The Lancet - Saturday 12 August 1967 ACUTE RESPIRATORY DISTRESS IN ADULTS Davo G, Astmavon ‘M.D. Ohio State D. Bop Bictow MD. Colorado "TUNIRCULOSIS ASSOCIATION FELLOW IN PULMONARY BISLASE ‘Tuomas L. Perry ‘M.D. Colorado Benxanp E. Levine ‘MD. Michigan From the Departments of Surgery and Medicine, University of Colorado Medical Center, Denver, Colorado, U.S.A. ‘The respiratory-distress syndrome in 12 Sao patients was manifested by acute onset of tachypnea, hypoxemia, and loss of compliance after a variety of stimuli; the syndrome did not respond to usual and ordinary methods of respiratory therapy. The clinical and pathological features closely resembled those seen in {infants with respiratory distress and to conditions in congsstive atelectasis and postperfusion lung. ‘The theoretical relationship of this syndrome to alveolar “surface active agent is postulated. Positive end-expiratory Pressure was most helpful in combating atelectasis and hypoxemia, Corticosteroids appeared to have value in the ‘treatment of patients with fat-embolism and possibly viral pacumonia, Introduction In the course of clinical and laboratory observations on | 272 adult patients receiving respiratory support, a few Patients did not respond to usual methods of therapy. ‘They exhibited a clinical, physiological, and pathological course of events that was remarkably similar to the infantile respiratory distress syndrome (hyaline-membrane disease). Difficult cases of respiratory failure in con- | junction with prolonged cardiopulmonary bypass (Baer and Osborn 1960), with congestive atelectasis (Berry and Sanislow 1963), with viral pneumonia (Petersdorf et al. 1959), and with fat-embolism (Ashbaugh and Petty 1966) | have ‘been recorded; and in these cases the patho- physiology of the illness closely resembled the infantile | respiratory distress syndrome and findings in patients | described here. Patients AA similar patiern of acute respiratory distress was seen in | 12 patients. ‘The clinical pattern, which we will refer to as the | respiratory-distress syndrome, "includes severe dyspnea, | tachypnee, cyanosis that is refractory to oxygen therapy, loss " Freent eddrw: 609 Han Bil Suet, Phoeis, Arizona an of lung compliance, and diffuse alveolar infiltration seen on chest X-ray. ‘No patient had a previous history of respiratory failure. 1 patient gave a history of mild asthma since childhood but had no disability or recent attacks, Another patient had a chronic ‘cough that was attributed to cigarette smoking. The remaining 10 patients did not have any previous pulmonary disease. Severe trauma preceded respiratory distress in 7 patients (table 1), Vira infection in 4 patients and acute pancreatitis in 1 patient were precipitating factors in the remainder. Respira- tory distress occurred as early as one hour and as late as ‘inety-six hours after the precipitating illness or injury. Shock ff varying degree and duration was prescat in 5 patients and ‘excessive fluid administration occurred in 7 patients. 4 patients developed acidosis with pH less than 73 before the onset of respiratory distress. Methods All patients were admitted to intensive-care units of the surgical or medical services. Blood-gas studies were performed fon arterial blood drawn by percutancous puncture of cither brachial or femoral artery. In most instances, blood was drawn. only during steady state. Po, measurements were determined ‘with a Clark electrode and oxygen saturation was measured on Soe, Pombteenbutey cu se] tee Se oe ae fa | Emon “rushed chest Dros. ingest pean320 avausr 12, 1967 ORIGINAL ARTICLES ‘rm Lancet ‘anLa I—RESPRATORY DATA Pox Pies Comptance coe Reino peor Fregoney) ynimin) | Soy Pree) on | lem Emin mH en 1 | Real onven @ Lin © we 8 oie } | Retr reaner eat) 0% oe | Reo OR sais 3 | Bema rapancr (rat) (00% eryem | 8 = 2 | Hennes pence crass Goos eee | 3 $ | Exproca topentr Go" emacs S wo | 8 | Reser ee % ua | me coir $ | Oxygen man tind a * | Rm S a wo ot 9 | bene eit (a (80% onren » wo | ow oo te | xestonsenLinied s w 2 rm | oo 12 | Bennett epiator (F2.4) (40° or) ” ize 2 yoo | ba | oon Ya~ Bepeed volume Poe Pro, Pyoy diet Svoy~ Arterial onynen situation. Parl presure of carbon Soxide i seal blood “Surmenention gradient between inopred go ad arterial ood. | «ao: ‘ra and vo inate the made of Bennet