Saturday 12 August 1967

ACUTE RESPIRATORY DISTRESS of lung compliance, and diffuse alveolar infiltration seen on
chest X-ray.
IN ADULTS No patient had a previous history of respiratory failure.
DAVID G. ASHBAUGH 1 patient gave a history of mild asthma since childhood but had
M.D. Ohio State no disability or recent attacks. Another patient had a chronic
ASSISTANT PROFESSOR OF SURGERY cough that was attributed to cigarette smoking. The remaining
10 patients did not have any previous pulmonary disease.
D. BOYD BIGELOW
M.D. Colorado
Severe trauma preceded respiratory distress in 7 patients
ASSISTANT IN MEDICINE AND AMERICAN THORACIC SOCIETY-NATIONAL
(table i). Viral infection in 4 patients and acute pancreatitis in
1 patient were precipitating factors in the remainder. Respira-
TUBERCULOSIS ASSOCIATION FELLOW IN PULMONARY DISEASE
tory distress occurred as early as one hour and as late as
THOMAS L. PETTY ninety-six hours after the precipitating illness or injury. Shock
M.D. Colorado of varying degree and duration was present in 5 patients and
ASSISTANT PROFESSOR OF MEDICINE excessive fluid administration occurred in 7 patients. 4 patients
BERNARD E. LEVINE developed acidosis with pH less than 7-3 before the onset of
M.D. Michigan respiratory distress.
AMERICAN THORACIC SOCIETY-NATIONAL TUBERCULOSIS ASSOCIATION Methods
FELLOW IN PULMONARY DISEASE* All patients were admitted to intensive-care units of the
From the Departments of Surgery and Medicine, surgical or medical services. Blood-gas studies were performed
on arterial blood drawn by percutaneous puncture of either
University of Colorado Medical Center, Denver, Colorado, U.S.A.
brachial or femoral artery. In most instances, blood was drawn
The respiratory-distress syndrome in 12 only during a steady state. P a02 measurements were determined
Summary with a Clark electrode and oxygen saturation was measured on
patients was manifested by acute onset of
tachypnœa, hypoxæmia, and loss of compliance after a TABLE I-ACUTE RESPIRATORY DISTRESS
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
congestive 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
hypoxæmia. Corticosteroids appeared to have value in the
treatment of patients with fat-embolism and possibly viral
pneumonia.
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
A similar pattern of acute respiratory distress was seen in
12 patients. The clinical pattern, which we will refer to as the
respiratory-distress syndrome, includes severe dyspnoea,
tachypnoea, cyanosis that is refractory to oxygen therapy, loss
* Present address: 909 East Brill Street, Phoenix, Arizona.
7511
320

TABLE II-RESPIRATORY DATA

VE=Expired volume. Sa0a= Arterial oxygen saturation.

Paco. = Partial pressure of carbon dioxide in arterial blood.
PtO)—PaO, gradient Oxygen-tension gradient between inspired gas and arterial blood.
=

P.R.I. and vol. indicate the model of Bennett respirator.

a dual beam oximeter (American Optical Company). Hydrogen-
ion concentration was measured with an Astrup electrode and
p ac02 was determined by the Astrup tonometric method. Tidal
volume was measured with a Wright respirometer. Central
venous pressure was measured manometrically through a
polyethylene catheter in the superior vena cava. Compliance
was estimated by dividing the tidal volume by the maximal
transtracheal 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
of minced fresh lung were obtained at necropsy in 2 patients
and measurements of surface tension were made within twelve
hours.
Routine gross and light-microscopic examination of necropsy
material were used for the assessment of the pathological
changes in the 7 patients who died.
Results
Table n shows the measurements made during acute
respiratory distress. All but 2 patients were receiving
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 hypoxaemia 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 Po2 and Pa02 in
3 patients was 536, 320, and 220 mm. Hg.
PaC02 ranged from 22 to 63 mm. Hg. 4 patients had
a PaC02 above 45 mm. Hg and all were receiving assisted
ventilation at the time of measurement. The remainder
had low or normal values. Hydrogen-ion concentration
was normal in most patients. The 3 patients (nos. 2, 5,
and 9) with Paco2 values over 50 mm. Hg had a moderate
degree of uncompensated respiratory acidosis.
Compliance values, as measured, reflect total compliance
in a dynamic state. In all patients ventilation was assisted
or controlled by a respirator and measurements were made

