, during both volume and pressure-limited modes of controlled mechanical ventilation in apneic donors, a partial V/Q mismatch is created as gas flows to the gravitationally nondependent areas while blood flow continues to favor gravitationally dependent zones. This mismatch cannot be corrected during donor care and most likely contributes to hypoxemia.

In addition to the disruption of the normal V/Q relationship due to donor apnea, several other factors may also increase V/Q mismatching. Regional changes in gas distribution may be imposed by localized airway obstruction caused by excessive production of sputum, infection, inflammation, allergic or reactive brochospasm, and so on. For example, imagine a localized area of bronchoconstriction or an isolated collection of mucus in a bronchus. The resulting obstruction or constriction in the airway may increase local resistance to airflow and redirect inspiratory gas to another lung unit where resistance to gas entry is less, that is, along a different path of lesser resistance. That lung unit may be adjacent to a capillary bed with a different and perhaps abnormal amount of blood flow. Thus, one can imagine various degrees of airflow obstruction, occurring and resolving at various times in any disease process. Such variations may worsen V/Q mismatching and the resulting hypoxemia.

Similarly, regional changes in blood flow may occur because of changes in arteriolar tone, adjacent airway pressures that might compress capillaries, fluctuations in pulmonary artery pressure, and so on. Such changes in perfusion may be independent of or simultaneous with changes in ventilation. When regional changes in perfusion and ventilation do not increase or decrease simultaneously and to the same magnitude, V/Q mismatching increases.

Two extremes in this continuum of potential V/Q mismatching have been identified. When a preponderance of lung units have less gas ventilation entering alveoli relative to capillary perfusion (ventilation

Shunt Assessment

The magnitude of the abnormal shunt effect may be estimated from the "rule-of-thumb" or more accurately quantified from the equation shown in Table 3.5 The "shunt equation" requires mixed venous blood obtained through a pulmonary artery catheter. Note that both of these methods require testing after the donor has received 100% oxygen (FIO^sub 2^ 1.0) for at least 10 minutes. Sequential shunt estimates may be helpful in assessing the progress of treatment.

Treatment of V/Q Mismatch Creating Shunt Effect

Treatment of symptoms of hypoxemia by adjusting the FIO^sub 2^ or mean airway pressure during mechanical ventilation has been previously reviewed.'' It is important to also treat the underlying cause of V/Q mismatch from which hypoxemia results. Airways may be completely or partially closed or obstructed for several reasons such as mucus plugging, bronchoconstriction, or compression. Naturally, the primary goal is to stop and/or reverse the cause of the abnormality. Therefore, aggressive treatment should continue for pneumonia, bronchospasm, excessive sputum production, abnormal sputum viscosity/tenacity, and so on. Therapy may include systemic antibiotics, aerosolized bronchodilators or mucolytics, systemic agents to alter sputum characteristics or production, anti-inflammatory agents, and more. Treatment of airway closure or instability may also be assisted by changing mechanical ventilator settings or using specialized respiratory care procedures to ensure maximal lung inflation within safe limits of airway pressure.

General pulmonary care includes bronchodilators, side-to-side turning, humidification of inspiratory gases, routine suctioning, and monitoring of oxygen saturation by pulse oximetry (SpO^sub 2^) or arterial blood gas analysis. Additional specific treatment of especially copious or , thick mucus can include agents such as acetylcysteine (Mycomyst) or dornase alfa (Pulmozyme). These agents liquefy mucus chemically by acting on its molecular structure7,8 and may allow more productive suctioning, thus reducing airway obstruction.

Expectorants, medications given orally to stimulate production of a thinner mucus, such as saturated solution of potassium iodide or glycerol guaiacolate probably do not act quickly enough to help during donor care. They are less important if the donor is well hydrated and full humidification of inspired gas is provided through the ventilator. Mucociliary transport may be accelerated by glucocorticosteroid or inhaled bronchodilators, but these interventions to clear airways are controversial.7

Steroid administration to donors has been supported by a retrospective observational study from a single transplantation program. The number of lungs transplanted was better after administration of a 14.5 mg/kg dose of methylprednisolone.9

