N-Acetylcysteine Enhances Recovery
From Acute Lung Injury in Man*
A Randomized, Double-Blind, Placebo-Controlled
Clinical Study
Peter M. Suter, M.D., F.C.C.P.; Guido Domenighetti, M.D.;
Marie-Denise Schaller, M.D.; Marie-Christine Laverriere, M.D.;
Rudolf Ritz, M.D.; and Claude Perret, M.D., F.C.C.P.
Objective: To detennine the effects of intravenous N-
acetylcysteine (NAC) on the development of severe adult
respiratory distress syndrome (ARDS) and mortality rate
in patients with mild-to-moderate acute lung injury and
to analyze the duration of ventilatory support and Flo1
required as weD as the evolution of the lung injury score.
Setting: Three university hospital ICUs and one regional
ICU in Switzerland.
Patients: Sixty-one adult patients presenting with mild-
to-moderate acute lung injury and various predisposing
factors for ARDS received either NAC, 40 mglkgld, or
placebo intravenously for 3 days.
MetJIJUrements: Respiratory dysfunction was assessed
daily according to the need for mechanical ventilation
and Flo2 , the evolution of the lung injury score, and the
Pa0plo2 ratio. The cardiovascular state, liver function,
and kidney function were also monitored. Data were
collected at admission (day 0), during the Arst 3 days,
and on the day of discharge from the ICU.
Results: The NAC and placebo groups (32 and 29
patients, respectively) were comparable at ICU admis-
sion for severity of illness assessed by the simplined
acute physiology score (SAPS) (10.8::!:: 4.6 vs 10.9::!:: 4.8)
and lung injury score (LIS) (1.39::!:: 0.95 vs 1.11 ::!:: 1.08)
(mean::!:: SD). Three patients in each group developed
ARDS. The 1-month mortality rate was 22 percent for
the NAC group and 35 percent for the placebo group
A cute lung injury characterized by a high-perme-
ability, low-pressure pulmonary edema can de-
velop following a number of predisposing diseases
resulting in different degrees of respiratory insuffi-
ciency. Patients with mild-to-moderate injury could,
within this continuum, represent an interesting subset
to evaluate a therapeutic approach of lung dysfunc-
tion . 1-~ The pathogenesis of acute lung injury and its
severest form, the adult respiratory distress syndrome
(ARDS), involves a number of mechanisms and medi-
ators. u .fi Toxic oxygen radicals of intra-cellular as well
as extracellular origin seem to play an important
*From the Intensive Care Units of the Departme nts of Anesthesia
and Ml•dieine. Universitv Hospitals of Gt>neva (Drs. Suter and
Lawrrii•rt> ), Lausanne (Drs. SdHtller and Pe rret ), and Basel (Dr.
Hitz). and the Hegional Hospital "La Caritit," Locarno (Dr.
Donw nighetti) , Switzt> rland.
Manuscript received Januarv 7, 1993: rt'vision accepted May 27.
Rq1rint requests: Dr. Suter, Surgical 1CU, Hopital Cantonal
Uui r.;ersitaire, CH-1200 Genew 14, Srcit;:,er/mul
190
(difference not statistically significant). At admission, 22 of
32 patients (69 percent) in the NAC group were mechani-
cally ventilated compared with 22 of 29 (76 percent) in the
placebo group. At the end of the treatment period (day 3),
5 of 29 (17 percent) in the NAC group and 12 of 25 (48
percent) in the placebo group were stiU receiving ventila-
tory support (p = O.ol), 1be Flo2 was 0.37less than admis-
sion value (day O) in the NAC group, and 0.20 less in the
placebo group (p < 0.04); the oxygenation index (Pa0plo2)
improved significantly (p < 0.05) from day 0 to day 3 only in
the NAC-treated group. 1be LIS showed a significant
regression (p = 0.003) in the NAC-treated group during the
first 10 days of treatment: no change was observed in the
placebo group. No adverse effects were observed during
the treatment with NAC.
