Acute respiratory distress syndrome

Study objectives: To investigate the long-term outcome of lung function in survivors of severe ARDS after modern treatment strategies including lung protective mechanical ventilation and prone positioning maneuvers.

Design: Follow-up cohort study.

Setting: University hospital pulmonary division and level 1 trauma center.

Patients: Sixteen survivors of severe ARDS (from 1992 to 1994) with a lung injury score [greater than or equal to] 2.5.

Measurements: The follow-up study (from 1995 to 1996) included interview, physical examination, chest radiographs, static and dynamic lung volumes, diffusion capacity of the lung for carbon monoxide (DLCO), blood gas analysis, and cardiopulmonary exercise testing (CPET).

Results: The mean [+ or -] SD interval between hospital discharge and functional assessment was 29.5 [+ or -] 8.7 months (range, 15.0 to 40.7 months). In approximately one half of the patients, mild abnormalities in static and dynamic lung volumes were found. In 25% (4 of 16 patients), lung function was obstructive; in 25% (4 of 16 patients), lung function was restrictive; and in 6.3% (1 of 16 patients), a combined obstructive-restrictive pattern was revealed. DLCO was impaired in 12.5% (2 of 16 patients); gas exchange during exercise was impaired in 45.5% (5 of 11 patients).

Conclusions: Residual obstructive and restrictive defects as well as impaired pulmonary gas exchange remain common after severe ARDS. CPET is a very sensitive measure to evaluate residual impairment of lung function after ARDS. Using CPET, reduced pulmonary gas exchange can be detected in many patients with normal DLCO.

Key words: ARDS; exercise test; follow-up studies; lung function tests; outcome assessment

Abbreviations: BMI = body mass index; CPET = cardiopulmonary exercise testing; DLCO = diffusing capacity of the lung for carbon monoxide; FI[O.sub.2] = fraction of inspired oxygen; LIS = lung injury score; mMRC = modified Medical Research Council; MOF = multile organ failure; P(A-a)[O.sub.2] = alveolar-arterial oxygen tension gradient; PEEP = positive end-expiratory pressure; PIP = peak inspiratory pressure; V[O.sub.2]max = maximal aerobic capacity; VD/VT dead space to tidal volume ratio

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The ARDS was first described > 30 years ago by Ashbaugh and colleagues. (1) It is characterized by dyspnea, tachypnea, arterial hypoxemia, diffuse bilateral infiltrates on chest radiography, and reduced pulmonary compliance. The following conditions are the most common causes of ARDS: sepsis, gastric aspiration, lung contusion, massive transfusion of blood, pneumonia, and major trauma. Fatality rates of ARDS are generally reported to exceed 50% and range from 10 to 90% depending on etiology, severity, definition of ARDS, and the presence of preexisting diseases. (2-5)

During recent years, intense efforts have been made to understand the pathophysiology of ARDS and to evaluate the effectiveness of various treatment modalities. (6,7) Newer ventilation strategies comprise the avoidance of high peak inspiratory pressure (PIP) and high tidal volumes (VTs), the application of high levels of positive end-expiratory pressure (PEEP) generally [greater than or equal to] 10 cm [H.sub.2]O, permissive hypercapnia, cyclic prone positioning, and nitric oxide inhalation. These measures aim at improving gas exchange and preventing ventilator-induced structural lung damage. Other interventions such as surfactant therapy, liquid ventilation, and steroids may be further therapeutic options; in some centers, extracorporeal lung assist is applied in highly selected patients. However, avoidance of high PIP and low VTs are the only treatment strategies with proven benefit on survival recently shown in a large, controlled, randomized, multicenter study. (5)

Reduced mortality may not be the only goal of modern ARDS treatment. It is well known that some survivors of ARDS have persistent lung function impairment consisting of restrictive or obstructive ventilatory defects, bronchial hyperreactivity, impaired diffusing capacity of the lung for carbon monoxide (DLCO), and a drop in Pa[O.sub.2] during exercise. Improvement or normalization of pulmonary function may be observed for up to 1 year after hospital discharge, and residual defects thereafter typically consist of an impaired oxygen transfer. This may be explained by fibrosis and microvascular obliteration, which are characteristic pathologic sequels after ARDS. (8,9) Pulmonary function has been studied in survivors of ARDS by several groups at various time intervals, the longest being 9 years, but only three studies describe cardiopulmonary exercise capacity in survivors of ARDS 3 to 24 months after ARDS (Table 1).

The aim of our study was to investigate the functional long-term outcomes in a well-characterized group of ARDS survivors. Since lung function can improve for up to 1 year, we chose to investigate the patient population beyond 1 year following hospital discharge.