respite. ‘a dual beam oximeter (American Optical Company). Hydrogen jon concentration was measured with an Astrup clectrode and P00, was determined by the Astrup tonometric method. Tidal volume was measured with a Wright respirometer. Central Yenous pressure was measured manometrically through polyethylene catheter in the superior vena cava. Compliance Mas estimated by dividing the tidal volume by the maximal Uuanstracheal pressure achieved during controlled or assisted ‘Ventilation in the relaxed or paralysed patient. Surface-tension ‘measurements were made on a modified Wilhelmy balance Using the technique described by Clements (1957). Specimens fof minced fresh lung were obtained at necropsy in 2 patients tnd measurements of surface tension were made within twelve hours. "Rouitine gross and light-microscopic examination of necropsy material were used for the astesiment of the pathological ‘changes in the 7 patients who died. Results ‘Table 1 shows the measurements made during acute respiratory distress. All but 2 patients were receiving respiratory support in the form of oxygen or a respirator when these measurements were made. Respiratory-rate was high in all patients except no. 9 who had total muscular paralysis. ‘The average rate of respiration for all patients was 42 per minute. Minute- ventilation, measured in 9 of the 12 patients, ranged from 8 to 48 litres per minute. ‘Hypoxia of arterial blood developed in every patient despite administration of oxygen or respiratory assistance. ‘Oxygen saturation ranged from 41%, in 1 patient breathing room air to 87% in a patient receiving 7 litres of nasal oxygen. Arterial hypoxemia was seen in 3 patients receiving 100% inspired oxygen. Patient 2 had a systemic blood-pressure of 65/40 mm. Hg when saturation was measured. The remainder had normal systemic blood~ pressure. ‘The gradient between inspired Po, and P,0; in 3 patients was 536, 320, and 220 mm. Hg. P,co, ranged from 22 to 63 mm. Hg. 4 patients had a P,co, above 45 mm. Hg and all were receiving assisted ‘ventilation at the time of measurement. ‘The remainder hhad low or normal values. Hydrogen-ion concentration was normal in most patients. The 3 patients (n0s. 2, 5, and 9) with P,co, values over 50 mm. Hg had a moderate degree of uncompensated respiratory acidosis. ‘Compliance values, as measured, reflect total compliance ina dynamic state. In all patients ventilation was assisted ‘or controlled by a respirator and measurements were made ‘when the patient was in a relaxed or steady state. Although ‘values obtained in this manner do not compare with values ‘obtained by methods for measuring static compliance, the ‘consistency of the data and the striking variation from identical measurements in patients with normal lungs indicate a high probability of significance and have been extremely valuable in following the course of this par- ticular illness, Compliance ranged from 0-009 to 0-019 2 ke Se et cueneeer eo (osama ts ere Weavaust 12, 1967 ORIGINAL ARTICLES 321 rm Fig. 2—Chest X-rays In four patients with respiratory-distrese ayadrome. (2) Case 1 (multiple trauma). (8) Case 3 (aremboism).. (@ Case 9 (viral pneumonia). (d) Case 8 (viral pneumonia. “The ssiking feature is the presence of bilsteral, symmetrical alveolar infiltrates. Films are portable, anterot-posterir, taken at 40 in. (16 em), litres per em, (normal in this laboratory is 0:050-0-125 litres per cm. water), ‘The minimum surface tension on specimens of minced Jung from patient 7 was 24 dynes per sq. cm. and on. patient 4 it was 21 dynes per sq. cm. (normal, less than 10 dynes per sq. em). Chest X-ray X-ray appearance of the chest closely paralleled the Fig. 3—Case 4: striking alveolar Seplllaries: (Hematoxylin stslectanls and tngorzemeat of “cad conin reduced to oot 450) clinical course (fig. 1). The earliest changes consisted of 1 patchy, bilateral alveolar infiltrate (fig. 1a). These find- ings were frequently confused with acute heart-failure and mild pulmonary cdema, When respiratory distress becomes more severe, the patchy infiltrates become more confluent (fig. 18) and before death, X-ray appearance was that of consolidation (fig. 1c). Clinical improvement was matched by X-ray improvement, and could be dramatic. The X-ray findings in patients with ‘trauma, fat-embolism, and viral pneumonia