Conclusions: Intravenous NAC treatment during 72 h
improved systemic oxygenation and reduced the need
for ventilatory support in patients presenting with mild-
to-moderate acute lung injury subsequent to a variety of
underlying diseases. Development of ARDS and mortal-
ity were not reduced signincantly by this therapy.
(Chest 1994; 105:190-94)
ARDS =adult respiratory distress syndrome; GSH " ~lu­
tathione; ICU ,. intensive care unit; LIS =lung inJury
score; NAC = N-acetylcysteine; NS =not significant;
SAPS = simplified acute physiology score
role. 6 ·7 Oxygen metabolites such as superoxide anion
(0 2 ' ), hydrogen peroxide (Hp 2 ), hydroxyl radical
('OH), and hypochlorous acid (HOC!) cause increased
vascular permeability in endothelial cell monolayers,N
in isolated lungs, 9 -10 and in vivo . 11 In human ARDS,
increased oxidant activity has been observed in ex-
pired breath or in bronchoalveolar lavage (BAL)
fluid 1 2 - 1 ~ as well as in granulocytes and red blood
cells. 15 ·16 In addition, patients with ARDS seem to
have a marked deficiency of the tripeptide antioxidant
glutathione (GSH) in the extracellular epithelial lining
fluid of the lower respiratory tract. 17 Glutathione acts
as an antioxidant for Hp 2• 1N The GSH deficiency
observed in ARDS could favor oxidative stress, thus
allowing functional and/or morphologic damage in the
lower respiratory tract, including an overshooting
inflammatory reaction and epithelial and endothelial
lesions resulting in pulmonary edema. N-acetylcyste-
ine (NAC) is a GSH agonist,l 9 and previous studies
have demonstrated that NAC administration increases
Enhanced Recovery From Acute Lung Injury (Suter eta/)
GSH levels in red blood cells, granulocytes, and Respiratory dysfunction was assessed daily by the requirement
plasma of patients with ARDS.15.20 for mechanical ventilatory support, the Fio2 administered, and the
evolution of the lung injury score~! using its first three components
Increasing GSH levels in the early phases of acute
{chest radiograph, Pa01flo2 ratio, and respiratory system compli-
lung injury with NAC could reduce or limit the extent ance). The Flo1 was controlled during mechanical ventilation using
of epithelial and endothelial damage and improve the the built-in oxygen cell of the ventilator. In extubated and sponta-
clinical course. N-acetylcysteine has been used at high neously breathing patients, Flo1 was regulated by using a Ventimask
dosages in the treatment of paracetamol intoxication or a similar device. The Flo1 obtained was checked regularly with
and was well tolerated. 21 a paramagnetic oxygen sensor {Oxydig, Drager, LUbeck, Germany).
Mechanical ventilation was initiated and maintained at the
The purpose of the present study was to assess the discretion of the physician in charge of the patient. The standards
effects of NAC on the development of ARDS and for mechanical ventilatory support, oxygen therapy. weaning crite-
mortality in patients with mild-to-moderate acute lung ria, and other treatment modalities are applied quite uniformly in
injury associated with known risk factors predisposing the four ICUs participating in the trial. Clinical and biochemical
to ARDS. Other important end points, such as dura- assessment was done regularly. Cardiovascular state, central ner-
vous system, kidney, and liver function were monitored closely.
tion of ventilatory support, Flo2 requirements, and
The patients were randomized to receive either NAC, 40 mglkgl
the clinical course of respiratory function were iden- d, or placebo, administered as a continuous intravenous infusion
tified at the end of the investigation and analyzed. over the first 3 days after admission to the ICU. This dose and
duration of treatment were chosen according to previous work on
MATERIALS AND METHODS
NAC in ARDS 15 and in other abnormalities. Adose of 40 mglkg is
one order of magnitude higher than what is normally applied in
Subjects and Protocol regimens of chronic respiratory disease and yet one order lower
During a 12-month period, patients with risk factors known to than the dose for paracetamol intoxication. We believed that this
predispose to the development of ARDS (see below), and presenting dose could offer sufficient efficacy as a preventive therapy in ARDS
with mild-to-moderate acute lung injury, were included in the trial without exposing to drug toxicity.2 1 N-acetylcysteine and placebo
in the four participating intensive care units (ICUs) in Switzerland were packed in similar numbered vials allowing randomization and
(Geneva, Lausanne, Basel, Locamo). double-blind administration.
