Extracorporeal Membrane Oxygenation for Fulminant Influenza Pneumonia

Extracorporeal Membrane Oxygenation for Fulminant Influenza Pneumonia* Edward A. Lefrak, M.D.; Paul M. Stevens, M.D.; /an Pitha, M.D.; Edward Balsinger, B.A.; George P. Noon, M.D., F.C.C.P.; and Heather D. Mayor, D.Sc., Ph.D. A 48-year-old healthy man developed diffuse pneumonia with refractory hypoxemia. Sputum cultures were negative for bacterial pathogens. Myxovirus particles were demonstrated by electronmicroscopy in the tracheal aspirate reftecting the high lafectivlty titer of the sputum. Positive end-expiratory pressure ventilation and ten days of extracorporeal membrane oxygenation were utitized to maintain the inspired oxygen concentration

The clinical course of bronchopulmonary infection produced by the influenza virus has been shown to span a wide spectrum between mild bronchiolitis and fulminant pneumonia. 1 Though the fatal form of this disorder has occurred most frequently in elderly patients or in those who were debilitated by For editorial comment, see page 343

an underlying disorder, death also has ensued in individuals who were healthy prior to the onset of the acute. respiratory illness. 2 The cause of death often has been profound hypoxemia that became unresponsive to standard modes of supportive therapy including positive end-expiratory pressure ventilation.a.5 Prolonged extracorporeal membrane lung assistance has been suggested as a mode of providing oxygenation for these patients without the risk of inducing oxygen toxicity to the lungs, thus furnishing additional time for recovery of pulmonary function to occur. 6 This supposition was based on the premise that the lung disease was potentially reversible. The clinical problem is that definitions of "reversibility" have not been delineated and thus it has remained impossible to select objectively which patients would be the most appropriate candidates for longterm extracorporeal support. This report describes a patient with severe influenza pneumonia and documents a degree of lung damage which was not reversible despite ten days of support with an extracorporeal membrane oxygenator. °From the Cora and Webb Mading Deparbnent of Surgery and the Departments of Medicine and Microbiology. Baylor College of Medicine, and The Methodist Hospital, Houston. Supported in part by research Grant no. GM 1965 04 from the U.S. Public Health Service and National Heart and Lung Institute Academic Award Grant no. HL 70078 and General Clinical Research Center Grant no. RR 00350. Manuscript received March 1; revision accepted April 24. Reprint requests: Dr. Le(rak, Baylor Col16ge of Medicifle, Homton 77025

CHEST, 66: 4, OCTOBER, 1974

at 70 percent or less in an eftort to prevent oxygen-induced hmg damage. Despite these therapeutic and snpportive measures, prognedve polmonuy fibrosis eDSDed preclndlng the patie~t's llli'VivaL This Calle demonstrated that the pulmonary parenc:hymal change produced by fulminant inftnenza pneumonia may not be revenlble even during prolonged maintenance of adeqnate arterial oxygen tension with an extracorporeal oxygenator.

A 48-year-old man was transferred to The Methodist Hospital on January 20, 1972 for consideration as a candidate for extracorporeal membrane oxygenation because of refractory hypoxemia secondary to diffuse bilateral pneumonia. He had been in excellent health until the previous week when he developed a dry cough, frontal headache, myalgia, and a temperature of 38.5•C. He was treated at home with bedrest, aspirin, oral fluids, and tetracycline. Two days after the onset of symptoms, he was admitted to another hospital because of persistent cough, dyspnea, fever, and mild dehydration. His blood pressure was 125/80 mm Hg. The pulse rate was 125, respirations 26, and temperature 39.5•C. Auscultation of the chest revealed diffuse rales, but the remainder of the physical examination was not remarkable. The chest roentgenogram showed a pattern of minimal diffuse interstitial infiltration. Sputum cultures for bacteria grew only a small number of alpha and gamma streptococci while blood and urine were sterile. The following day there was diffuse radiologic infiltration associated with severe respiratory distress. Despite an inspired oxygen concentration of 40 percent, the arterial PO! was only 50 mm Hg. The P002 was 36 mm Hg. Tissue culture of the sputum was positive for A2/Hong Kong influenza virus. Treatment with amantadine and cephalothin were instituted. During the next three days, the degree of pulmonary infiltration increased and the level of consciousness became depressed. The arterial blood pressure and urine output were maintained with the intermittent use of intravenous ispProterenol and furosemide. Controlled ventilation with 5 em H20 end-expiratory pressure and 60 percent oxygen resulted in transient improvement in the arterial oxygen tension to 60 mmHg. On the fifth hospital day, the arterial P02 was 38 mm Hg in spite of ventilation with 100 percent oxygen. With 15 em H20 of positive end-expiratory pressure, the Pa02 improved to 65 mm Hg, but it consequently fell to 45 mm Hg in the next two hours. In view of the refractory hypoxemia and deteriorating hemodynamic, neurologic, and renal status, he was transferred to The Methodist Hospital for extracorporeal membrane oxygenator support. At the time of admission to the hospital, the blood pressure was 100/60, pulse 120, and the temperature 39.5•C. The patient was obtunded, but there were no clinical or electro-

