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PULMONARY RESPONSE TO INJURY* C. JAMES CARRICO, M.D. Professor of Surgery The University of Washington School of Medicine Director of Trauma Center Harborview Hospital

Seattle, Washington

1LMONARY failure after injury gained increasing recognition as a clini1cal problem during the Vietnam conflict.' Young, previously healthy marines and soldiers, after being resuscitated and treated for their injuries, frequently developed severe respiratory distress. In many instances this respiratory failure progressed relentlessly to death. Similar occurrences have since been reported in civilian populations, and it now appears that between 1 /' and 2% of patients who have sustained severe injuries develop progressive respiratory failure."2 It is now believed that this syndrome is analogousI to that seen under a variety of clinical circumstances, i.e., the adulIt respiratory distress syndrome (ARDS). This form of acute respiratory failure was once believed to arise from a particular clinical situation, which explains the existence of eponyms such as "traumatic wet lung," "shock lung," and "post-traumatic pulmonary insufficiency." It is now recognized, however, that a variety of pulmonary insults ranging from direct traumatic lung injury to systemic sepsis can result in a similar pathophysiologic and clinical response. Thus, rather than being a distinct entity, ARDS represents a unified pulmonary response to many injuries.

PATHOPHYSIOLOGY

The common denominator of ARDS appears to be injury to the alveolar capillary membrane and leakage of protein-rich fluid into the interstitium of the lung. The capillary leak results not only in interstitial pulmonary edema but in alveolar collapse and atelectasis with clinical manifestations, *Presented as part of a Symposium on Diagnosis and Management of Abdominal and Thoracic Trauma sponsored by the New York Hospital-Cornell Medical Center and the New York Academy of Medicine in cooperation with Science & Medicine Publishing Co., Inc., under a grant from Pfizer Laboratories, New York, N.Y., and held at the Cornell Medical Center on October 28, 1978. Address for reprint requests: Harborview Medical Center (2A- 16), 325 Ninth Avenue, Seattle,

Wash. 98104

Bull. N.Y. Acad. Med.

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PULMONARY

%

/,Q+ (J U

RESPONSE

Normal

Normal

DeWd Spoce \hMntilotion

MIXED ARTERIAL P02 (PO2) Effect of relative changes in ventilation and perfusion on pulmonary goas exchangc. Reproduced with permission from Shires, G.T., Carrico, C.J.. and Canizaro. P.C.: Pulillon'.tr) Responses. In: Shock (vol. XIII of Major Probleinv in Clinic(al SurgcrY). Philadelphia. Saunders, 1973. chap. 4. pp. 61-93.

including decreased pulmonary compliance, a decreased functional residual capacity (FRC), and hypoxemia poorly responsive to oxygen therapy. This derangement in oxygenation appears to result from severe imbalances in ventilation and perfusion. Normally, when a group of alveoli become poorly ventilated or totally closed, compensatory mechanisms decrease blood flow around these alveoli. Ultimately, both ventilation and perfusion to that particular alveolar unit are again balanced, so that the resulting dead space ventilation or pathological shunting is minimized. The effects of loss of these compensatory mechanisms are shown in the figure. Progressive decrease in blood flow with continued normal ventilation primarily affects carbon dioxide elimination. The hith ventilation to perfusion ratio (higch V/Q ratio) results in increased dead space ventilation, but arterial oxygenation remains relatively constant. In contrast, progressive decrease of ventilation while perfusion is mainVol. 55, No. 2, February 1979

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TABLE I. POSSIBLE ETIOLOGIES OF ARDS FOLLOWING INJURY

Ischemic pulmonary injury Pulmonary infection Systemic infection (sepsis) Aspiration Fat embolisms Microembolisms Soft tissue trauma Multiple transfusions Intravascular coagulation Fluid overload Crystalloid/colloid Oxygen toxicity Microatelectasis Direct pulmonary injury Reproduced with permission from Shires, G. T., Carrico, C. J., and Canizaro, P. C.: Pulmonary Responses. In: Shock (vol. XIII of Major Problems in Clinical Surgery). Philadelphia, Saunders, 1973, chap. 4, pp. 61-93.

tained (low V/Q ratio) results in hypoxia. So long as there is ventilation of the alveoli, this hypoxia should respond to oxygen. But perfusion of alveoli that have collapsed or cannot be ventilated for other reasons results in hypoxia unresponsive to oxygen, i.e., intrapulmonary shunting. Actually, both these ventilation-perfusion abnormalities appear to operate in ARDS. In some areas of the lung there is normal perfusion with little or no ventilation; in other areas ventilation of nonperfused alveoli OCC! 1rs.

