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CATASTROPHIC PULMONARY FAILURE: CLINICAL MANIFESTATIONS AND CONCEPTS OF THERAPY* JAMES P. SMITH, M.D. Associate Professor of Clinical Medicine Director, Respiratory Intensive Care Unit
WILLIAM A. BRISCOE, M.D. Professor of Medicine
THOMAS K. C. KING, M.D. Associate Professor of Medicine Cornell University Medical College New York, N.Y.
( { ATASTROPHIC pulmonary failure is the final common pathway of a '- wide variety of medical, surgical, and traumatic disorders which provoke lung disease so severe that while the patient is breathing oxygen in a concentration of 80% or more, arterial oxygen tension (PaO2) is 50 mm. Hg or less.' Synonyms for this syndrome include shock lung, wet lung, and the adult respiratory distress syndrome.2 The primary event which triggers the illness may be medical (e.g., severe pneumonia, pulmonary edema, fluid overload, sepsis, or pancreatitis) or surgical (e.g., hemorrhagic shock, massive trauma, fat embolism, or extensive surgery itself).3 A vicious circle tends to develop. Pulmonary failure requires treatment with high concentrations of inspired oxygen in order to support life; high-dose oxygen, however, is toxic to the lung, especially to the Type II alveolar cells which produce pulmonary surfactant. The impediment to oxygen transfer is increased and the need for still higher and increasingly toxic concentrations of inspired oxygen (FI02) is generated. Thus, the lungs deteriorate and the pulmonary failure increases as the result of *Presented as part of a Symposium on Selected Aspects of Pulmonary Disease held by the Section on Medicine of the New York Academy of Medicine March 3, 1976. This research was supported in part by Public Health Service Research Grants HL 12531, HL 05944, and HL 70357 from the National Heart and Lung Institute, Bethesda, Md., and by a grant from the Routh Fund, New York, N.Y. Address for reprint requests: James P. Smith, M.D., Cornell University Medical College (F-440), 1300 York Avenue, New York, N.Y. 10021.
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treatment. Unless this vicious circle is interrupted, death ensues from arterial hypoxemia while the patient is breathing 100% oxygen. The pathological appearances include atelectasis, vascular congestion, formation of hyaline membrane, and interstitial cellular proliferation superimposed on the pathologic changes induced by the primary disorder. Those changes obviously vary greatly according to the primary disease, but they virtually always include an increase in extravascular water in the lung and interstitial and alveolar infiltrates of various kinds and degrees. The primary objective of the treatment of catastrophic pulmonary failure, then, is to provide adequate oxygenation to the tissues without inducing oxygen toxicity of the lungs. It should be emphasized that some degree of arterial hypoxemia is tolerable. In general, a PaO2 of 50 mm. Hg, which corresponds to the knee of the oxygen-hemoglobin dissociation curve (Figure 1), is the immediate goal of oxygen therapy. When cardiac Bull. N. Y. Acad. Med.
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output and hemoglobin concentration are nearly normal, lowering of the PaO2 to 50 mm. Hg by disease reduces oxygen saturation by only 10% below normal and does not, per se, cause tissue hypoxia. Whenever PaO2 is much above this level while the patient is breathing a toxic F102 of more than 50% oxygen, the inspired oxygen should be reduced. Below 50 mm. Hg, however, there is a major drop in arterial oxygen saturation with only small decreases of PaO2. Hence, 50 mm. Hg sets the dividing line between tolerable and intolerable degrees of hypoxemia. Once the inspired oxygen is reduced below 50% the lung is no longer at risk of oxygen toxicity. In that case the outcome of catastrophic pulmonary failure is determined largely by the response of the primary disorder to treatment. Despite a decade of investigation, the chronology of intrapulmonary events and the precise pathogenesis of the syndrome (except in cases of overwhelming infectious infiltration or gross inundation of the lung by edema) are incompletely known. However, it is now known that left ventricular failure is not a prerequisite and that catastrophic pulmonary failure can proceed to death without oxygen toxicity being. present. Experimental evidence on hemorrhagic shock in dogs suggests that a primary event is constriction of small pulmonary arteries or veins4'5 with resultant injury to the lung, loss of surfactant function, and capillary transudation. Several causes of this response have been considered: autonomic neurogenic discharge as a result of cerebral hypoxia, the effects of circulating humoral agents, lactic acidosis, tissue hypoxia, and cellular macroaggregates derived from injured nonpulmonary tissues. An early rise in pulmonary vascular resistance without change in pulmonary venous (wedge) pressure also has been observed in patients with catastrophic pulmonary failure. Thus, data in both experimental animals and patients suggest that events in the pulmonary circulation play an important role. A positive correlation of the level of pulmonary vascular resistance with the duration and severity of pulmonary dysfunction and with survival in critically ill patients recently has been shown. Alterations of pulmonary mechanics and function are those anticipated from the pathologic findings. There is decreased pulmonary compliance ("stiff lung") with the requirement for high inflation pressures and increased work of breathing. There is a high recoil tendency and a low functional residual capacity. The profound hypoxemia may become resistant even to the inhalation of 100% oxygen. Such hypoxemia conventionally is attributed to shunting of blood through totally unventilated atelectaVol. 53, No. 6, July-August 1977
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tic alveoli. However, recent work has shown that in patients with catastrophic pulmonary failure this may not be the case.6 This minority opinion is supported by observations made in experimental animals and in patients with the syndrome. In anesthetized dogs the rise in arterial oxygen tension in response to graded increases in the inspired oxygen concentration was measured before and after the creation of a surgical shunt. The right atrium was cannulated Bull. N. Y. Acad. Med.