EXTRACORPOREAL MEMBRANE OXYGENAnON FOR PNEUMONIA 385

A

B Extntorponol PuiiP Flow tclalnt

DAYS

FiGURE 3. Parameters of oxygen transport (the number of days refers to the duration of treatment after the patient

was transferred to the Methodist Hospital).

c

0

FIGURE 1. Chest x-ray films (for details see text). encephalographic signs of localizing neurologic damage. The chest roentgenograms showed diffuse bilateral confluent infiltrates ( Fig IA). The electrocardiogram was normal. A specimen of tracheal aspirate was negatively stained with 2 percent phosphotungstic acid for electron microscopic examination. Typical spherical myxovirus-like particles with surface spikes were found ( Fig 2). The particle count was 108 per mi. Sputum, blood, and urine cultures were negative for bacterial pathogens. Using a balloon-tipped flow directed catheter, it was ~ ~rmined that the central venous pressure was 8 mm Hg, the right ventricular pressure 20/5 mm Hg, and the pulmonary artery pressme 20/10 mm Hg, and the pulmonary capillary

FIGURE 2. (A) Myxovirus-like particles noted in the tracheal aspirate ( X50,000). The surface spikes were well preserved in those particles obtained by direct tracheal aspiration ( B, C), but they were not as easily discernible in the pharyngeal washing sample ( D) ( X80,000).

386 LEFRAK ET AL

wedge pressure 5 mm Hg. The arteriovenous oxygen difference was 4.5 vol percent. During the subsequent two hours, an intravenous drip of levarterenol ( 4 ~tg/min) was required to maintain the systolic arterial blood pressure between 90 and 110 mm Hg. Despite 20 em H20 of positive end-expiratory pressure ventilation with 100 percent oxygen, the arterial P02 was only 48 mm Hg. The P002 was 39 mm Hg. Extracorporeal membrane oxygenation was instituted to avoid the prolonged use of 100 percent oxygen and to provide supplemental oxygenation. A venovenous cannulation circuit was utilized to obtain extracorporeal blood flow rate of 2.5 L/min through the membrane oxygenator system. There was an immediate increase in the arterial P02 to 90 mm Hg in spite of a decrease in the inspired oxygen concentration from 100 to 60 percent (Fig 3). Following 24 hours of extracorporeal membrane oxygenation, there was marked radiographic clearing of the pulmonary infiltrates (Fig 1B). This change was accompanied by a rise in the radial arterial P02 to 110 mm Hg during ventilation with 60 percent oxygen and cessation of extracorporeal membrane oxygenation. The calculated intrapulmonic shunt fraction decreased from 56 to 16 percent. During temporary ventilation with 100 percent oxygen, the arterial P02 was 327 mm Hg. At this time, extracorporeal membrane lung support was discontinued and the venous cannulae were removed. Twelve hours later, the chest roentgenogram revealed recurrence of the bilateral confluent pulmonary infiltrates (Fig 1C). The Pa02 fell to 45 mm Hg during ventilation with 60 percent oxygen and the use of 15 em H20 of positive end-expiratory pressure (Fig 3). The intrapulmonic shunt increased to 60 percent of total pulmonary blood flow. Extracorporeal membrane oxygenation was reinstituted. During the subsequent nine days, the arterial P02 was maintained above 60 mm Hg using an extracorporeal flow rate of 3.8-5.0 L/min, an inspired oxygen concentration of 60~70 percent, and 5 em H20 positive end-expiratory pressure ventilation. Oxygen delivery by the membrane oxygenator was 150-300 ml/min. Thrombocytopenia was the only direct complication of the extracorporeal circuit. The plasma hemoglobin remained below 15 mg percent and repeat blood cultures were negative for bacteria. There was further deterioration in the patient's level of consciousness, but no associated focal electroencephalographic abnormalities were observed. The daily chest radiographs revealed an unchanging pattern of diffuse bilateral pulmonary infiltration (Fig 1D) and on the tenth