Intermittent percussive ventilation therapy applies short bursts of pressurized gas at a rapid frequency (100-300 bursts/min) to the airway. Administered every 2 to 4 hours in association with bronchodilators, the percussive effects of this treatment may mobilize retained secretions and promote sputum clearance.10 Conventional postural drainage and chest physiotherapy may be helpful, especially if lobar collapse is present.11,12 However, positioning the donor to use gravity effectively for airway clearance is difficult especially when the donor is hemodynamically unstable. Other adverse hemodynamic consequences such as hypotension during physiotherapy are also documented." Similarly, high-frequency chest wall oscillation using The Vest (Hill-Rom, St Paul, Minn) has been proposed to augment removal of secretions.14 An effect has been documented in the donor population but was not statistically significant.15

Bronchoscopy allows removal of sputum directly from areas of obstruction. However, the bronchoscope is able to reach only the first 3 or 4 of the 23 anatomic divisions of the airway. Therefore, it is most valuable when obstruction of larger airways has caused significant lobar atelectasis.11,16 Sputum samples obtained during bronchoscopy may also be helpful during decisions to accept the lung or when planning subsequent treatment for the recipient.

Inspiratory maneuvers may open or "recruit" closed airways. Delivery of a larger tidal volume is the initial approach to lung expansion. Caution must be used, however, to avoid a peak airway pressure that might reduce cardiac output or injure lung tissue.6 Historically, the term, "critical opening pressure," was used to indicate some, usually unquantified, peak airway pressure that would expand collapsed, and possibly obstructed, airways.17,18 High airway pressure is no longer used during recruitment because of possible barotrauma.19,20 Techniques that apply higher airway pressures for brief periods of time, usually using a resuscitation bag or briefly sustained mechanical inflation techniques, are proposed to reexpand airways and reverse shunt effects.21,22

Equally important to these recruitment procedures is prevention of recollapse of lung units, that is, measures to prevent "de-recruitment."23 Preventing de-recruitment is largely a function of the positive end-expiratory pressure (PEEP) set on the ventilator.23 Selecting an appropriate PEEP to prevent closure of small lung units may require data from simultaneous measurements of airway pressure and gas flow from the ventilator, usually provided by the respiratory care practitioner.24,25

Large pleural effusions may cause "compressive atelectasis" that may contribute to hypoxemia.26,27 A lateral decubitus chest radiograph, ultrasound examination, or chest computed tomography scan may document that an effusion is present and allow an estimate of its volume.28 Whether drainage of pleural effusions has a beneficial effect remains a matter of controversy,27-29 but that option should be considered.

During severe hypoxemia, 2 extreme interventions, prone body positioning and administration of nitric oxide, may be considered. Inhaled nitric oxide is a powerful capillary vasodilator. When delivered as part of the inhaled gas, nitric oxide travels only to open airways and causes capillary dilatation, thereby increasing blood flow adjacent to these ventilated airways and improving V/Q matching. Administration of nitric oxide is usually effective in increasing the PaO^sub 2^.30 Placing the donor in the prone (face-down) position is logistically difficult but is often effective in increasing the PaO^sub 2^ while an expedited transfer to the operating room is implemented."31

Summary

Reversal of the shunt effect from a V/Q mismatch is directed toward opening airways that are adjacent to capillaries where perfusion is relatively greater than available gas entry. Improving ventilation to such areas may require removal of obstructing material, reversal of bronchoconstriction, thoracentesis, or airway expansion and stabilization by using ventilatory techniques.

Oxygen Diffusion and Diffusion Abnormalities

Several important processes normally ensure that oxygen is available to donor organs. Appropriate amounts of oxygen must not only be present in the inhaled gas (FIO^sub 2^), but must reach alveoli adjacent to functioning capillaries (V/Q matching), diffuse across the alveolocapillary membrane, bind with adequate amounts of hemoglobin, and be carried by sufficient cardiac output to reach donor organs. Disruption in any of these components may reduce oxygen delivery. The organ procurement coordinator can influence each of these steps during donor care to maintain or improve oxygen availability.

The fraction of oxygen in the inspired gas (FIO^sub 2^) has been previously discussed.'' Recall that FIO^sub 2^ can easily be increased during mechanical ventilation from ambient 0.21 (21%) to 1.0 (100%) to improve short-term oxygen availability. High FIO^sub 2^ risks the histopathological changes of oxygen toxicity, although these changes evolve rather slowly.32 However, nitrogen is quickly "washed out" of the lung within minutes of 100% oxygen ventilation. Loss of the airway "splinting" effect provided by nitrogen in the air space may lead to functional or anatomic closure of poorly ventilated airways throughout the lung and worsen V/Q mismatch.33(p169)

Oxygen delivery to small bronchi depends upon the "bulk" distribution of oxygen forward to distal airways as mentioned earlier. Airway pressure from the mechanical ventilator drives gas over and/or around normal airway divisions or abnormal obstructions, along its path-of-least resistance toward the alveoli. These regional variations in airway resistance or compliance greatly influence the resultant gas delivery and hence V/Q matching or potential mismatching.