In order to collect patients with comparable lung dysfunction for Informed consent was obtained from the patient or, if this was
a pharmacologic treatment regimen, we used the expanded defini- not possible because of the clinical condition, from the next of kin.
tion suggested by Murray et al,12 and only considered patients The protocol was submitted to and approved by the committees for
presenting with an initial lung injury score (LIS) between 0.1 and ethics in human research of the university hospital of Basel,
2.5. Patients with cardiogenic pulmonary edema and/or chronic
heart failure were excluded on the basis of medical history, results
Table 1-C~ ofHrtienl Group., SAPS Seal.
of clinical examination, and the use of a pulmonary artery catheter
and l.Mng Injury ~ (US) at Admiaion to the ICU*
in all unclear situations. The following predisposing factors for the
Treatment Group N-acetylcysteine Placebo
development of ARDS were considered.23
Sepsls, defined as proposed by Bone, 24 was clinical evidence of No. of patients 32 29
infection, le, respiratory rate above 20 cycles/min or minute Sex, MIF MIS 2316
ventilation over 10 Umin if mechanically ventilated, heart rate Age,y 46.6±19.7 48.1±21.9
more than 90 beats/min, core or rectal temperature outside the range Rarige 16-76 16-78
of 35.5° to 38.0°C, a white blood cell count above 12,000 or below ~ risk factors (n)
4,000/j11 or 20 percent or more immature cells plus evidence of altered Multiple trauma 9 7
organ perfusion (le, acute change in mental status, Pa01flo2 less than Multiple trauma and 7 5
280, plasma lactate concentration greater than upper limit of normal, aspiration
and urine output below 0.5 nil/kg of body weight for at least 1 h). Sepsis 5 6
Multiple trauma included patients with multiple major fractures Sepsis and aspiration 1 3
(two or more major long bones or !instable pelvic fracture) associated
Aspiration 6 3
with trauma to another region of the body such as craniocerebral or
Near drowning 2 1
abdominal, requiring surgical intervention.
Necrotizing pancreatitis 1 1
Aspiration was defined as recent (during the previous 6 h)
Hemorrhagic shock 1 3
inhalation of gastric contents, documented by suctioning of gastric
Associated diseases and complications
material from the bronchial tree or by fiberoptic bronchoscopy
Coma 17 13
shOwing typical mucosal lesions.
Necrotizing pancreatitis was seen as severe abdominal pain,
Pulmonary infection 11 6
Shock 7 10
vomiting, increased serum amylase levels, circulatory shock, and a
Ranson score of 3 or above.15 Septicemia 8 9
Hemorrhagic shock was defined as requiring administration of Acute reDal failure 3 3
more than 20 U of blood within 24 h. Simplified acute physiology 10.8±4.60 10.9±4.80
Near drowning was defined as an immersion accident requiring score""
endotracheal intubation. us• 1.39±0.95 1.11±1.08
Patients younger than 16 years, pregnant wome.n, immunocom- Outcome
promised patients, and those with a severe lung injury {LIS > 2.5) 22 ICU ~y. days, 11.3±10.5 12.2±9.6
or cardiogenic pulmonary edema were excluded from this trial. mean.±SD
Data were callected at admission to the ICU {baseline), on the first Development of ARDS, n 3 3
3 days after admission, and on the day of discharge from the unit. Mortality rate, n (~) 7 (22) 10 (35)
Severity of illness was assessed by the simplified acute physiological
•Differences between the two patient groups are statistically not
score {SAPS). 26
significant.