CHEST, 66: 4, OCTOBER, 1974

FIGURE 4A (upper). Diffuse consolidation of the lung ( X5), (bar = 1 em). FIGURE 4B ( lower). Proliferation of fibroblasts, thickened alveolar septa, hyperplasia and pleomorphism of the alveolar epithelium ( X450). day of membrane oxygenator support, cardiac arrest and death occurred. Postmortem Examination of the Lungs

The lungs were consolidated and did not collapse when the pleurae were incised. The right lung weighed 1425 gm and the left lung weighed 1140 gm. The cut surface of the pulmonary parenchyma appeared coarsened and ..consolidated" suggesting the presence of interstitial fibrosis ( Fig 4A). Microscopic examination of this tissue showed markedly thickened alveolar septa which were compressing the alveoli into narrow irregular slits ( Fig 4B). The widened septa contained prominent fibroblasts, collagen fibers, and structureless material representing edema Huid. There were very few inHammatory cells in the interstitial space and hyaline membranes lined many of the alveoli and respiratory bronchioli. Electronmicroscopy revealed bundles of collagen fibers with large amounts of endoplasmic reticulum and Golgi complexes within the fibroblasts indicating the presence of active collagen production. DISCUSSION

Extracorporeal membrane oxygenation has been employed to gain additional time for recovery to occur in patients with severe hypoxemia secondary to pneumonia, fat emboli, and the "post-traumatic shock-lung syndrome."7 Although a few patients appear to have been helped by this technique, most patients who were assisted with membrane oxyCHEST, 66: 4, OCTOBER, 1974

genators have died due to associated illness or because their lungs did not recover sufficient function to maintain life. A recent literature review revealed that only 6 of the 41 patients who have been supported by a membrane oxygenator for acute respiratory failure survived to leave the hospital, yielding a salvage rate of 15 percent. 7 These clinical results suggest that current concepts of "reversible lung disease" may be erroneous and that a more complete understanding of the natural history of acute pulmonary disease processes is necessary for selection of the most appropriate type of respiratory therapy available. The clinical course and pathologic findings of the patient described in this report provide this type of information for severe influenza pneumonia in a previously healthy adult. The viral infection described was so extensive that virus particles were seen by electronmicroscopic examination of the patient's sputum. The clinical course thereafter was one of progressive deterioration interrupted by two transient episodes of improved oxygenation, the first following continuous positive pressure ventilation and the second, after 24 hours of extracorporeal membrane oxygenation. Since the improvement in oxygenation is often outstanding with continuous positive pressure ventilation, this mode of respiratory therapy always should be tried prior to institution of extracorporeal membrane oxygenation unless obvious contraindications exist. Marked improvement in arterial oxygen tension without significant increase of the arteriovenous oxygen content difference imparts a good prognosis and may preclude the need for membrane oxygenator support.9 In our patient, there was an initial increase of the arterial P02 with continuous positive pressure ventilation; however, the hypoxemia recurred and could not be overcome with up to 20 em H20 of positive end-expiratory pressure. This profound degree of respiratory failure fulfilled our current operational definition of refractory hypoxemia and thus served as the indication for extracorporeal membrane oxygenator support. The clearing of the chest roentgenogram and decrease in the degree of intrapulmonic shunting recorded after 24 hours of membrane oxygenation suggested that at least a portion of the lung disease was still reversible. It is possible that part of the pulmonary dysfunction immediately prior to use of the membrane oxygenator was due to short-term exposure to 100 percent oxygen and secondary pulmonary edema and that lowering the inspired oxygen concentration to 60 percent during membrane oxygenation contributed to the decrease in lung infiltration and pulmonary shunt fraction. 10•11 However, the subsequent deterioration in spite of an inspired oxygen concentration of less than 70 percent most