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and connected through a roller pump to the left atrium. The pump was adjusted to produce shunting of between one quarter and one half of the cardiac output. Before shunting, the arterial oxygen tension increased from 100 mm. Hg in dogs breathing air to more than 600 mm. Hg while they breathed 100% oxygen. This steep rise or "profile" of change in oxygen tension in response to change in concentration of inspired oxygen is expected and is compatible with a normal degree of shunting, that is, less than 5% of the cardiac output. After creation of shunts, the same increase in concentration of inspired oxygen produced a very small rise in arterial oxygen tension, i.e., a flat oxygen profile. Data for three dogs are shown in Figure 2; inspired oxygen is plotted on the horizontal axis and arterial oxygen tension is shown on the vertical axis. The solid lines indicate the expected behavior of arterial oxygen tension given a certain amount of shunting. Note that large shunts, for example, 70% of the cardiac output, result in low arterial oxygen tensions which are not expected to rise significantly when the inspired oxygen concentration is increased. A somewhat smaller shunt produces a similar flat profile but at a higher level of PaO2. Only smaller shunts of 30% or less of the cardiac output produce a different oXygen profile in which the PaO2 rises sharply because the amount of oxygen in arterial blood becomes sufficient to saturate hemoglobin fully. When inspired oxygen was increased in the three dogs shown here, their observed oxygen profiles are in agreement with the theoretically predicted response for that level of shunt (50% and 25%). These observations are in contrast with the data obtained from patients with catastrophic pulmonary failure whose oxygen profiles are presented in Figure 3. The interrupted lines are those calculated for the response of arterial oxygen tension to changes in inspired oxygen concentrations at various levels of shunt. In these desperately ill patients, all of whom had arterial oxygen tensions of the order of 50 mm. Hg or less while breathing 100% oxygen-unlike the observations in the dogs with surgically created shunts-not one has an oxygen profile conforming to the theoretic shunt line. These responses of man with the shock lung syndrome to breathing concentrations of 100%, 80%, and 60% oxygen, thus, cannot be explained purely on the basis of shunt. Rather, these data are compatible with a condition in which some parts of the lung have a very low diffusing capacity yet receive a relatively large portion of the cardiac output. The diffusing capacity in the abnormal regions of the lung has been calculated by King and Briscoe6 to be in the order of one 50th or 100th of normal. Vol. 53, No. 6, July-August 1977
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This reduction is compatible with increased thickening of the alveolar capillary membrane to a comparable degree. As a practical matter, it should be apparent that there are significant therapeutic and prognostic differences between the behavior of the lung in shunt and in situations involving very low diffusing capacity. In the case of shunt, the concentration of inspired oxygen administered during therapy could be reduced without increasing arterial hypoxemia significantly and with reduced risk of oxygen toxicity. However, with low diffusing capac-
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ity, attempts to lower the risk of oxygen poisoning by reducing F102 may be expected to cause intolerable hypoxemia and often do so. Also, in two patients in whom serial measurements were made the oxygen profile provided a guide to prognosis. The condition of one such patient, represented by the black triangles in the figure, changed during a one-week period from an upper to a lower oxygen profile; she died two days after the last measurement. The clinical manifestations of catastrophic pulmonary failure vary somewhat, depending on the cause. In the disorders which are more typically considered medical-for example, bacterial or viral pneumonia-the symptoms of the syndrome evolve steadily. In cases initiated by trauma, shock, excessive transfusion, and postcirculatory perfusion states there is characteristically a latent period varying from a few hours to three or four days. Once established, however, the final common pathway of the syndrome is rather stereotyped and may be divided arbitrarily into three stages of severity. In the first stage, clinical pulmonary findings are not impressive but dyspnea is present and tachypnea is constant. Examples include advancing pneumonia and the onset of the syndrome after a latent period of relative well-being following shock or surgery. Roentgenograms show modest interstitial or alveolar infiltration or only a subtly visible appearance resembling ground glass, suggesting an increase of interstitial fluid. Hypoxemia is present despite hyperventilation, with hypocapnia and respiratory alkalosis. This initial hypoxemia is readily corrected by 40% or less inspired oxygen. Further evolution may be aborted by a high index of suspicion of the syndrome in settings in which it is likely to occur, prompt confirmation of its onset by x rays and measurement of the arterial blood gases, specific therapy of the initiating disorder-especially antibiotics in pneumonia or sepsis and the early administration of an effective diuretic (e.g., furosemide, initially 80 mg. administered intravenously) and restriction of parenteral fluids in all cases except those in which it is known with certainty that intravascular volume is low. The second stage appears with progression of the underlying cause with or without an element of iatrogenic impairment from fluid overload. The physician may be surprised to find that the patient is breathing more rapidly and that fatigue is becoming prominent. Changes in behavior, with irritability, restlessness, poor cooperation with nursing care, and frequently with rejection of oxygen-delivery devices signal early cerebral hypoxia. Vol. 53, No. 6, July-August 1977
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The increase in the work of breathing is obvious. Chest roentgenograms show more definite and diffuse changes. Hyperventilation, sustained at a high energy cost, is mediated both by mechanical stimuli from the lungs ("stiffening") and by progressive hypoxemia. The latter requires greater than 50% and sometimes 100% inspired oxygen for a tolerable PaO2 to be attained. Delivery of such high F102 is obtainable by means of fairly tight-fitting, low-dead-space, nonrebreathing face masks attached to an oxygen reservoir bag. These masks, delivering potentially toxic F102, are indicated for a variable but generally short period (24 to 48 hours), while all other therapeutic measures are employed to avoid the final stage. In the third stage the physician confronts the potential vicious circle already discussed. The patient usually is obtunded or precomatose. Endotracheal intubation and mechanical ventilation should be undertaken 1) before hypercapnia (i.e., ventilatory insufficiency) appears, 2) if progressive hypoxemia precipitates metabolic acidosis, 3) if it appears that the patient is no longer able to sustain the work of breathing, or 4) if hypotension or shock develops. No set limit for arterial oxygen tension or saturation identifies this point in time. The objective of controlled mechanical ventilation is to obviate the work of breathing, improve arterial oxygenation, prevent cardiorespiratory arrest, and allow the employment of nontoxic concentrations of inspired oxygen. This is facilitated by use of a drug which paralyzes the peripheral nervous system (pancuronium bromide or curare) and by application of positive end-expiratory pressure (PEEP). The latter maneuver causes the lung at the end of expiration to remain at a higher functional residual capacity than would prevail if the patient expired to atmospheric pressure. Presumably, this stabilizes or recruits a population of alveolar units that ordinarily would collapse, theoretically providing better distribution of gas and blood within the lungs and improving oxygen diffusion with a resultant increase of arterial oxygen tension. In general, PEEP is indicated whenever PaO2 of 60 mm. Hg or more is not maintained with an inspired oxygen of 50% or more. Since graded increases in PEEP usually result in progressive increase in PaO2, it is prudent to start with 5 cm. H20 pressure and to increase by steps of 5 cm. H20 to the "ideal" level. Most often the increase of PaO2 is accompanied by clinical improvement. However, in a minority of patients PEEP induces a fall in cardiac output which, despite the increase in PaO2, may reduce net oxygen delivery to the tissues. To avoid and correct this problem as well as to provide optimal over-all care, patients reaching the Bull. N. Y. Acad. Med.