ETIOLOGY

A variety of factors seem capable of evoking ARDS in the trauma patient (Table I). In many instances these factors are interrelated. Primary causative factors. Systemic sepsis is the most consistent precursor of ARDS. In fact, if one excludes patients with burns, intracranial, lesions, and pulmonary contusion, the ARDS syndrome is rarely seen unless accompanied by severe sepsis.9 Although the specific mechanisms of septic lung damage remain speculative, factors that have been implicated include direct endothelial damage to the pulmonary capillaries and alveoli, disturbances in the clotting mechanism, release of vasoactive and bronchoconstrictive substances, and decrease in activity or amount of pulmonary surfactant or both. Thoracic injury with resulting pulmonary contusion is yet another important cause of ARDS. The underlying lung injury may be unappreciated, especially when flail chest is a predominant clinical feature. In fact, recent Bull. N.Y. Acad. Med.

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investigations suggest that the respiratory failure associated with flail chest is due to underlying pulmonary contusion rather than to instability of the chest wall. "'" These studies have shown that positive end-expiratory pressure (PEEP) results in more rapid clinical improvement than does standard therapy, i.e., stabilization of the chest wall with controlled mechanical ventilation. Because pulmonary contusion is, in effect, a form of ARDS, timely initiation of PEEP appears to speed recovery and may abort otherwise progressive lung damage. Less frequent causes of ARDS include fat embolism from multiple long-bone fractures or from significant soft-tissue injury,' aspiration of gastric contents, massive head injury, and prolonged use of high-oxygen concentrations resulting in oxygen toxicity. Generally, oxygen concentrations greater than 40% to 50% are required to produce toxic effects. Time is also a factor in that the higher the oxygen tension, the less the time that is required to produce symptoms and signs of lung damage. Contributing factors. Because hemorrhagic shock is common in severely injured patients, it was once assumed to play a major role in the etiology of ARDS. However, experimental studies have shown that extreme hemorrhagic shock lasting more than several hours is required to produce severe hypoxemia. 12 Moreove- clinical studies have shown that the highest incidence of pulmonary dysfunction occurs in patients with sepsis, regardless of the presence or absence of shock.'5 Therefore, while hemorrhagic shock may increase the lung's vulnerability to other injurious agents, it does not seem to be a primary cause of respiratory failure following trauma. Although viral and bacterial pneumonias may lead to ARDS, pneumonia is usually a complication rather than a precursor of the syndrome. However, because pneumonia aggravates the pulmonary derangements, scrupulous measures to prevent this complication are mandatory. Microemboli with release of vasoactive substances, injury to pulmonary capillaries and alveoli, and hemodynamic effects may also impair pulmonary function. Theories about the source of microemboli in ARDS include stored blood, formation of intravascular microaggregates from arterial hypotension, hypovolemia, low-flow states and trauma, and disseminated intravascular coagulation (DIC). Although there is no question that massive fluid overload is deleterious, its role in the production of ARDS remains controversial. Animals massively transfused with balanced electrolyte solutions develop fulminant Vol. 55, No. 2, February 1979

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TABLE II. PERSONS AT GREATEST RISK OF DEVELOPING POSTINJURY ARDS

Patients with the following: Sepsis (systemic and pulmonary) Massive soft tissue injury with or without long bone fractures Direct pulmonary injury Massive transfusion of whole blood Aspiration of gastric contents