respiratory support in the form of oxygen or a respirator when the patient was in a relaxed or steady.state. Although
when these measurements were made. values obtained in this manner do not compare with values
Respiratory-rate was high in all patients except no. 9 obtained by methods for measuring static compliance, the
who had total muscular paralysis. The average rate of consistency of the data and the striking variation from
respiration for all patients was 42 per minute. Minute- identical measurements in patients with normal lungs
ventilation, measured in 9 of the 12 patients, ranged from indicate a high probability of significance and have been
8 to 48 litres per minute. extremely valuable in following the course of this par-
Hypoxxmia of arterial blood developed in every patient ticular illness. Compliance ranged from 0-009 to 0-019

Fig. 1-Case 1 (multiple trauma): chest X-rays.

(a) 3 hours after injury. (b) 12 hours after injury. (c) 18 hours after injury.
 321

Fig. 2-Chest X-rays in four patients with respiratory-distress syndrome.

(a) Case 1 (multiple trauma). (b) Case 3 (fat-embolism). (c) Case 9 (viral pneumonia). (d) Case 8 (viral pneumonia).
The striking feature is the presence of bilateral, symmetrical alveolar infiltrates. Films are portable, anterior-posterior, taken at 40 in.
(16 cm.).
litres per cm. (normal in this laboratory is 0050-0 125 clinical course (fig. 1). The earliest changes consisted of
litres per cm. water). a patchy, bilateral alveolar infiltrate (fig. la). These find-
The minimum surface tension on specimens of minced ings were frequently confused with acute heart-failure and
lung from patient 7 was 24 dynes per sq. cm. and on mild pulmonary oedema. When respiratory distress
patient 4 it was 21 dynes per sq. cm. (normal, less than becomes more severe, the patchy infiltrates become
10 dynes per sq. cm.). more confluent (fig. lb) and before death, X-ray
Chest X-ray appearance was that of consolidation (fig. Ic). Clinical
X-ray appearance of the chest closely paralleled the 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 (fig. 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
cut 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.
Microscopic appearance of the lungs was consistent in
the 5 patients who died early in the course of the illness.
Striking features were hyperxmia, dilated engorged
capillaries, and areas of alveolar atelectasis (fig. 3). Inter-
Fig. 3-Case 4: striking alveolar atelectasis and engorgement of stitial and intra-alveolar haemorrhage and oedema were also
capillaries. (Haematoxylui and eosin reduced to ’/, of x 450.) common (fig. 4). Alveolar macrophages were numerous.
A striking finding was the presence of hyaline membranes