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third stage of catastrophic pulmonary failure should be treated in intensive-care units equipped to monitor pulmonary artery and pulmonary venous (wedge) pressure and cardiac output. These observations often are necessary to evaluate accurately left ventricular performance and the state of the intravascular volume and to supplement the critically important clinical assessments of cerebral, cardiac, and renal functions-namely, the patient's level of consciousness, blood pressure, and urine output. Sometimes too much attention and effort are focused on the PaO2 as an island of information while other important determinants of cellular oxygen supply (hemoglobin concentration, arterial oxygen saturation, arterial oxygen content, and cardiac output) and indicators of the adequacy of that delivery (mixed venous oxygen tension and saturation and the arterialvenous 02 difference) are ignored. In general, PEEP-induced reduction of cardiac output by decrease of venous return to the right heart is seen most commonly in hypovolemic patients. However, the indiscriminate infusion of blood, plasma, albumin, or saline solution without careful attention to the pulmonary artery and wedge pressures may cause iatrogenic worsening of oxygen transfer. Recently, high levels of PEEP, in excess of the conventional upper limit of 15 cm. H20, i.e., to 25 or even 45 cm. H20, have been used to interrupt the vicious circle produced by ever-increasing F102. The use of these high pressures has been complicated by pneumothorax in 15% of patients, but cardiac output did not fall when intravascular volume was adequate.7 Ideally, before the vicious circle is reached, and certainly after its development, the following measures should be undertaken and frequently reviewed to increase the availability of oxygen to the cells: 1) To increase PaO2 consider: a) Reducing extravascular lung water with diuretics as discussed above. b) Increasing alveolar ventilation. This usually is of very limited value, but the setting of minute volume to maintain the arterial carbon dioxide tension (PaCO2) at 30 to 35 mm. Hg rather than 45 to 50 mm. Hg may produce a small rise in PaO2 in the critical range. c) Administering corticosteroids in high doses. The use of these drugs is controversial. Their proponents suggest that they improve the pulmonary microcirculation and decrease infiltration and edema, thereby improving the transfer of oxygen. Usually they are Vol. 53, No. 6, July-August 1977
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best avoided in patients with pulmonary failure caused by infection. 2) To increase arterial oxygen content in anemic patients, transfuse packed red cells or whole blood, if volume considerations permit, to near normal hemoglobin ranges. Physicians often overlook this important means of maintaining tissue oxygenation when only marginal PaO2 can be attained safely. Fresh blood provides better oxygen transport, and efficient filters prevent infused cell fragments and other debris from doing further injury to the lung. 3) To improve cardiac output: a) Increase or decrease fluids according to the pressure and the clinical monitoring indices discussed above. b) Use cardiotonic drugs when left ventricular failure is present, and vasopressors when shock or hypotension are refractory to more basic measures. c) Adjust PEEP as discussed above. 4) To decrease utilization of oxygen consider reducing body temperature, especially in highly febrile patients, by drugs or hypothermic blanket. In extreme instances of catastrophic pulmonary failure, when all therapeutic attempts have failed and when irreparable pulmonary oxygen toxicity appears inevitable, consideration can be given to two special techniques which have had limited clinical trials. In the first method, an extracorporeal support system, part of the cardiac output is drained continuously from a catheter in a femoral vein into a membrane oxygenator and returned by a pump to a catheter in a large artery. The oxygen thus supplied to the blood theoretically allows reduction of the inspired oxygen to a nontoxic level. The other method is hyperbaric oxygenation in a chamber. This technique has a short-lived utilization period as the risk of oxygen toxicity is compounded by the use of high pressures. Unless the patient is close to recovery from the underlying disease and requires only a very short period of support, exposure to extremely high tensions of inspired oxygen appears to be self-defeating. The following case of catastrophic pulmonary failure illustrates the clinical manifestations and problems under discussion. A 58-year-old black woman was hospitalized because of myalgias, cough, dyspnea, and fever of two-weeks' duration. On arrival at another hospital she was acutely ill but alert. Her blood pressure was 90/60 mm. Hg, pulse rate 115/min., respiratory frequency 60/min., and temperature 41'C. Bilateral rales were Bull. N. Y. Acad. Med.