Final oxygen migration to the pulmonary alveoli, where most oxygen uptake occurs, requires oxygen to diffuse within other distal airway gases (water vapor, nitrogen, and carbon dioxide) to the alveolar surface. This gas-in-gas movement is largely driven by a higher concentration (partial pressure) of oxygen in the proximal small airways than in the distal alveolar sacs.

Oxygen then dissolves in the surface layer over the type I alveolar epithelial cell, migrates (diffuses) through that cell and the adjacent capillary endothelial cell into the capillary lumen, where it enters the red blood cell and binds to hemoglobin. Along this "diffusion pathway," the oxygen molecule traverses the lung's interstitial space between the alveolar epithelial cell and the capillary endothelial cell. Normally the interstitial space and the diffusion distance that oxygen must migrate are very short. However, this distance and the viscosity of the pathway may be increased by any process causing pulmonary edema, acute respiratory distress syndrome (ARDS), chronic fibrosis, and so on, and it may limit oxygen diffusion proportionately.

Treatment of Diffusion Abnormalities

Altered diffusion of oxygen producing hypoxemia may also be due to increased interstitial fluid between the alveolar epithelial cells and the capillary endothelial cells. This fluid may represent simple transudation of protein-free plasma water from the intravascular space into the interstitial space due to increased precapillary or postcapillary hydrostatic pressure, as may occur in pulmonary venous hypertension, congestive heart failure, or when administration of crystalloid fluids is excessive.34 Factors that control fluid removal from the alveolar and interstitial lung spaces are complex.35 However, increasing cardiac output through appropriate assessment and intervention may be an important way to reduce "cardiogenic" pulmonary edema. Changes in the permeability characteristics of the pulmonary capillaries or decreased serum protein levels, especially albumin, may substantially increase the amount of interstitial edema. Further alterations in membrane characteristics, as often occurs in a systemic inflammatory response that includes ARDS, may also allow proteins to leave the blood and enter the interstitial oxygen diffusion pathway. Elongation of the distance oxygen must diffuse and changes in the viscosity of the interstitial area by albumin, other proteinaceous material, inflammatory cells, and so on may encumber the diffusion process, reduce oxygen migration, and worsen hypoxemia.33(pp87-88)

Therapeutic relocation of interstitial edematous fluid back into the intravascular compartment may be possible.36-38 However, macromolecules (such as albumin), white blood cells, fibrinous exudates, proteins, cytokines, and so on trapped in the interstitial space may be less easily removed. Interstitial edematous fluid may respond to an oncotic gradient, higher in the plasma than in the interstitial space.36 The protein-based oncotic gradient depends on the level of intravascular protein, especially albumin, being higher within the intravascular plasma compartment than in interstitial fluid. Unfortunately, hypoalbuminemia and a low plasma oncotic pressure (colloid osmotic pressure) are common after trauma, infection, and many other medical conditions that affect donors. Hypoalbuminemia has been causally associated with development of ARDS.37,38 Direct administration of 5% or 25% albumin intravenously will reliably elevate the serum level of albumin. The effectiveness of albumin administration in translocating edema fluid from the interstitium back into the blood, however, remains controversial,36-41 and such treatment should be decided by each organ procurement organization.

Summary

Within an ICU setting, it is not usually possible to distinguish between V/Q mismatch and a diffusion defect causing hypoxemia. Publications and opinion have indicated that V/Q mismatch is far more common,3,33(pp87-88) but diffusion abnormalities are likely when cardiac failure occurs,33(pp87-88) as is also common among donors. Factors that may suggest an accumulation of interstitial edema include diffuse infiltrates or pleural effusions seen on chest radiographs without significant atelectasis; radiographic evidence of consolidation/pneumonia; abnormal hemodynamic data such as high pulmonary artery occlusion pressure; other historical, laboratory, or clinical evidence of congestive heart failure; hypoalbuminemia; or chronic malnutrition. These factors may all contribute to the pathological occurrence of increased interstitial fluid/ material that slows oxygen diffusion and contributes to hypoxemia.