EXTRACORPOREAL MEMBRANE OXYGENATION FOR PNEUMONIA 387

likely reflected the effects of the initial insul'f"to the.;. lung parenchyma. These data demonstrated that in this patient with fulminant influenza pneumonia, progressive pulmonary fibrosis occurred precluding survival despite the use of extracorporeal membrane oxygenator support to improve systemic oxygenation and lower the inspired oxygen concentration. REFERENCES

1 Lindsay MI Jr, Hermann EC Jr, Morrow GW Jr, et al: Hong Kong influenza: Clinical, microbiologic, and pathologic features in 127 cases. JAMA 214:1825-1832, 1970 2 Oseasohn R, Adelson L, Kaji M: Clinicopathologic study of thirty-three fatal cases of Asian influenza. N Engl J Med 260:509-518, 1959 3 Burk RF, Schaffner W, Koenig MG: Severe influenza virus pneumonia in the pandemic of 1968-1969. Arch Intern Med 127:1222-1128, 1971 4 Masterson J: Respiratory complications of epidemic influenza. J Irish Med Assoc 62:37-40, 1969

5 Noble RL, Lillington GA, Kempson RL: Fatal diffuse influenza pneumonia: premortem diagnosis by lung biopsy. Chest 63:644-646, 1973 6 Hill JE, Fallat RJ, Leva! MR, et al: Prolonged extracorporeal oxygenation: Some special problems. Mt Sinai J Med 40:199-206, 1973 7 Lefrak EA, Stevens PM, Noon GP, et al: Current status of prolonged extracorporeal membrane oxygenation for acute respiratory failure. Otest 63:773-82, 1973 8 Leftwich EI, Witorsch RJ, Witorsch P: Positive endexpiratory pressure in refractory hypoxemia: A critical evaluation. Ann Intern Med 79:187-193, 1973 9 Nicotra MB, Stevens PM, Viroslav J, et al: Physiologic evaluation of positive end-expiratory pressure ventilation. Chest 64:10-15, 1973 10 Hyde RW, Rawson AJ: Unintentional iatrogenic oxygen pneumonitis-response to therapy. Ann Intern Med 71: 517-531, 1969 11 Kapanci Y, Tosco R, Eggennann J, et al: Oxygen pneumonitis in man: Light and electron-microscopic morphometric studies. Chest 62:162-169, 1972

Modern Architecture There is now a general body of theory and practice that constitutes a Modern style which is rapidly becoming as clearly defined as the Greek style or the Gothic style is. It is a legitimate prerogative of society to evaluate modern architecture as a practical as well as an esthetic achievement. When Le Corbusier said, in 1927, "The house is a machine for living in," he was simplifying for the sake of his point. Yet the perennial popularity of his dictum proves that people want to judge architecture on the basis of sheer performance. We have indeed come to expect from modern buildings the same degree of functional efficiency that we get from our automobiles and refrigerators. As a matter of fact, it is remarkable

388 LEFRAK ET AL

how well modern architecture measures up to this test. In almost every type of building-office, factory, dam, school, hospital, stadium-modem architecture judged solely on performance, works. Architecture has now scraped itself clean of the encrustations of the past. It has rediscovered the inherent beauty of materials. It has learned that architecture is more a question of sculpture than of draftsmanship and that space is the secret of design. It now knows that space between buildings is as important as the space within them. Peter J: Masters of Modern Architecture. New York, Bonanza, 1958

CHEST, 66: 4, OCTOBER, 1974