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Fig. 4. Chest x ray of a 58-year-old woman with catastrophic pulmonary failure showing bilateral basilar interstitial and alveolar infiltrations at time of admission.
heard. The leukocyte count was 6,000/mm.3 and the hematocrit 33%. Gram stains and acid-fast stains of the sputum were negative. The intermediate tuberculin test was negative also. Initially, 35% oxygen by mask provided an arterial oxygen tension of 65 mm. Hg. The presumptive diagnosis was viral or other pneumonia; therapy was started with penicillin and aspirin. During the next two days there was clinical deterioration and progressive hypoxemia despite increases in inspired oxygen concentration. Cardiorespiratory arrest occurred on the third day. After resuscitation, the arterial oxygen tension was only 34 mm. Hg, with an inspired oxygen concentration of 40% delivered by a volume-cycled respirator. Consequently the inspired oxygen concentration was increased to 60% and PEEP of 10 cm. water was applied. The arterial oxygen tension increased temporarily to 76 mm. Hg, but over the course of the next day it fell; coma and shock developed. The concentration of Vol. 53, No. 6, July-August 1977
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Fig. 5. Chest x ray of same woman as in Figure 4 four days later, showing all zones of the lung involved with a dense alveolar and interstitial infiltrate which produced a "white lung" pattern.
inspired oxygen was increased to 100% prior to transfer of the patient to the New York Hospital for consideration of treatment with an extracorporeal membrane oxygenator system. The initial roentgenogram of the chest showed a modest degree of bilateral basilar infiltration compatible with viral or other interstitial pneumonia (Figure 4). At the time of transfer all zones of the lung were involved with a dense alveolar and interstitial infiltrate which produced a "white lung" pattern (Figure 5). The blood pressure was 100/60 mm. Hg, the pulse 110/min., and temperature 39°. Monitored parameters did not indicate left ventricular failure or hypervolemia. With inspired oxygen concentration at 80%, the arterial oxygen tension was 39 mm. Hg and the arterial oxygen saturation was 75%. Arterial carbon dioxide tension was maintained at approximately 30 mm.
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Hg. Packed red cell transfusions were given and these raised the hematocrit value to 40%. Arterial oxygen tension, saturation, and content, thus, were considered adequate. However, the presence of shock, resistance to treatment, and the approaching point of no return in terms of the danger of oxygen toxicity prompted use of the extracorporeal membrane oxygenator. This allowed reduction of the inspired oxygen concentration to 50%, corrected shock, and provided six days for the underlying condition to be reversed. However, this did not occur, and the patient died on the 13th hospital day. The findings anticipated at autopsy were those of unresolved viral pneumonia, with some degree of organization and fibrosis based on the duration of the illness. In fact, however, the surprising and saddening finding was diffuse involvement of all lung fields by miliary tuberculosis. There were no signs of oxygen toxicity. This case adds miliary tuberculosis to the long list of disorders that may cause catastrophic pulmonary failure and emphasizes the need for specific diagnosis and consideration of lung biopsy in all patients.8 Current criteria for use of the extracorporeal support system are: 1) The presence of an acute, reversible underlying disorder 2) Inadequate tissue oxygenation despite all conventional measures 3) Toxic concentrations of inspired oxygen in use for less than 72 hours 4) No hemorrhagic disorder and no chronic disease with short expected survival The therapeutic technique includes surgical cannulation of the inferior vena cava in order to drain blood by gravity to flow through two or more membrane oxygenators, each with a surface area of three square meters, connected in parallel. The fully saturated blood then is conducted to a pump and returned to the patient by means of a cannula placed in the subclavian artery (and sometimes also the femoral artery) to complete the venoarterial circuit. The method has proved safe; the required total body heparinization has been manageable. Neither platelet consumption nor hemolysis causes difficulty. The availability of pumps which are safe and relatively simple to operate has permitted treatment of these patients in a medical-pulmonary intensive-care unit without the requirement of specially trained pump technicians. Future development of still more efficient pumps with higher flow capability can be expected to improve the technique additionally. Experience with extracorporeal systems such as this for long-term support of patients with catastrophic pulmonary failure is limited and the
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salvage rate up to now has been extremely low. The present high level of enthusiasm and interest in the procedure will undoubtedly lead to increased use of the method. However, the critical question to be answered is: in how many patients will the treatment be shown to be both necessary and successful? It is our present belief that with steadily improved early care the role of this technique in the treatment of catastrophic pulmonary failure will remain small.
2.
3.
4.
REFERENCES Briscoe, W. A., Smith, J. P., Ber- 5. Bergofsky, E. H.: Pulmonary insufficiency after nonthoracic trauma: Shock gofsky, E., and King, T. K. C.: lung. Am. J. Med. Sci. 264:93, 1972. Catastrophic pulmonary failure. Am. J. 6. King, T. K. C., Weber, B., Okinaka, Med. 60:248, 1976. A., Friedman, S. A., Smith, J. P., Ashbaugh, D. G., Bigelow, D. B., and Briscoe, W. A.: Oxygen transfer Petty, T. C., and Levine, B. E.: in catastrophic respiratory failure. Acute respiratory distress in adults. Chest 65:40S-44S, 1974. Lancet2:319, 1967. Moore, F. D., Lyons, J. H., Pierce. 7. Kirby, R. R., Downs, J. B., Civetta, J. M., Modell, J. H., Dannemiller, F. E. C., Morgan, A. P., Drinker, P. J., Klein, E. F., and Hodges, M.: A., MacArthur, J. D., and Dammin, High level positive end expiratory G. J.: Post-traumatic pulmonary insufpressure (PEEP) in acute respiratory ficiency. Philadelphia, Saunders. insufficiency. Chest 67:156, 1975. 1969. Veith, F. J., Panossian, A., Nehisen, 8. Homan, W., Harman, E., Braun, N. M. T., Felton, C. P., King, T. K. C., S. L., Wilson, J. W., and Hagstrom, and Smith, J. P.: Miliary tuberculosis J. W. C.: A pattern of pulmonary vaspresenting as acute respiratory failure: cular reactivity in the pathogenesis of Treatment by membrane oxygenator post-traumatic pulmonary insuffiand ventricle pump. Chest 67:366, ciency. J. Trauma 8:788, 1968. 1975.
Bull. N. Y. Acad. Med.
CATASTROPHIC PULMONARY FAILURE: CLINICAL MANIFESTATIONS AND CONCEPTS OF THERAPY* JAMES P. SMITH, M.D. Associate Professor of Clinical Medicine Director, Respiratory Intensive Care Unit
WILLIAM A. BRISCOE, M.D. Professor of Medicine
THOMAS K. C. KING, M.D. Associate Professor of Medicine Cornell University Medical College New York, N.Y.