MATERIALS AND METHODS

Between 1992 and 1994, 1,394 patients were admitted to our trauma surgical ICU and registered in a central ICU database. In 1995, this patient database was used to identify patients with ARDS or other lung-related problems. In a second step, the original patient records were screened. Only patients who retrospectively met the diagnostic criteria for ARDS as defined by the American-European Consensus Conference on ARDS in 1994 (6) and who additionally showed a lung injury score (LIS) of > 2.5 as described by Murray et al (39) were selected for the study. Patients with mild or only short episodes of ARDS (resolved after adequate treatment within 24 h) were not included. Twenty-five patients met the diagnostic criteria: acute onset of respiratory failure, Pa[O.sub.2]/fraction of inspired oxygen (FI[O.sub.2]) [less than or equal to] 200 mm Hg regardless of PEEP level, bilateral infiltrates on chest radiography, a pulmonary artery wedge pressure [less than or equal to] 18 mm Hg or no clinical evidence of left heart dysfunction, and a LIS > 2.5 indicating severe ARDS. The diagnosis of ARDS was made at a mean interval of 8.7 days (range 2 to 17 days) after initiation of mechanical ventilation. Respiratory care management with low-volume, pressure-limited ventilation and additional supportive measures (eg, cyclic prone positioning) were standardized in all patients.

Patients received ventilation with a Siemens Servo 900 C ventilator (Siemens-Elema AB; Solna, Sweden), and PIP was limited to [less than or equal to] 35 cm [H.sub.2]O. Pressure-controlled ventilation with an inspiratory/expiratory ratio of 1:1 was instituted as soon as gas exchange deteriorated. PEEP was initially set at 10 cm [H.sub.2]O and then titrated in small increments up to 16 cm [H.sub.2]O (best PEEP) according to the best oxygenation achieved and an optimized pressure/volume relationship. If PIP was > 35 cm [H.sub.2]O, pressure amplitude was adapted, taking into account that VTs (determined by applied PEEP and PIP limitation) decreased and that PaC[O.sub.2] raised to supranormal levels (permissive hypercapnia). An ensuing respiratory acidosis was not corrected. We did not hesitate to use FI[O.sub.2] as high as 1.0 if necessary to maintain Pa[O.sub.2] > 60 mm Hg. Whenever possible and if no contraindications were present, intermittent cyclic prone positioning was instituted. Once positioning maneuvers were initiated, patients were kept in each position as long as gas exchange (Pa[O.sub.2]/FI[O.sub.2] ratio) improved or remained at the same level. If gas exchange deteriorated, the patients were repositioned. Continuous cyclic repositioning procedures were continued as long as gas exchange was stabilized on a Pa[O.sub.2]/ FI[O.sub.2] ratio > 150 mm Hg and the PaC[O.sub.2] was normalized when measured in the supine position. The treatment protocol has been published in detail elsewhere. (40)

Twenty-two of the 25 patients (88%) survived and were discharged. Subsequently, they were requested by letter to participate in the present study. After obtaining institutional review board approval and written informed consent, 16 patients were included in this present study between autumn 1995 and spring 1996. The visits were scheduled exclusively for the follow-up examinations.

Six patients were not enrolled because of the following reasons: one patient with severe alcohol abuse and lack of permanent domicile was unavailable for follow-up, one patient committed suicide following a good recovery from ARDS, one patient permanently left the country and was not accessible for the study, and three patients refused to participate in the follow-up examinations. According to the surgical patient records and information from close relatives, none of these six patients had substantial pulmonary impairment after recovery from ARDS.

To characterize the study population the following scores were used: LIS (as described by Murray et al (30)) at the time of fully established ARDS. All patients had an LIS [greater than or equal to] 2.5 indicating severe ARDS. Trauma patients were additionally scored with the injury severity score. (41) Based on the APACHE (acute physiology and chronic health evaluation) II score, as assessed within the first 24 h of ICU admission, predicted mortality was calculated? With the multiple organ failure (MOF) score (as described by Goris et al (43) and modified by Ertel et al (44)), the numbers of failed organ systems were taken into account at the time of LIS evaluation without considering CNS dysfunction in patients with primary head trauma. Demographic data, hospital admission diagnosis, suspected etiology for ARDS, the different scores, time in the ICU, and the duration of mechanical ventilation are summarized in Table 2. The follow-up studies consisted of the following: physical examination; chest radiography in posteroanterior and lateral projections; interviews specifically designed to define smoking history, dyspnea, and daily activities; and perceived quality of life.