pulmonary edema, but the resulting hypoxia quickly responds to assisted ventilatory therapy.1",4 Clinical studies have also been unable to show a correlation between the amounts of fluid administered and the development of progressive pulmonary insufficiency analogous to ARDS.' '7 Considerable debate also concerns the role of colloid or crystalloid solutions in producing ARDS. Hypervolemia produced by either may result in pulmonary edema, but the edema responds quickly to standard treatment. Once a capillary leak is present, however, colloid solutions might gain access to the pulmonary interstitium and further derange oncotic pressure relations. CLINICAL PRESENTATIONS AND DIAGNOSIS Four clinical stages of ARDS have been described.18 The first is quite subtle and is characterized by spontaneous hyperventilation with hypocarbia, diminished pulmonary compliance, and respiratory alkalosis. If the process continues, the patient progresses to the second stage, during which respiratory problems become more apparent. Persistent hyperventilation-with worsening hypocarbia, progressive hypoxemia, and decreased compliance- increase in cardiac output, and pulmonary shunt fractions indicate that further pulmonary deterioration is imminent. Chest roentgenograms are characteristically normal during the two early stages. As the syndrome advances to stage three (progressive pulmonary insufficiency) and stage four (terminal hypoxia with cardiac asystole), interstitial edema and diffuse infiltrates are observed on the roentgenograms. In stage four widespread consolidation is often also apparent. Thus, ARDS displays a spectrum of clinical severity that ranges from mild dysfunction to progressive and potentially fatal pulmonary failure. There is a strong clinical impression and growing evidence that by identifying patients in stage one or early stage two and aggressive management the severity of ARDS may be greatly limited and its mortality decreased.19 Bull. N.Y. Acad. Med.

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TABLE III. ASSESSMENT OF PULMONARY FUNCTION

Oxygenation Partial pressure oxygen arterial blood

Acceptable PaO, > 90 mm. on 406% FIO.,

Institute therapy < 90 mm. Hg on 40% FH0.O or

Partial pressure oxygen arterial blood to fraction inspired oxygen ratio (PaO2 /FIO.) Alveolar-arterial oxygen gradient Ventilation Partial pressure carbon dioxide arterial blood Minute volume Mechanics Rate Effective

PaO., /FIO., > 350

< 300

50 to 200 mm. Hg

200 mm. Hg or increasing

35 to 40 mm. Hg

30 or decreasing

< 12 liters/min.

Increasing

12 to 25/min. 50 cc./cm. H20

25 or increasing 50 or decreasing

decreasing

compliance Reproduced with permission from Carrico, C.J. and Horovitz, J.H.: Monitoring the critically ill surgical patient. Adv. Surg. 11:101-27, 1977.

Table II lists patients at high risk of developing ARDS after injury. It is recommended that such cases be promptly admitted to the intensive care unit for frequent and regular monitoring of pulmonary function. Because optimal lung function depends on a normal cardiovascular status, hemodynamic monitoring should also be instituted. The most commonly used pulmonary function tests are shown in Table III. Because patients with ARDS have an elevated shunt fraction, the alveolar-arterial oxygen difference (AaDO.), after the patient breathes 100% oxygen for 10 to 15 minutes, would seem to allow rapid diagnosis, but because high oxygen concentrations may harm such patients, this test is not recommended. From our experience, the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaOFIO2) is the most practical and reliable tool in high-risk ARDS patients whose clinical condition has not warranted insertion of a Swan-Ganz catheter. A decreasing PaO2/FI02 value, a fall to less than 300, or both signifies significant deterioration of pulmonary function and the need for therapeutic intervention. The precise therapeutic intervention indicated depends on a careful evaluation of the clinical situation. Specifically, four general categories Vol. 55, No. 2, February 1979

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need to be considered. These include pre-existing lung disease (either acute or chronic), hypoventilation, volume overload, and ARDS. Identification of patients with preexisting lung disease depends upon a careful history and physical examination as well as an overall clinical appraisal. Such patients are not protected from superimposed ARDS, and the overall clinical evaluation is greatly aided by evaluating changes in oxygenation indices (e.g., PaO.,/FI02.) rather than absolute levels. Hypoventilation is identified by evaluation of blood gases. An increase in arterial PCO., is the sine qua non of hypoventilation. Because ARDS is usually associated with hyperventilation (a decreased PaCO.,), identification of patients with hypoventilation is usually straightforward. Identification of patients with volume overload is somewhat more difficult and requires careful clinical evaluation, physical examination, and measurements of filling pressures. A central venous pressure clearly in the hypervolemic range is helpful, but in many patients insertion of a Swan-Ganz catheter and measurement of pulmonary capillary wedge pressure is necessary to make this differentiation. If the above possibilities are excluded and the clinical situation is compatible with the diagnosis of ARDS, then the management described later is reasonable. The classic diagnosis of ARDS usually requires the demonstration of hypoxia, an appropriate clinical setting, decreased pulmonary compliance, and a roentgenogram compatible with diffuse interstitial pulmonary edema. However, if early therapy is to be instituted and severe complications avoided, beginning empirical treatment prior to a concrete diagnosis seems reasonable. Other clinical findings, such as an unusually high minute volume, low effective compliance, and rapid respiratory rate, support a presumptive diagnosis of ARDS. MANAGEMENT