( { ATASTROPHIC pulmonary failure is the final common pathway of a '- wide variety of medical, surgical, and traumatic disorders which provoke lung disease so severe that while the patient is breathing oxygen in a concentration of 80% or more, arterial oxygen tension (PaO2) is 50 mm. Hg or less.' Synonyms for this syndrome include shock lung, wet lung, and the adult respiratory distress syndrome.2 The primary event which triggers the illness may be medical (e.g., severe pneumonia, pulmonary edema, fluid overload, sepsis, or pancreatitis) or surgical (e.g., hemorrhagic shock, massive trauma, fat embolism, or extensive surgery itself).3 A vicious circle tends to develop. Pulmonary failure requires treatment with high concentrations of inspired oxygen in order to support life; high-dose oxygen, however, is toxic to the lung, especially to the Type II alveolar cells which produce pulmonary surfactant. The impediment to oxygen transfer is increased and the need for still higher and increasingly toxic concentrations of inspired oxygen (FI02) is generated. Thus, the lungs deteriorate and the pulmonary failure increases as the result of *Presented as part of a Symposium on Selected Aspects of Pulmonary Disease held by the Section on Medicine of the New York Academy of Medicine March 3, 1976. This research was supported in part by Public Health Service Research Grants HL 12531, HL 05944, and HL 70357 from the National Heart and Lung Institute, Bethesda, Md., and by a grant from the Routh Fund, New York, N.Y. Address for reprint requests: James P. Smith, M.D., Cornell University Medical College (F-440), 1300 York Avenue, New York, N.Y. 10021.
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80 60 100 40 20 OXYGEN PRESSURE (P02) mm Hg Fig. 1. Oxygen-hemoglobin dissociation curve.
treatment. Unless this vicious circle is interrupted, death ensues from arterial hypoxemia while the patient is breathing 100% oxygen. The pathological appearances include atelectasis, vascular congestion, formation of hyaline membrane, and interstitial cellular proliferation superimposed on the pathologic changes induced by the primary disorder. Those changes obviously vary greatly according to the primary disease, but they virtually always include an increase in extravascular water in the lung and interstitial and alveolar infiltrates of various kinds and degrees. The primary objective of the treatment of catastrophic pulmonary failure, then, is to provide adequate oxygenation to the tissues without inducing oxygen toxicity of the lungs. It should be emphasized that some degree of arterial hypoxemia is tolerable. In general, a PaO2 of 50 mm. Hg, which corresponds to the knee of the oxygen-hemoglobin dissociation curve (Figure 1), is the immediate goal of oxygen therapy. When cardiac Bull. N. Y. Acad. Med.
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output and hemoglobin concentration are nearly normal, lowering of the PaO2 to 50 mm. Hg by disease reduces oxygen saturation by only 10% below normal and does not, per se, cause tissue hypoxia. Whenever PaO2 is much above this level while the patient is breathing a toxic F102 of more than 50% oxygen, the inspired oxygen should be reduced. Below 50 mm. Hg, however, there is a major drop in arterial oxygen saturation with only small decreases of PaO2. Hence, 50 mm. Hg sets the dividing line between tolerable and intolerable degrees of hypoxemia. Once the inspired oxygen is reduced below 50% the lung is no longer at risk of oxygen toxicity. In that case the outcome of catastrophic pulmonary failure is determined largely by the response of the primary disorder to treatment. Despite a decade of investigation, the chronology of intrapulmonary events and the precise pathogenesis of the syndrome (except in cases of overwhelming infectious infiltration or gross inundation of the lung by edema) are incompletely known. However, it is now known that left ventricular failure is not a prerequisite and that catastrophic pulmonary failure can proceed to death without oxygen toxicity being. present. Experimental evidence on hemorrhagic shock in dogs suggests that a primary event is constriction of small pulmonary arteries or veins4'5 with resultant injury to the lung, loss of surfactant function, and capillary transudation. Several causes of this response have been considered: autonomic neurogenic discharge as a result of cerebral hypoxia, the effects of circulating humoral agents, lactic acidosis, tissue hypoxia, and cellular macroaggregates derived from injured nonpulmonary tissues. An early rise in pulmonary vascular resistance without change in pulmonary venous (wedge) pressure also has been observed in patients with catastrophic pulmonary failure. Thus, data in both experimental animals and patients suggest that events in the pulmonary circulation play an important role. A positive correlation of the level of pulmonary vascular resistance with the duration and severity of pulmonary dysfunction and with survival in critically ill patients recently has been shown. Alterations of pulmonary mechanics and function are those anticipated from the pathologic findings. There is decreased pulmonary compliance ("stiff lung") with the requirement for high inflation pressures and increased work of breathing. There is a high recoil tendency and a low functional residual capacity. The profound hypoxemia may become resistant even to the inhalation of 100% oxygen. Such hypoxemia conventionally is attributed to shunting of blood through totally unventilated atelectaVol. 53, No. 6, July-August 1977
J. P. SMITH AND OTHERS
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100 60 so IN5PIRED OXYGEN COfCEN TRATION % Fig. 2. The predicted (solid lines) and observed (broken lines) response of arterial oxygen tension to increase of inspired oxygen concentration in three dogs with created right to left shunts.
tic alveoli. However, recent work has shown that in patients with catastrophic pulmonary failure this may not be the case.6 This minority opinion is supported by observations made in experimental animals and in patients with the syndrome. In anesthetized dogs the rise in arterial oxygen tension in response to graded increases in the inspired oxygen concentration was measured before and after the creation of a surgical shunt. The right atrium was cannulated Bull. N. Y. Acad. Med.