Treatment includes improving cardiac output, reducing excessive intravascular volume (without inducing hypotension), using diuretics, and attempting to translocate interstitial fluid back into the plasma by supporting the plasma oncotic pressure.

Hypercarbia

Insufficient alveolar ventilation leading to incomplete removal of alveolar carbon dioxide causes hypercarbia. Removal of carbon dioxide is primarily determined by the minute alveolar ventilation: V^sub ALV^ = (V^sub T^ - V^sub D^)f where V^sub T^ is tidal volume, V^sub D^ is physiological dead space, and f is rate. If the ventilator tidal volume, rate, or both are inadequate, carbon dioxide may not be adequately flushed from the alveoli, thus decreasing the pulmonary capillary-to-alveolar carbon dioxide partial pressure gradient that normally drives diffusion of carbon dioxide from the blood into the airway. Without a suitable arterial-to-alveolar carbon dioxide gradient, carbon dioxide remains in the blood through the pulmonary circulation and hypercarbia results. In addition, elevated alveolar levels of carbon dioxide also reduce the oxygen content/partial pressure in the alveolus, thus reducing the alveolar-to-arterial oxygen gradient, decreasing entry of oxygen into the diffusion pathway. Appropriate ventilator adjustments that correct carbon dioxide retention will improve the PaO^sub 2^ only in the amount (mm Hg) the PaCO^sub 2^ was elevated. Therefore, correction of this cause of hypercarbia has only a minor effect on treating hypoxemia.

Increased dead space may also cause hypercarbia as shown in the minute alveolar ventilation equation. As previously discussed, physiological dead space may be another manifestation of V/Q mismatching wherein a preponderance of well-ventilated, but less well perfused, lung units is present. When ventilator adjustments increase the minute ventilation (V^sub T^ × f) to above normal (~8 L/min), but do not resolve hypercarbia, an increased dead-space effect can be assumed. Measurement of the dead-space effect as a fraction of the tidal volume (V^sub D^/V^sub T^) is possible with the assistance of the respiratory care practitioner and may be repeated to ensure that treatment is successful. Practical interventions to reverse high dead space as a cause of hypercarbia are limited to ensuring adequate perfusion of the lung through optimizing cardiac output and reducing airway pressure. Although pulmonary emboli may also cause increased dead space, thrombolytic therapy is contraindicated during donor care because of the imminent surgery. Short-term anticoagulation using a heparin infusion could be initiated and stopped before surgery but is generally impractical. Correction of elevated dead-space effect also may improve hypoxemia, often substantially more than reversal of simple hypoventilation would improve hypoxemia.

Summary

The combination of hypoxemia and hypercarbia should first be addressed by increasing the ventilator tidal volume and/or rate. If the PaCO^sub 2^ returns to normal, no further reduction in the PaCO^sub 2^ is needed, and the maximum benefit to oxygenation has been achieved. If normalizing the minute ventilation is not sufficient, it is reasonable to consider diagnosis of a dead-space effect and manipulation of airway or hemodynamic variables to reduce the dead-space effect.

Conclusion

Treating hypoxemia is a common challenge for organ procurement coordinators. Improvement in PaO^sub 2^:FIO^sub 2^ is important when lungs are being considered for transplantation and may improve their later function in the recipient. Hypoxemia, in addition, may impair the function of other organs eligible for transplantation and, therefore, requires effective therapy.

Interventions directed toward recognized pulmonary conditions, such as pneumonia, must continue throughout donor care. Immediate treatment of severe hypoxemia should include increasing the FIO^sub 2^ to 100% and ensuring a normal minute ventilation and PaCO^sub 2^. Because V/Q mismatching, producing a shunt effect, is the most common cause of hypoxemia, subsequent therapy must include techniques to recruit airways and prevent derecruitment by increasing mean airway pressure and usually PEEP, within safe limits of peak/plateau airway pressure. Treatment may require removal of excessive secretions and reversal of bronchospasm while ensuring optimal cardiac performance and pulmonary perfusion. In addition, relocation of interstitial edema using diuretics and colloid administration may improve oxygen diffusion.

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David J. Powner, MD, Michael J. Hewitt, RRT-NPS, RCP, Robert L. Levine, MD

Vivian L. Smith Center for Neurologic Research, University of Texas Health Science Center at Houston, Tex (DJP, RLL), Memorial Hermann Hospital, Houston, Tex (MJH)

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