were highly consistent (fg. 2). Necropsy ‘At necropsy in 7 patients, gross inspection showed heavy and deep reddish-purple lungs, average weight was 1150 g. for the right lung and 960 g. for the left lung. On ccut section the appearance resembled liver tissue. Except for isolated patches, the lungs were non-crepitant; all ‘major pulmonary vessels were patent and free of thrombus ‘or embolus; the tracheobronchial tree was free of obstruction. ‘Microscopie appearance of the lungs was consistent in the 5 patients who died early in the course of the illness. ‘Striking features were hyperemia, dilated engorged capillaries, and areas of alveolar atelectasis (fig 3). Inter stitial and intra-alveolar hemorrhage and cedema were also ‘common (fig. 4). Alveolar macrophages were numerous. ‘A striking finding was the presence of hyaline membranes Fig. $—Case 6: hyaline membranes. (Hematoxylin and eotla, ‘educed te "y of X 400)322 avaust 12, 1967 (fig. 5) in all but 1 patient. Diffuse interstitial inflam- mation and fibrosis without notable hypersmia was present in 2 patients who died after a protracted course. Both patients had hyaline membranes. Therapeutic Trials Early lack of understanding of the pathophysiology involved led to the clinical trial of a variety of drugs, respirators, and fluid regimens—some were of doubtful value, while others seemed beneficial. Therapeutic Trials of Doubiful Value Digitalis was given to 10 patients before or during respiratory distress. Although fluid overload and acute heart-failure may have contributed to respiratory distress in 7 of these patients, digitalis had no noticeable effect on the course or outcome. ‘Ansibiotics,Patient 9 improved, but the concomitant ‘use of other treatment casts doubt on the role of the ‘antibiotics. 9 other patients did not respond to antibiotic, therapy, although they may have helped prevent sub- sequent infection in three of the surviving patients. TTolazoline hydrochloride was administered intravenously to 3 patients at a dosage of 1 mg. per kg. body-weight. Patient 9 seemed clinically improved but, again, other therapeutic measures were applied at the same time, 2 patients did not respond. lintermittent positive-pressure respiration.—Patient 9 was ventilated with an experimental volume-cycled respirator incorporating deep breath at regular intervals. Every two tutes the respirator delivered a deep breath that was double the patient's tidal volume. Recovery in this patient ‘may have been partly due to the respirator. The other 11 patients were initially managed on pressure-cycled respirators, which proved inadequate; they would not deliver adequate volumes at the high pressures required. Volume respirators were subsequently used in 7 patients: ventilation improved, but little change was seen in hypoxemia. Corticosteroids.—Patient 3 with fat-embolism, who had become comatose and increasingly cyanotic despite venti latory assistance and 100°,, oxygen, improved dramatically after intravenous corticosteroids. Respiratory assistance was terminated five days after starting corticosteroid therapy and the patient recovered. Patient 9 also improved with corticosteroids, but was receiving other therapy. ‘The remaining 7 patients did not benefit from cortico- steroids. Therapeutic Trials of Apparent Value Continuous positive-pressure respiration was used in the management of 5 patients. End-expiratory pressures ‘were maintained at 5-10 cm. water. All 5 patients demon strated a rise in Po, or oxygen saturation with the use of end-expiratory pressure. P,cO, rose slightly in response to the drop in minute-ventilation. Arterial blood-pressure and central venous pressure improved or remained stable. ‘Table tt demonstrates the effect of 7 cm. water of expiratory retard on minute-ventilation and arterial blood gases in patient 11. Recovery of respiratory function was complete in 3 patients; all 3 were injury cases, and recovery after con- tinuous positive-pressure respiration was rapid and Progressive, Clinical status, X-ray appearance, and blood- ‘gases improved at the same time. 1 patient died, cighteen_ hhours after injury, from shock and respiratory failure, “Massive hemorrhage from a ruptured spleen and lacerated. intercostal arteries required both thoracic and abdominal ce ORIGINAL ARTICLES ‘THe LANCET {ARLE