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and connected through a roller pump to the left atrium. The pump was adjusted to produce shunting of between one quarter and one half of the cardiac output. Before shunting, the arterial oxygen tension increased from 100 mm. Hg in dogs breathing air to more than 600 mm. Hg while they breathed 100% oxygen. This steep rise or "profile" of change in oxygen tension in response to change in concentration of inspired oxygen is expected and is compatible with a normal degree of shunting, that is, less than 5% of the cardiac output. After creation of shunts, the same increase in concentration of inspired oxygen produced a very small rise in arterial oxygen tension, i.e., a flat oxygen profile. Data for three dogs are shown in Figure 2; inspired oxygen is plotted on the horizontal axis and arterial oxygen tension is shown on the vertical axis. The solid lines indicate the expected behavior of arterial oxygen tension given a certain amount of shunting. Note that large shunts, for example, 70% of the cardiac output, result in low arterial oxygen tensions which are not expected to rise significantly when the inspired oxygen concentration is increased. A somewhat smaller shunt produces a similar flat profile but at a higher level of PaO2. Only smaller shunts of 30% or less of the cardiac output produce a different oXygen profile in which the PaO2 rises sharply because the amount of oxygen in arterial blood becomes sufficient to saturate hemoglobin fully. When inspired oxygen was increased in the three dogs shown here, their observed oxygen profiles are in agreement with the theoretically predicted response for that level of shunt (50% and 25%). These observations are in contrast with the data obtained from patients with catastrophic pulmonary failure whose oxygen profiles are presented in Figure 3. The interrupted lines are those calculated for the response of arterial oxygen tension to changes in inspired oxygen concentrations at various levels of shunt. In these desperately ill patients, all of whom had arterial oxygen tensions of the order of 50 mm. Hg or less while breathing 100% oxygen-unlike the observations in the dogs with surgically created shunts-not one has an oxygen profile conforming to the theoretic shunt line. These responses of man with the shock lung syndrome to breathing concentrations of 100%, 80%, and 60% oxygen, thus, cannot be explained purely on the basis of shunt. Rather, these data are compatible with a condition in which some parts of the lung have a very low diffusing capacity yet receive a relatively large portion of the cardiac output. The diffusing capacity in the abnormal regions of the lung has been calculated by King and Briscoe6 to be in the order of one 50th or 100th of normal. Vol. 53, No. 6, July-August 1977
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Fig. 3. The response of arterial oxygen tension to increase of inspired oxygen concentration (oxygen profile) in patients with catastrophic pulmonary failure (solid lines) and predicted responses (broken lines) for various levels of shunts.
This reduction is compatible with increased thickening of the alveolar capillary membrane to a comparable degree. As a practical matter, it should be apparent that there are significant therapeutic and prognostic differences between the behavior of the lung in shunt and in situations involving very low diffusing capacity. In the case of shunt, the concentration of inspired oxygen administered during therapy could be reduced without increasing arterial hypoxemia significantly and with reduced risk of oxygen toxicity. However, with low diffusing capac-
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ity, attempts to lower the risk of oxygen poisoning by reducing F102 may be expected to cause intolerable hypoxemia and often do so. Also, in two patients in whom serial measurements were made the oxygen profile provided a guide to prognosis. The condition of one such patient, represented by the black triangles in the figure, changed during a one-week period from an upper to a lower oxygen profile; she died two days after the last measurement. The clinical manifestations of catastrophic pulmonary failure vary somewhat, depending on the cause. In the disorders which are more typically considered medical-for example, bacterial or viral pneumonia-the symptoms of the syndrome evolve steadily. In cases initiated by trauma, shock, excessive transfusion, and postcirculatory perfusion states there is characteristically a latent period varying from a few hours to three or four days. Once established, however, the final common pathway of the syndrome is rather stereotyped and may be divided arbitrarily into three stages of severity. In the first stage, clinical pulmonary findings are not impressive but dyspnea is present and tachypnea is constant. Examples include advancing pneumonia and the onset of the syndrome after a latent period of relative well-being following shock or surgery. Roentgenograms show modest interstitial or alveolar infiltration or only a subtly visible appearance resembling ground glass, suggesting an increase of interstitial fluid. Hypoxemia is present despite hyperventilation, with hypocapnia and respiratory alkalosis. This initial hypoxemia is readily corrected by 40% or less inspired oxygen. Further evolution may be aborted by a high index of suspicion of the syndrome in settings in which it is likely to occur, prompt confirmation of its onset by x rays and measurement of the arterial blood gases, specific therapy of the initiating disorder-especially antibiotics in pneumonia or sepsis and the early administration of an effective diuretic (e.g., furosemide, initially 80 mg. administered intravenously) and restriction of parenteral fluids in all cases except those in which it is known with certainty that intravascular volume is low. The second stage appears with progression of the underlying cause with or without an element of iatrogenic impairment from fluid overload. The physician may be surprised to find that the patient is breathing more rapidly and that fatigue is becoming prominent. Changes in behavior, with irritability, restlessness, poor cooperation with nursing care, and frequently with rejection of oxygen-delivery devices signal early cerebral hypoxia. Vol. 53, No. 6, July-August 1977
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The increase in the work of breathing is obvious. Chest roentgenograms show more definite and diffuse changes. Hyperventilation, sustained at a high energy cost, is mediated both by mechanical stimuli from the lungs ("stiffening") and by progressive hypoxemia. The latter requires greater than 50% and sometimes 100% inspired oxygen for a tolerable PaO2 to be attained. Delivery of such high F102 is obtainable by means of fairly tight-fitting, low-dead-space, nonrebreathing face masks attached to an oxygen reservoir bag. These masks, delivering potentially toxic F102, are indicated for a variable but generally short period (24 to 48 hours), while all other therapeutic measures are employed to avoid the final stage. In the third stage the physician confronts the potential vicious circle already discussed. The patient usually is obtunded or precomatose. Endotracheal intubation and mechanical ventilation should be undertaken 1) before hypercapnia (i.e., ventilatory insufficiency) appears, 2) if progressive hypoxemia precipitates metabolic acidosis, 3) if it appears that the patient is no longer able to sustain the work of breathing, or 4) if hypotension or shock develops. No set limit for arterial oxygen tension or saturation identifies this point in time. The objective of controlled mechanical ventilation is to obviate the work of breathing, improve arterial oxygenation, prevent cardiorespiratory arrest, and allow the employment of nontoxic concentrations of inspired oxygen. This is facilitated by use of a drug which paralyzes the peripheral nervous system (pancuronium bromide or curare) and by application of positive end-expiratory pressure (PEEP). The latter maneuver causes the lung at the end of expiration to remain at a higher functional residual capacity than would prevail if the patient expired to atmospheric pressure. Presumably, this stabilizes or recruits a population of alveolar units that ordinarily would collapse, theoretically providing better distribution of gas and blood within the lungs and improving oxygen diffusion with a resultant increase of arterial oxygen tension. In general, PEEP is indicated whenever PaO2 of 60 mm. Hg or more is not maintained with an inspired oxygen of 50% or more. Since graded increases in PEEP usually result in progressive increase in PaO2, it is prudent to start with 5 cm. H20 pressure and to increase by steps of 5 cm. H20 to the "ideal" level. Most often the increase of PaO2 is accompanied by clinical improvement. However, in a minority of patients PEEP induces a fall in cardiac output which, despite the increase in PaO2, may reduce net oxygen delivery to the tissues. To avoid and correct this problem as well as to provide optimal over-all care, patients reaching the Bull. N. Y. Acad. Med.