Ventilatory support. When ARDS is suspected, initial therapy should provide marginally ventilated alveoli with mechanical ventilatory support and, if necessary, recruitment of collapsed or partially occluded alveoli by applying intermittent positive end-expiratory pressure (PEEP) to the airway. Once airway control is attained by an endotracheal or a nasotracheal tube, mechanical ventilation is usually begun with a volume ventilator. Tidal volumes commonly employed are in the range of 12 to 15 cc./kg. at a rate of 12 to 14 breaths/min. The ventilator is adjusted so that the patient can trigger additional breaths. Bull. N.Y. Acad. Med.

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Ordinarily, ventilatory support is started at an FIG0 of 0.4. Blood gases are checked within 20 minutes. In a small number of patients this simple ventilatory support provides sufficient alveolar stabilization to produce rapid improvement of oxygenation. In most patients, however, this is not the case, and definitive measures aimed at maintenance and improvement of oxygenation must be undertaken. The ventilator is set at a minimum rate as outlined above and the patient allowed to trigger the ventilator for additional breaths as desired. This modality of ventilatory support can be described as assisted mechanical ventilation (AMV). In general, no attempt is made to paralyze the patient or control his ventilatory rate totally. This second method of controlled mechanical ventilation (CMV) is rarely employed. A small number of patients on AMV will spontaneously hyperventilate and reduce their arterial PCO, below 30 mm. Hg. When this occurs, sedation is usually adequate to bring the arterial PCO., back to an acceptable level. Maintenance of oxygenation. Because pulmonary shunting in ARDS is caused by continued perfusion of nonventilated alveoli, simply increasing the F10., may increase the arterial PO., but will have no beneficial effect on the shunt and may, in fact, promote further atelectasis. Thus, every effort should be directed toward limiting the FIO., to less than 0.5. The prime method to support oxygenation depends on stabilizing unstable alveoli by increasing end-expiratory volume. This can be accomplished by inserting a one-way valve that requires a fixed amount of pressure to open in the expiratory line to produce continuous positive airway pressure (CPAP). The same result can be obtained using a ventilator with such a mechanism incorporated in its expiratory phase, usually referred to as positive end-expiratory pressure (PEEP). The clinical benefits of PEEP in ARDS are well established and consist of increased functional residual capacity (FRC), increased compliance, increased PaO., and increased V/Q ratio (when initially low), decreased pulmonary shunting, and decreased mortality. To determine the best level of PEEP, patients are started at a fairly low level, usually 5 cm. of H.,O. After 10 to 15 minutes, assessment of respiratory parameters is repeated. Stepwise increases in PEEP at increments of 3 to 5 cm. H.,O pressure are continued until salutary results are demonstrated. Because some patients may show a delayed response to PEEP, the Vol. 55, No. 2, February 1979