In1—EFFECT OF POSITIVE END-EXPIRATORY PRESSURE IN PATIENT HT Pos mm Ha) Pos mm Serco, Pedy (me He) secoare (en He operations, Despite an initial improvement in arterial ‘oxygen saturation from 65 t0 90", with the use of Continuous positive-pressure ventilation, the patient was ever successfully resuscitated and died in refractory Shock, acidosis, and respiratory failure. ‘The second patient survived cleven days after drug ingestion and Possible viral pneumonia. Arterial oxygen saturation could ‘be maintained above 90°, throughout this period only by the use of continuous positive-pressure ventilation, Ventilation without positive end-expiratory pressure resulted in immediate hypoxemia. ‘The patient sub- sequently died of overwhelming sepsis and acute inter- stitial pneumonia, ‘Only 2 of 7 patients not treated with continuous positive-pressure ventilation survived; and one of these Survivors was patient 3 who had responded dramatically to corticosteroids, ‘This apparent increase in survival following the use of continuous positive-pressure ventila- tion is uncertain with such a small number of patients, but may prove to be significant when more experience is gained. Discussion ‘The aetiology of this respiratory-distress. syndrome remains obscure. Despite a variety of physical and possibly biochemical insults the response of the hung was Similar in all 12 patients. In this small series of patients, it is impossible to assign a relative value to shock, fluid overload, acidosis, prior hypoxamia, trauma, aspiration, ‘and viral infection, Most patients had combinations of these insults in varying degrees of severity. Jenkins et al. (1950) described the syndrome of con- gestive atelectasis, and thought that fluid overload was the Sole causative agent. 5 patients could have had their ‘disease precipitated in this way, but in 7 others, fluids were kept at a minimum prior to development of the syndrome, ‘Acidosis and hypoxemia constrict pulmonary vasculature (Lloyd 1966) and are thought to play an important role in. the development of infantile respiratory-distress syndrome (Chu et al. 1965). 5 patients had periods of hypoxemia and acidosis before onset of respiratory distress. Many fother patients treated for severe hypoxemia and acidosis recover of die and never show any evidence of pulmonary response. "Moon (1948) found congestion and atclecasis in the tungs at necropsy of patients who had died from shock. ‘These findings in man have been corroborated, by Hardaway ct al, (1967). Jouasset-Strieder et al. (1966) found a decrease in pulmonary capillary blood-volume in dogs subjected to harmorthagie shock, while Eaton (1947) found, in dogs, acute pulmonary cedema and increased Iymphflow accompanied by laboured breathing and hypoxzmia, ‘These findings confirm but do not clarify the role of the lung in shock. While shock may be {precipitating factor i is not necessary for either in the velopment or the prolongation of respiratory distress.avoust 12, 1967 ORIGINAL ARTICLES THE LANCET 323, Correction of shock had no effect on respiratory distress in this series. Respiratory distress inpatients with severe fat~ embolism is well documented (Sproule et al. 1964, Ashbaugh and Petty 1966). Sevitt (1962) has described the pathological findings in the lungs and they are con- sistent with those in this series. Peltier (1957) has postulated that breakdown of neutral triglycerides into free fatty acids with resultant chemical pneumonitis is the mechanism for this particular form of the respiratory- distress syndrome. Petersdorf ct al. (1959) described the pulmonary lesions scen in patients who had died of Asian influenza and noted that they were similar to findings seen during the influenza cpidemic of the 1914-18 war. They found, as we did, heavy, and deep-red, lungs with cedematous congestion, alveolar nccrosis, and hyaline membranes. ‘Oxygen has been indicted as a possible cause of severe respiratory distress and death from respiratory failure (Nash et al, 1967). None of our patients had received high ancentrations of oxygen for prolonged periods before the set of respiratory distress. Oxygen toxicity is therefore, ‘likely to have been an etiologic agent in this series. In view of the similar response of the lung to a variety of stimuli, a common mechanism of injury may be