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third stage of catastrophic pulmonary failure should be treated in intensive-care units equipped to monitor pulmonary artery and pulmonary venous (wedge) pressure and cardiac output. These observations often are necessary to evaluate accurately left ventricular performance and the state of the intravascular volume and to supplement the critically important clinical assessments of cerebral, cardiac, and renal functions-namely, the patient's level of consciousness, blood pressure, and urine output. Sometimes too much attention and effort are focused on the PaO2 as an island of information while other important determinants of cellular oxygen supply (hemoglobin concentration, arterial oxygen saturation, arterial oxygen content, and cardiac output) and indicators of the adequacy of that delivery (mixed venous oxygen tension and saturation and the arterialvenous 02 difference) are ignored. In general, PEEP-induced reduction of cardiac output by decrease of venous return to the right heart is seen most commonly in hypovolemic patients. However, the indiscriminate infusion of blood, plasma, albumin, or saline solution without careful attention to the pulmonary artery and wedge pressures may cause iatrogenic worsening of oxygen transfer. Recently, high levels of PEEP, in excess of the conventional upper limit of 15 cm. H20, i.e., to 25 or even 45 cm. H20, have been used to interrupt the vicious circle produced by ever-increasing F102. The use of these high pressures has been complicated by pneumothorax in 15% of patients, but cardiac output did not fall when intravascular volume was adequate.7 Ideally, before the vicious circle is reached, and certainly after its development, the following measures should be undertaken and frequently reviewed to increase the availability of oxygen to the cells: 1) To increase PaO2 consider: a) Reducing extravascular lung water with diuretics as discussed above. b) Increasing alveolar ventilation. This usually is of very limited value, but the setting of minute volume to maintain the arterial carbon dioxide tension (PaCO2) at 30 to 35 mm. Hg rather than 45 to 50 mm. Hg may produce a small rise in PaO2 in the critical range. c) Administering corticosteroids in high doses. The use of these drugs is controversial. Their proponents suggest that they improve the pulmonary microcirculation and decrease infiltration and edema, thereby improving the transfer of oxygen. Usually they are Vol. 53, No. 6, July-August 1977
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best avoided in patients with pulmonary failure caused by infection. 2) To increase arterial oxygen content in anemic patients, transfuse packed red cells or whole blood, if volume considerations permit, to near normal hemoglobin ranges. Physicians often overlook this important means of maintaining tissue oxygenation when only marginal PaO2 can be attained safely. Fresh blood provides better oxygen transport, and efficient filters prevent infused cell fragments and other debris from doing further injury to the lung. 3) To improve cardiac output: a) Increase or decrease fluids according to the pressure and the clinical monitoring indices discussed above. b) Use cardiotonic drugs when left ventricular failure is present, and vasopressors when shock or hypotension are refractory to more basic measures. c) Adjust PEEP as discussed above. 4) To decrease utilization of oxygen consider reducing body temperature, especially in highly febrile patients, by drugs or hypothermic blanket. In extreme instances of catastrophic pulmonary failure, when all therapeutic attempts have failed and when irreparable pulmonary oxygen toxicity appears inevitable, consideration can be given to two special techniques which have had limited clinical trials. In the first method, an extracorporeal support system, part of the cardiac output is drained continuously from a catheter in a femoral vein into a membrane oxygenator and returned by a pump to a catheter in a large artery. The oxygen thus supplied to the blood theoretically allows reduction of the inspired oxygen to a nontoxic level. The other method is hyperbaric oxygenation in a chamber. This technique has a short-lived utilization period as the risk of oxygen toxicity is compounded by the use of high pressures. Unless the patient is close to recovery from the underlying disease and requires only a very short period of support, exposure to extremely high tensions of inspired oxygen appears to be self-defeating. The following case of catastrophic pulmonary failure illustrates the clinical manifestations and problems under discussion. A 58-year-old black woman was hospitalized because of myalgias, cough, dyspnea, and fever of two-weeks' duration. On arrival at another hospital she was acutely ill but alert. Her blood pressure was 90/60 mm. Hg, pulse rate 115/min., respiratory frequency 60/min., and temperature 41'C. Bilateral rales were Bull. N. Y. Acad. Med.