Dyspnea

Shortness of breath was assessed using the American Thoracic Society modified Medical Research Council (mMRC) score. (45)

Pulmonary Function Studies

Pulmonary function tests were performed after inhalation of two puffs of salbutamol adhering to standard criteria (46,47) with the SensorMedics Autobox plethysmograph (SensorMedics; Yorba Linda, CA). Reference values were taken from the European Community for Steel and Coal. (46,48) DLCO was determined by the single-breath carbon monoxide technique using an infrared analyzer (Model 66200; SensorMedies), which utilizes methane as inert tracer gas.

Blood Gas Analysis

Arterial blood samples were obtained at rest from the radial artery while the patient was sitting and breathing room air and immediately before the end of the exercise test. Blood gas analysis was performed utilizing an automated blood gas measurement system (AVL 993; AVL Medical Instruments; Schaffhausen, Switzerland).

Cardiopulmonary Exercise Testing

An electronically braked cycle ergometer (Bosch; Medicare; Zurich, Switzerland) was used for cardiopulmonary exercise testing (CPET). The exercise protocol consisted of a progressive ramp with a slope of 5 W/min to exhaustion. Expiratory ventilation, oxygen uptake, and carbon dioxide output were measured breath by breath and averaged over successive 15-s intervals by a computerized exercise and metabolic measurement system (VMax; SensorMedics). Heart rate and rhythm were monitored by a three-lead ECG. The dead space to tidal volume ratio (VD/VT) was calculated at rest and at maximal exercise according to the following formula:

VD/VT = [(PaC[O.sub.2] - mixed expired PC[O.sub.2])/PaC[O.sub.2]] - 0.115/VT, substituting the corresponding values for PaC[O.sub.2], mixed expired PC[O.sub.2], and VT measured at rest and at maximal exercise, respectively (mechanical dead space, 0.115 L).

Data Analysis

Data were stored in spreadsheet format on a personal computer and calculated using Microsoft Excel 2000 for Windows 98 (Microsoft; Redmond, WA). Results are presented as mean [+ or -] SD and range.

RESULTS

Mean interval between hospital discharge and follow-up examination was 29.5 [+ or -] 8.7 months (range, 15.0 to 40.7 months). The mean age of the study population at the time of functional assessment was 43.0 [+ or -] 14.1 years. Nine patients (56%) were smokers before onset of ARDS. Six patients (67%) resumed smoking, while the remaining three patients (33%) did not resume smoking after recovery, and seven patients (44%) remained nonsmokers.

Dyspnea

Only 2 patients (12.5%) complained about shortness of breath during strenuous exercise (mMRC score, 1), 2 patients reported dyspnea during moderate activity (mMRC score, 2), whereas the 12 other patients (75%) did not complain about shortness of breath at all (mMRC score, 0). Fourteen patients claimed that their general physical performance has not decreased, although 2 of them reported dyspnea (mMRC scores of 1 and 2, respectively) when asked for exercise tolerance. Both of these patients were obese (body mass index [BMI], 30 and 47, respectively). The two remaining patients complained about a considerable drop of physical capacity after recovery from ARDS, their shortness of breath being classified as mMRC scores of 1 and 2, respectively.

Physical Examination

The mean BMI was 28.8 [+ or -] 7.1; in three patients, BMI was > 30. In two patients, a slight chest wall deformity was noticed. Breath sounds were normal except in four patients, in whom a few rales were audible. Chest radiographic findings were normal in 11 patients (69%) and revealed minor abnormal findings in five cases.

Pulmonary Function

Lung Volumes: Lung function was normal in seven patients and impaired in nine patients. Four patients (25%) had an obstructive ventilatory defect, four patients (25%) had a restrictive defect, and one patient (6.25%) had a combined obstructive and restrictive ventilatory defect (Tables 3, 4). Two patients with an obstructive pattern were former smokers and had stopped smoking after ARDS, whereas the two other patients never had smoked.

Gas Exchange: DLCO was reduced only in 2 of 16 patients (Table 5).

CPET: CPET was performed in 12 patients. Four patients did not undergo exercise testing: two patients were paraplegic, one patient was handicapped by a stiff hip, and one patient was not available for this part of the study. Nine patients stopped exercising due to general fatigue, and three patients stopped due to dyspnea. Maximal aerobic capacity (V[O.sub.2]max) was normal in 4 of 12 patients. Heart rate reserve was reached by only two patients. Anaerobic threshold revealed normal values in seven patients, was abnormal in one patient, and could not be determined in four patients. Breathing reserve was equal or more than predicted in 11 patients and less than predicted in 1 patient. CPET revealed a reduced oxygen uptake in 6 of 11 patients. Exercise data are summarized in Tables 5, 6.