CHEST I 105 I 1 I JANUARY, 1994 191

 -- •
Geneva, and Lausanm•.
80 NAC
Statistical Methods
0~
70 ~ PlacebO

- so
Initial homogeneity assessment of the two groups was performed
by I test and X' analysis. The before and after comparisons were U) 60
done with the sign test, the paired I test, and the Wilcoxon-Pratt
test depending on the distribution of the data. Between-group
cCl)
comparisons were performed with the X' test, the Student I test, ;::
ca
and the Wilcoxon-Man-Whitney fU test according to the distribu- CL 40

tion of the data. Data are presented as mean values :t standard
de,iations unless speeifled otherwise.
RESULTS
Characterization of Patients
A total of 61 patients (47 men and 14 women) were
recruited for the study (Table 1). All were considered
evaluable for data analysis. Thirty-two patients received
NAC and 29 received placebo. The two groups were well
matched for demographic characteristics on trial entry.
The SAPS for severity of disease26 was 10.8 :!:: 4.6 in the
NAC group and 10.9 :!:: 4.8 in the placebo group (x :!:: SD,
not significant [NS]). On admission, the lung injury
score 22 was 1.39 :!:: 0.95 in the NAC group, a value not
significantly different compared with the placebo group
of 1.11 :!:: 1.08. Risk factors and associated conditions
were similar in the two groups. Three patients in each
group developed severe lung injury (ARDS) defined as a
LIS above 2.5Y Seven of 32 patients (22 percent) in the
treatment group and 10 of 29 (3.5 percent) in the placebo
group died (NS). During the study. adverse events due to
NAC were not detected.
VentilatonJ Support, Flo 2 , Lung Function
Twenty-two patients in each group (69 percent in
the NAC and 76 percent in the placebo group)
required ventilatory support at ICU admission (day O);
at day 3, the percentage of patients receiving ventila-
tory support was significantly reduced in the treated
group from 69 to 17 percent (p = 0.01 ), whereas in the
placebo group this decrease (from 76 to 48 percent)
-
'tJ
Cl)
30
.!!
;:: 20
cCl)
> 10
0
Days
FIC:URE l. Percentage of patients requiring mechanical ventilatory
~upport in the N-ac<'tykysteine (NAC) and placebo group. Evolution
from days 0 (admission) through day 3 (end of NAC treatment). The
triangle identifies a significant difference between the two groups at
day 3 (p =0.01). The asterisks identifY a significant differen(-e in the
treated group on day 2 and 3 vs admission (day 0; p = 0.01).
the NAC group from 1.39 :!:: 0.95 to 0.67 :!:: 0.70,
p <0.01, between ICU admission and day 10. No
significant change was observed in the placebo group.
At ICU admission, the mean chest radiograph score
was higher in the NAC than in the placebo group
( 1.8 :!:: 1.1 vs 1.1 :!:: 1.1; p < 0.05). Up to day 3 this
score increased in the placebo group (p < 0.05), whereas
it did not change significantly in the NAC group up to
day 3, but decreased until the discharge from the ICU
(from 1.8 :!:: 1.1 at admission to 1.1 :!:: 1.1, p < 0.01).
DISCUSSION
Despite major improvements in patient care, ARDS
still remains a formidable clinical challenge and carries
400
- - - - - NAC

... d
was not significant, p = 0.01 between groups (Fig 1).
At day 0, there was no significant difference between
•·····• Placebo
**
the two groups \vith regard to Flo 2 administered. At
.