postulated. ‘The loss of lung compliance, refractory cyanosis, and microscopic atelectasis point to alveolar instability as a likely source of trouble. ‘The inability to find obstruction in bronchioles or bronchi would tend to rule out the larger airways as a cause for rapidly decreasing compliance. Clements et al, (1958) described the theoretical con- siderations fora surface-active agent (surfactant). Several workers have described a decrease in surfactant in respiratory distress. in the newborn (Avery and Mead 1959) and postperfusion lung (Gardner et al. 1962). Others have postulated that the surface-active agent is produced in the granular pncumocyte (Klaus et al. 1962). 2 of our patients had decreased surface activity. ‘The inability to measure the surface-active agent directly isa serious obstacle in the effort to link this agent with clinical and pathological states. However, the theoretical basis for its presence is convincing, ‘measurements seem to indicate that its los with the development of the clinical, physiological, and pathological conditions seen in the 12 patients in this ‘The value of positive end-expiratory pressure was first noted in patient 5, and only then because it was tried as a last resort in a patient dying of acute respiratory failure. ‘The theoretical basis for positive end-expiratory pressure coincides with the theoretical basis for loss of lung com~ pliance. If surfactant is diminished, alveoli should collapse fon expiration when the end-expucatory pressure is at atmospheric levels. Collapsed alveoli require greater Bressurcs for reopening, this explaining the notable lose compliance. Positive end-expiratory pressure would theoretically prevent complete collapse and improve oxygenation by maintaining alveolar ventilation; and observations in 5 of ‘our paticnts support this hypothesis. Arterial oxygen saturation improved despite decrease in minute-ventila~ tion, In 3 patients, the alveolar arterial oxygen gradient also’ decreased. 3’ of 5 patients so treated survived, compared with 2 out of 7 not treated with positive cnd-expiratory pressure. “The use of positive end-expiratory pressure merely buys time: unless the underlying process can be successfully treated or reversed the prognosis is grave. In patients 8 and 11 the underlying illness could not be corrected. Despite improvement in blood-gases seen in patient 11 after positive end-expiratory pressure, the underlying lesion never cleared. In contrast, 3 patients survived massive chest trauma. All showed immediate improve ment after positive end-expiratory pressure, and a rapid reversal of the basic lesion. Taylor and Abrams (1966) have shown that contact with blood or plasma can inactivate surface activity in the alveoli. In patients with Jung trauma, this syndrome is probably precipitated by intra-alveolar hemorrhage. As this hemorthage i cleared, surface activity is restored and compliance returns to more normal levels. “The value of corticosteroids probably les in their anti- inflammatory antiedema effec. In our series, cortico- steroids were most useful in the management of 1 patient with fat-embolism and in 1 patient with Guillain-Barre paralysis, Schulz (1963) has shown that the granular pneumocyte may be damaged in fat-embolism; and this ‘ay explain the development ofthis syndrome in patients with fateembolism since this cll is thought to be the site of surfactant production. Corticosteroids are of questionable value in the treat= ment of patients who develop this syndrome after trauma. “The disease is of short duration in these patients provided they can be sustained during the critical period of respiratory distress. We thank Dr. T. N. "equess for eeprins shoud be addres to D. G. A. 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(1989) Pu Emvolim, Sproviy}ady J Les Gabere,P-A'L- 1968) Cox. mad 7.90, 120. anon Ft, Abra, ic Es 1008) oe 7 Med 9, 348 «To attempt to learn by lectures only is idle and un~ profitable ake ‘them as guides to direct your observation, your ‘your meditation; but to suppose that the ‘mere iSening wo Tecures should confer excellence would not be lest futile than for a traveller to bestride a guide-post and vainly expect that it should, without effort on his part, convey him to the destination to which it points."—Lancet, Nov. 5, 1825 p.213.