DISCUSSION

Clinical studies focusing on ARDS have most commonly been performed during the acute phase or within the first months after recovery. Less data are available on lung function during long-term follow-up of ARDS survivors. Residual impairment has been investigated by several groups since the beginning of the 1980s and seems to be common. Between 1972 and 2001, 30 studies and case reports including up to 51 patients have been published. The longest elapse of lung function testing after ARDS ranged between 3 months and 115 months (Table 1).

In our study population consisting of 16 patients after severe ARDS, we investigated the functional long-term outcome including CPET at least 1 year after hospital discharge. The subjects belong to a cohort of trauma patients with severe ARDS showing a survival rate of 88%, which appears to represent one of the best outcomes when compared to literature. (2-4) This rate is probably attributable to trauma as the underlying risk factor for ARDS. An almost identical outcome in trauma patients has been reported recently by Eisner and colleagues. (5)

In approximately one half of our patients, we found mild abnormalities in static and dynamic lung volumes. Apart from one patient with a combined obstructive-restrictive pattern, obstructive and restrictive ventilatory disturbances were equally distributed in the study group.

DLCO was impaired in a small minority (12.5%) of patients, but exercise testing revealed abnormal gas transfer rate in nearly 50% of the exercised subjects. This latter result is of major interest and is discussed below.

Cohort

The studies of the 1970s and early 1980s are limited due to a relatively wide variability of diagnoses and severity of ARDS, because of a lack of clear definitions and widely accepted scoring systems (introduction of LIS (39) in 1988, and first American-European Consensus Conference on ARDS (6) in 1994). Nine of the trials that are listed in Table 1 were published after the introduction of the LIS, and only three investigations were reported after the first American-European Consensus Conference. Therefore, inclusion criteria were sometimes not rigorous, and even "ARDS" patients without need of mechanical ventilation had been included. In later trials, patients probably experienced more severe lung injury, and the groups were more homogenous and comparable to recently performed studies. Unique to our study is the homogeneity of the cohort with respect to the cause for hospital admission, etiology, diagnostic criteria, severity, and treatment strategy of ARDS.

Lung Function

Residual obstructive ventilatory defects in ARDS survivors are described in a relatively wide range, from 0 to 33%, and restriction occurred in 0 to 50% of patients tested at least 6 months after ARDS. (9,10,13,16-19,21,24,26,31) Interestingly, all articles reporting normal lung volumes or very low rates of either obstruction or restriction were published between 1976 and 1985 where, for reasons indicated above, cohorts were likely more heterogeneous and lung injuries in the surviving population were most likely less severe. (21,24,31) In more recent studies, the proportion of patients with impairment have ranged constantly higher, from 18 to 33% for airway obstruction and from 15 to 45% for lung restriction. (13,16-18) Schelling and colleagues (10) reported that even 5.5 years after recovery from ARDS, rates of obstructive and restrictive lung function are still in the same range. This may indicate that no further improvement of lung function occurs > 1 year after recovery from ARDS. Our observation that one third of ARDS survivors have an obstructive ventilatory defect (including one patient with combined obstructive-restrictive disease) is consistent with the newer literature. (10,13,18,19)

Since smoking history may be related to obstructive ventilatory defects, former nicotine abuse has to be considered in this context. Fifty-six percent of our patients were smokers before the onset of ARDS, and only in two patients was lung function obstructive > 1 year after ARDS (both patients stopped smoking after hospital discharge), whereas three patients with obstructive lung function had a negative smoking history. These findings suggest that smoking history cannot explain the observed obstructive ventilatory defects in our population of ARDS survivors. These conclusions are supported by the studies of Ghio and colleagues, (18) and recently by Schelling et al, (10) where no predictive value of smoking status in determining impairment of lung function after ARDS was found. Elliott and coworkers (19) revealed in a population of 100% nonsmokers surviving ARDS an obstructive pattern in 25%. The rate of lung restriction in approximately one third of our patients (mild in four patients, mild to moderate in one patient) is comparable to the literature. (10,16,17,19)

There is considerable evidence of abnormal lung architecture occurring during the chronic phase of ARDS due to considerable fibrotic changes. It is well known that mechanical ventilation, particularly with high PIP, high VTs, and low PEEP levels, may trigger, sustain, or worsen ARDS, and detection of restrictive changes in earlier studies is not surprising. Surprisingly, the percentage of patients with lung restriction after ARDS remains more or less constant up to now despite pressure-limited ventilation strategies and additional therapeutic tools as used by us and others. (11,40) However, our patients represent a group with most severe ARDS probably not seen in earlier studies carried out in ARDS survivors.