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technique should not be abandoned in the absence of immediate benefit. Each patient has a different level of ideal PEEP, best assessed by measuring arterial PO., while carefully monitoring for deleterious effects. The primary deleterious effects that can occur include decreased cardiac output and resultant decrease in oxygen transport, barotrauma (pneumothorax and subcutaneous or mediastinal emphysema), and worsening of oxygenation by maldistribution of ventilation. Adverse effects on cardiac output are unusual in patients with adequate intravascular volume receiving PEEP at less than 10 cm. H.,O pressure. The previous suggestion that measurements of compliance could be used to detect the potential of adverse effect on cardiac output has not been supported, and patients receiving PEEP at 10 cm. H.,O levels or higher should have their cardiac output measured directly. The effective compliance is a very useful technique for avoiding barotrauma. Compliance can be measured at each level of PEEP and should either stay the same or increase on higher levels. Any decrease in effective compliance when PEEP levels are raised suggests that the therapy is exceeding the elastic limit of the lung and that a potential for pressure injury to the lung exists. Under these circumstances (a decrease in compliance), the PEEP is usually reduced to the next lower level and the clinical situation evaluated. Harmful effects on distribution of ventilation can usually be detected by a fall rather than by the expected rise in arterial PO., or by an unexpected rise in arterial PCO.,. Civetta et al. have suggested an alternate method to manage these patients.211 This depends on intermittent mandatory ventilation (IMV) to control arterial PCO., and CPAP for support of oxygenation. The same general principles as outlined above apply to this method of support. The ventilatory rate is adjusted to keep the PCO., in an acceptable range (usually below 40), and CPAP is used similarly to PEEP for support of oxygenation. Fluid therapy and hemoglobin concentrations. Fluid balance should be maintained as close to normal as possible, both to avoid the deleterious effects of hypervolemia on oxygenation and to minimize decreases in cardiac output associated with PEEP therapy. Although diuretics have been suggested to reduce the pulmonary edema of ARDS,18'21 they have no demonstrated benefit in the absence of left-heart overload. Further, overzealous diuresis can decrease intravascular volume and thus produce a Bull. N.Y. Acad. Med.

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drop in cardiac output, which will only compound the hypoxia.22 This is particularly likely in patients being treated with PEEP. In our view, diuretics are indicated only when elevation of pulmonary artery wedge pressure indicates fluid overload. Efforts should be made to improve the quantities of oxygen the blood is able to transport and unload. To accomplish this, hemoglobin concentrations should be maintained in the range of 12 to 14 gm./100 ml. Maintenance of normal acid-base balance is also important, because derangements can impair cardiovascular function and the ability of hemoglobin to deliver oxygen to the tissues. Prevention of pulmonary infection. Patients with ARDS are especially prone to secondary pulmonary infections. There is growing awareness of the significance of adequate nutrition in supporting host defenses. As soon as their condition is stabilized, patients should be kept in positive nitrogen balance with hyperalimentation, either enterally or parenterally. Antibiotic therapy. Prophylactic use of broad-spectrum antibiotics is usually avoided since this practice may result in the emerging of resistant strains of bacteria, but specific antibiotics chosen on the basis of serial sputum cultures are administered when pulmonary infection exists. Daily serial sputum cultures are routinely performed to detect early infection. Because a positive culture in intubated patients may indicate colonization of the tracheobronchial tree rather than overt infection, it is advisable to couple the sputum cultures with Gram-stain analysis. An overt bacterial pneumonia is most likely when the Gram stain shows white cells, when the patient develops fever, or when chest roentgenograms show changes. Although Gram-negative anaerobic organisms are occasionally encountered, most pneumonias complicating ARDS are caused by Gramnegative aerobes, such as Pseudomonas aerluginosa, Serratia, Herellea, and Protets sp. Steroids and heparin. Although corticosteroids have been advocated, these agents have not proved consistently helpful in the treatment of ARDS'2:3-27 Short courses of high-dose steroid therapy may be useful in selected patients-for example, those with pulmonary fat embolism and, perhaps, those patients in whom septic shock or gastric-acid aspiration are etiologic factors. Some investigators believe that disseminated intravascular coagulation (DIC) plays a major role in ARDS.28 In our experience, DIC is rarely a problem in ARDS patients. When clotting problems develop, they are often due to low platelet levels following massive Vol. 55, No. 2, February 1979

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TABLE IV. MINIMAL CRITERIA FOR WITHDRAWING VENTILATORY SUPPORT

Clinical stability Inspiratory force 250 Torr (FIO. = 1.0) or equivalent oxygenation index Dead space/tidal volume < 0.6 Vital capacity > 10 ml./kg.