Fig. 4-Case 1: intra-alveolar hemorrhage and cedema. (Haema- Fig. 5-Case 6: hyaline membranes. (Haematoxylin and eosin,
toxylin and eosin, reduced to "I. of x 100.) reduced to "f. of x 400.)
322
(fig. 5)in all but 1 patient. Diffuse interstitial inflam-
mation and fibrosis without notable hyperaemia 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 Doubtful 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.
Antibiotics.-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.
Tolazoline 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.
Intermittent positive-pressure respiration.-Patient 9 was
ventilated with an experimental volume-cycled respirator
incorporating deep breath at regular intervals. Every two
minutes 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
hypoxaemia.
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 P a02 or oxygen saturation with the use of
end-expiratory pressure. PaC02 rose slightly in response
to the drop in minute-ventilation. Arterial blood-pressure
and central venous pressure improved or remained stable.
Table demonstrates the effect of 7 cm. water of
ill
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, eighteen
hours after injury, from shock and respiratory failure.
Massive hxmorrhage from a ruptured spleen and lacerated
intercostal arteries required both thoracic and abdominal
TABLE III-EFFECT OF POSITIVE END-EXPIRATORY PRESSURE IN PATIENT II
WITH VIRAL PNEUMONIA
operations. Despite an improvement in arterial
initial
oxygen saturation from 65 to 90% with the use of
continuous positive-pressure ventilation, the patient was
never successfully resuscitated and died in refractory
shock, acidosis, and respiratory failure. The second
patient survived eleven 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 hypoxaemia. 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 lung 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 hypoxaemia, 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 hypoxaemia 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 hypoxaemia
and acidosis before onset of respiratory distress. Many
other patients treated for severe hypoxsemia and acidosis
recover or die and never show any evidence of pulmonary
response.
Moon (1948) found congestion and atelectasis in the
lungs at necropsy of patients who had died from shock.
These findings in man have been corroborated by
Hardaway et al. (1967). Jouasset-Strieder et al. (1966)
found adecrease in pulmonary capillary blood-volume in
dogs subjected to haemorrhagic shock, while Eaton (1947)
found, in dogs, acute pulmonary oedema and increased
lymph-flow accompanied by laboured breathing and
hypoxsemia. These findings confirm but do not clarify
the role of the lung in shock. While shock may be
a precipitating factor, it is not necessary for either in the
development or the prolongation of respiratory distress.

Correction of shock had no effect on respiratory distress;
in this series.
Respiratory distress in patients with severe fat-
embolism is well documented (Sproule et al. 1964,,
Ashbaugh and Petty 1966). Sevitt (1962) has describedl
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 intoI
free fatty acids with resultant chemical pneumonitis is the
mechanism for this particular form of the respiratory-
distress syndrome.
Petersdorf et al. (1959) described the pulmonary lesions
seen in patients who had died of Asian influenza and noted
that they were similar to findings seen during the influenza
epidemic of the 1914-18 war. They found, as we did,
heavy, and deep-red, lungs with cedematous congestion,
alveolar necrosis, 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
concentrations of oxygen for prolonged periods before the
onset of respiratory distress. Oxygen toxicity is, therefore,
unlikely to have been an aetiologic 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 for a 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 pneumocyte (Klaus et al. 1962).
2 of our patients had decreased surface activity.
The inability to measure the surface-active agent
directly is a serious obstacle in the effort to link this agent
with clinical and pathological states. However, the
theoretical basis for its presence is convincing, and indirect
measurements seem to indicate that its loss is associated
with the development of the clinical, physiological, and
pathological conditions seen in the 12 patients in this
series.
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
on expiration when the end-expiratory pressure is at
atmospheric levels. Collapsed alveoli require greater
pressures for reopening, thus explaining the notable loss
of compliance.
Positive end-expiratory pressure would theoretically
prevent complete collapse and improve oxygenation by
maintaining alveolar ventilation; and observations in 5 of
our patients 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
end-expiratory pressure.
323
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
lung trauma, this syndrome is probably precipitated by
intra-alveolar haemorrhage. As this haemorrhage is cleared,
surface activity is restored and compliance returns to
more normal levels.
The value of corticosteroids probably lies in their anti-
inflammatory antioedema effect. 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
may explain the development of this syndrome in patients
with fat-embolism since this cell 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. Vincent who reviewed the pathological
material for us.
Requests for reprints should be addressed to D. G. A., Department
of Surgery, University of Colorado Medical Center, Denver,
Colorado 83220, U.S.A.
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"... To attempt to learn by lectures only is idle and un-
profitable ; take them as guides to direct your observation, your
reading, your meditation; but to suppose that the mere
listening to lectures should confer excellence would not be less
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.