Pulmonary Gas Exchange

It is obvious that structural pulmonary damage caused by the ARDS and the consecutive chronic changes may negatively affect pulmonary gas exchange. A lowered DLCO has been reported to occur in 33 to 82% of patients [greater than or equal to] 6 months after ARDS and is the most common observed pulmonary function abnormality. (10,11,13,17-19,24,26) Even in recently published studies, reduced DLCO remained high in 60 to 80% of subjects. (10,11,13)

Luhr and colleagues (11) studied a population with comparable severity of ARDS defined by LIS. Despite a similar severity of ARDS and elapsed time of lung function testing after acute illness, they found a diminished DLCO in 69% of their patients, which is considerably more frequent than in our studied patients. Luhr et al (11) treated their patients with inhaled nitric oxide. No detailed ventilation protocol was presented, but PEEP levels were 7 [+ or -] 2 cm [H.sub.2]O and PIP did not exceed 33 [+ or -] 6 cm [H.sub.2]O at the beginning and 29 [+ or -] 8 cm [H.sub.2]O at the end of inhaled nitric oxide treatment, respectively. PEEP levels seem to be relatively low, whereas PIP in some patients up to 39 mm Hg is not excessively high. No prone positioning was used.

In contrast, our treatment protocol consisted of a low-volume, pressure-limited ventilation and additional supportive measures (eg, cyclic prone positioning). As proven by Eisner et al, (5) lung-protective ventilation limiting PIPs and VTs is responsible for better survival rates. Attenuated development of lung fibrosis leading to impaired gas transfer due to thickness of the alveolar septum may additionally be a result from lung-protective ventilation. This could in part explain the above-described, remarkably differing DLCO values obtained in our study to those from Luhr et al (11) and most former studies, and this has to be further investigated.

Exercise Testing

Our present investigation includes comprehensive CPET in 12 of the 16 patients. Although a number of earlier studies used blood gas analysis to detect changes in blood oxygenation during exercise, in only three patients was CPET used to investigate the long-term follow-up of ARDS survivors. (15,21,24)

Exercise testing in a follow-up study of Knoch et al (15) revealed a normal cardiopulmonary exercise tolerance comparable to the level of untrained people. Elliott and colleagues (24) measured in all survivors an increase of the alveolar-arterial oxygen tension gradient (P[A-a][O.sub.2]) during exercise, indicating an impaired oxygen transfer during exercise in a patient group with diminished DLCO in 54%. Buchser et al (21) reported in seven of nine patients (78%) an abnormal increase of P(A-a)[O.sub.2] during exercise testing.

We found a reduced oxygen transfer in almost half of the exercised subjects. However, this rate is roughly four times more than found by DLCO measurements (12.5%). The difference between the rate of reduced DLCO and the rate of impaired gas transfer with CPET in our study as well as it has been reported by Elliott and colleagues (24) contribute to the known fact that exercise testing is much more sensitive in detecting even minor abnormalities in pulmonary gas transfer.

Limitations of the Study

Our study has some major limitations: it is a retrospective, noncontrolled study that enrolled only a small subpopulation of trauma patients with very severe ARDS. Additionally, the findings in this cohort of previously healthy trauma patients may differ substantially from findings in patients with underlying chronic diseases. Therefore, conclusions cannot be generalized to a broader, nonuniform population with ARDS.

CONCLUSION

We conclude that residual obstructive and restrictive defects as well as an impaired gas exchange remain common up to 3 years after ARDS. Furthermore, our data confirm that CPET is a very sensitive measure to evaluate residual impairment of lung function after severe ARDS and show that impaired pulmonary gas exchange can be detected in many patients with normal DLCO.

ACKNOWLEDGMENT: We thank Professor Peter A. Ward, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, for linguistic advice.

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* From the Institute of Anesthesiology (Drs. Neff and Stein), University Hospital Zurich; Department of Surgery (Dr. Stocker), Division of Trauma Surgery, University Hospital Zurich; Department of Internal Medicine (Dr. Frey), Regional Hospital Sursee; and Department of Internal Medicine (Dr. Russi), Pulmonary Division, University Hospital Zurich, Switzerland.

Manuscript received January 11, 2002; revision accepted June 11, 2002.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Erich W. Russi, MD, FCCP, Department of Internal Medicine, Pulmonary Division, University Hospital Zurich, Raemistrasse 100 CH-8091, Zurich, Switzerland; e-mail: erich.russi@dim.usz.ch

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