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Fig. 4. Chest x ray of a 58-year-old woman with catastrophic pulmonary failure showing bilateral basilar interstitial and alveolar infiltrations at time of admission.
heard. The leukocyte count was 6,000/mm.3 and the hematocrit 33%. Gram stains and acid-fast stains of the sputum were negative. The intermediate tuberculin test was negative also. Initially, 35% oxygen by mask provided an arterial oxygen tension of 65 mm. Hg. The presumptive diagnosis was viral or other pneumonia; therapy was started with penicillin and aspirin. During the next two days there was clinical deterioration and progressive hypoxemia despite increases in inspired oxygen concentration. Cardiorespiratory arrest occurred on the third day. After resuscitation, the arterial oxygen tension was only 34 mm. Hg, with an inspired oxygen concentration of 40% delivered by a volume-cycled respirator. Consequently the inspired oxygen concentration was increased to 60% and PEEP of 10 cm. water was applied. The arterial oxygen tension increased temporarily to 76 mm. Hg, but over the course of the next day it fell; coma and shock developed. The concentration of Vol. 53, No. 6, July-August 1977
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Fig. 5. Chest x ray of same woman as in Figure 4 four days later, showing all zones of the lung involved with a dense alveolar and interstitial infiltrate which produced a "white lung" pattern.
inspired oxygen was increased to 100% prior to transfer of the patient to the New York Hospital for consideration of treatment with an extracorporeal membrane oxygenator system. The initial roentgenogram of the chest showed a modest degree of bilateral basilar infiltration compatible with viral or other interstitial pneumonia (Figure 4). At the time of transfer all zones of the lung were involved with a dense alveolar and interstitial infiltrate which produced a "white lung" pattern (Figure 5). The blood pressure was 100/60 mm. Hg, the pulse 110/min., and temperature 39°. Monitored parameters did not indicate left ventricular failure or hypervolemia. With inspired oxygen concentration at 80%, the arterial oxygen tension was 39 mm. Hg and the arterial oxygen saturation was 75%. Arterial carbon dioxide tension was maintained at approximately 30 mm.
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Hg. Packed red cell transfusions were given and these raised the hematocrit value to 40%. Arterial oxygen tension, saturation, and content, thus, were considered adequate. However, the presence of shock, resistance to treatment, and the approaching point of no return in terms of the danger of oxygen toxicity prompted use of the extracorporeal membrane oxygenator. This allowed reduction of the inspired oxygen concentration to 50%, corrected shock, and provided six days for the underlying condition to be reversed. However, this did not occur, and the patient died on the 13th hospital day. The findings anticipated at autopsy were those of unresolved viral pneumonia, with some degree of organization and fibrosis based on the duration of the illness. In fact, however, the surprising and saddening finding was diffuse involvement of all lung fields by miliary tuberculosis. There were no signs of oxygen toxicity. This case adds miliary tuberculosis to the long list of disorders that may cause catastrophic pulmonary failure and emphasizes the need for specific diagnosis and consideration of lung biopsy in all patients.8 Current criteria for use of the extracorporeal support system are: 1) The presence of an acute, reversible underlying disorder 2) Inadequate tissue oxygenation despite all conventional measures 3) Toxic concentrations of inspired oxygen in use for less than 72 hours 4) No hemorrhagic disorder and no chronic disease with short expected survival The therapeutic technique includes surgical cannulation of the inferior vena cava in order to drain blood by gravity to flow through two or more membrane oxygenators, each with a surface area of three square meters, connected in parallel. The fully saturated blood then is conducted to a pump and returned to the patient by means of a cannula placed in the subclavian artery (and sometimes also the femoral artery) to complete the venoarterial circuit. The method has proved safe; the required total body heparinization has been manageable. Neither platelet consumption nor hemolysis causes difficulty. The availability of pumps which are safe and relatively simple to operate has permitted treatment of these patients in a medical-pulmonary intensive-care unit without the requirement of specially trained pump technicians. Future development of still more efficient pumps with higher flow capability can be expected to improve the technique additionally. Experience with extracorporeal systems such as this for long-term support of patients with catastrophic pulmonary failure is limited and the
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salvage rate up to now has been extremely low. The present high level of enthusiasm and interest in the procedure will undoubtedly lead to increased use of the method. However, the critical question to be answered is: in how many patients will the treatment be shown to be both necessary and successful? It is our present belief that with steadily improved early care the role of this technique in the treatment of catastrophic pulmonary failure will remain small.
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REFERENCES Briscoe, W. A., Smith, J. P., Ber- 5. Bergofsky, E. H.: Pulmonary insufficiency after nonthoracic trauma: Shock gofsky, E., and King, T. K. C.: lung. Am. J. Med. Sci. 264:93, 1972. Catastrophic pulmonary failure. Am. J. 6. King, T. K. C., Weber, B., Okinaka, Med. 60:248, 1976. A., Friedman, S. A., Smith, J. P., Ashbaugh, D. G., Bigelow, D. B., and Briscoe, W. A.: Oxygen transfer Petty, T. C., and Levine, B. E.: in catastrophic respiratory failure. Acute respiratory distress in adults. Chest 65:40S-44S, 1974. Lancet2:319, 1967. Moore, F. D., Lyons, J. H., Pierce. 7. Kirby, R. R., Downs, J. B., Civetta, J. M., Modell, J. H., Dannemiller, F. E. C., Morgan, A. P., Drinker, P. J., Klein, E. F., and Hodges, M.: A., MacArthur, J. D., and Dammin, High level positive end expiratory G. J.: Post-traumatic pulmonary insufpressure (PEEP) in acute respiratory ficiency. Philadelphia, Saunders. insufficiency. Chest 67:156, 1975. 1969. Veith, F. J., Panossian, A., Nehisen, 8. Homan, W., Harman, E., Braun, N. M. T., Felton, C. P., King, T. K. C., S. L., Wilson, J. W., and Hagstrom, and Smith, J. P.: Miliary tuberculosis J. W. C.: A pattern of pulmonary vaspresenting as acute respiratory failure: cular reactivity in the pathogenesis of Treatment by membrane oxygenator post-traumatic pulmonary insuffiand ventricle pump. Chest 67:366, ciency. J. Trauma 8:788, 1968. 1975.
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