N
day 3, the Flo 2 was significantly decreased in the NAC
group (0.29 :!:: 0.09 vs 0.48 :!:: 0.24 at admission;
0
ir *
- 300
p < 0.01) whereas in the placebo group there was no
~ .. ·f I
significant decrease (0.35:!:: 0.11 vs 0.45:!:: 0.20). The
difference in Flo 2 between the two groups was signifi-
cant on day 3 (p < 0.05). The oxygenation index PaOj
--··· f
Flo 2 was similar at admission for both groups (25.5 :!:: 113
mm Hg in the NAC vs 248 :!:: 99 mm Hg in the 200 --------------------~,~~------.----
0 2 3 DISCHARGE
placebo group. NS) and increased significantly in the
Days
NAC group reaching 294 :!:: 99 mm Hg on day 3
(p<0.05). No significant change was noted in the FIGURE 2. Mean values:tSEM of PaOjFio, (hypoxemia index, 22)
at admission (day 0) through day 3 (end of N-acetylcysteine [NAC]
placebo group (Fig 2). There was no statistical differ- treatment) and the day of discharge from the ICU in treated and
ence in PaOJFio2 between the NAC- and placebo- placebo-treated patients. One ast<•risk indicates p < 0.05 vs day 0;
treated patients. The lung injury score decreased in two asterisks. p = 0.01 vs day 0.

192 Enhanced Recovery From Acute Lung Injury (Suter et at)

a high mortality rate. 27 Recent clinical studies suggest
that patients with ARDS undergo relevant oxidative
stress. 12- 14•16•19•28 Toxic oxygen products cause -cellular
and subcellular damage and activate epithelial cells,
macrophages, or endothelial cells. Oxygen radicals are
also recognized as mediators between primary and
secondary effectors, either directly or via cytokine
release (ie, tumor necrosis fa~tor) with subsequent
formation of reactive oxygen. 29 Thus, oxygen-free radi-
cals are important proinflammatmy agents and it seems
desirable to control their activity in states of overshooting
inflammation. Endogenous antioxidants and particularly
glutathione (GSH) normally constitute an effective
control of toxic oxygen. Glutathione is detected in high
concentrations in the extracellular epithelial lining fluid
of the lower respiratory tract of normal subjects30 and
could act as a first-time scavenger of toxic oxygen
intermediates and protect against lung cell damage and
injury. 18·31 Patients with severe acute lung injury of the
ARDS type have a marked decrease of GSH in epithelial
lining fluid, plasma, and blood cells. 1s. 17·20 Glutathione
depletion in plasma and granulocytes in ARDS is
reversible by NAC-mediated glutathione rescue. 20
The present trial examines the effects of NAC in
patients presenting with mild-to-moderate acute lung
injury. At ICU admission, our two groups were similar
for severity of illness and lung injury score. We were
unable to find a preventive effect of NAC on the
progression to ARDS. Survival had a tendency to be
higher in the NAC group. N-acetylcysteine may have
positive hemodynamic effects in critically ill patients,
ie, improvement in cardiac output, systemic oxygen
transport, and consumption. 15•32·33 The mechanisms
involved in these changes are not entirely clear. N-
acetylcysteine possibly restores the decreased activity
of endothelium-derived relaxing factor, 32 •34 thereby
improving microcirculation. The most interesting find-
ing of our study is the improvement seen in oxygen-
ation index and LIS, which are sensitive markers of the
severity of acute respiratory failure and prognosis.22·35
Fewer patients in the NAC group were receiving
mechanical ventilatory support at day 2 and 3 and this
group had a tendency to have a shorter ICU stay
(median 7 days vs 10 days for the placebo group).
In conclusion, the present study suggests that early
intravenous administration of NAC in patients with
mild-to-moderate acute lung injury improves pulmo-
nary gas exchange and may reduce the duration of
mechanical ventilatory support. Ho~ever, the number
of patients included is small and the causes of acute
lung injury is heterogeneous. Further and larger trials
have to be done to define if this therapy can prevent
ARDS and improve outcome.
ACKNOWLEDGMENTS: We would e~ress our thanks toR. Ruffmann,
M.D., Head of the Medical Division oflnpharzam SA, Zambon Group,
for stimulating discussions and collaboration, and to G. Krejci, Ph.D.,
Clinical Investigations, Ltd, London, U.K., for the statistical analysis.
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Enhanced Rec:Overy From Acute Lung Injury (Suter et s1}