transfusion with banked blood devoid of platelets. Such patients respond well to platelet administration. Withdrawal of ventilatory support. Withdrawal of ventilatory support can be considered in two general areas: withdrawal from PEEP and removal of the patient from the ventilator. Premature or too rapid lowering of PEEP (or of CPAP) can result in rapid deterioration of oxygenations which is very difficult to reverse.:" In our experience, premature lowering of PEEP can be avoided if the following guidelines are followed: the patient is clinically stable and the patient shows no evidence of ongoing or increasing sepsis. Based on these guidelines, the combination of adequate arterial oxygenation (PaO.,/FIO., over 200) and persistent increases in the arterial PO. over a 12-hour period combined with a stable or increasing effective pulmonary compliance gives reasonable assurance that PEEP can be safely lowered by 3 to 5 cm. H.,O. These attempts at decreasing PEEP are not begun until the patient's FIO., has been satisfactorily reduced to 0.4 or less. Indications for removing the patient from the ventilator, in contrast to indications for lowering PEEP, are shown in Table IV. Thus, some patients may still require end-expiratory pressure but not respiratory support for the maintenance of adequate ventilation. In these patients particularly, the use of intermittent mandatory ventilation (IMV) with CPAP allows gradual removal of the patient from the ventilator while maintaining positive airway pressure to support oxygenation. Thus, our procedure usually is as follows. We begin weaning by decreasing the F102. level to 0.4 or less as rapidly as is consistent with continued clinical improvement. After the patient is stabilized on FIO., at this level, end-expiratory pressure (PEEP or CPAP) is lowered in a stepwise fashion at no shorter than six- to 12-hour intervals. The third step, which may proceed concomitantly, involves decreasing the rate of ventilatory support by using the guidelines outlined in Table IV and removal of the patient from the ventilator. Bull. N.Y. Acad. Med.

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In summary, pulmonary failure following injury is an infrequent but important potential complication. Early recognition and vigorous therapy involving support of lung volume can significantly ameliorate the adverse effects of this complication.

Discussion QUESTION: Dr. Carrico, would you comment on positive end-expiratory pressure (PEEP) as prophylactic treatment and on mannitol as therapy for adult respiratory disease syndrome (ARDS)? DR. CARRICO: The first question revolves around the issue of whether PEEP simply supports oxygenation or whether it also alters the course of the illness. Although that question is not yet totally resolved, it seems that PEEP may alter the course of the disease. If that is true, then the earlier PEEP treatment is started, the better the results are. Because a risk is also involved in using PEEP, our approach is not to use it as a routine prophylactic in all patients but to monitor high-risk patients carefully and at the first signs of oxygen deterioration start ventilatory support. In other words, we try to start patients on PEEP in phase one instead of in phase three or four, when the need for PEEP is clinically obvious. Regarding the second question, mannitol may draw fluid out of the interstitium; it is vasoactive, and it also changes distribution of blood. But at this point, although it may seem an attractive idea, we really do not know enough to recommend its use. QUESTION: Dr. Carrico, Trunkey and his group have suggested that resuscitation with colloids leads to increased protein in the lungs. What are your feelings, from a clinical standpoint, about ARDS resuscitation with colloid versus crystalloid solutions'? DR. CARRICO: The question refers to a publication by Trunkey and his group3' and several other investigators32 who demonstrated that after experimental hemorrhagic shock in animals, use of whole blood and colloids led to more protein accumulation in the lung than use of electrolyte solutions with whole blood. Although these findings are valid, do they really matter clinically'? We use whole blood and crystalloids, and our results are very good: the incidence of pulmonary failure is about 1%. We therefore see no clinical advantage in adding a colloid to the blood, with its inherent potential of increasing the protein concentration in the lungs. So, while Trunkey's data are valid, it does not necessarily mean that people will be hurt by giving them colloids. But, on the other hand, these data Vol. 55, No. 2, February 1979

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suggest that colloids will be of little benefit and that there is no evidence indicating that colloids help. Further, colloids are very expensive. So our approach is to give whole blood and an electrolyte solution rather than colloids. DR. PETER C. CANIZARO: I would add that a capillary leak may be present in many injuries and disease states that characteristically produce third-space losses-a leak similar to that present in the bum wound. Several years ago, Baxter et al. demonstrated that. plasma given during the early phase of burn resuscitation leaks out into the interstitial space about as rapidly as it is given.: