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Prediction of Prognosis for Acute Respiratory Distress Syndrome with Thin-Section CT: Validation in 44 Cases¹

¹ From the Dept of Respiratory Medicine (K.I., M.S., H. Muranaka, H. Miyakawa, Y.S.), Div of Intensive Care Unit (Y.G., Y.K.), and Dept of Diagnostic Radiology (Y.Y.), Graduate School of Medical Sciences, Kumamoto Univ, Kumamoto, Japan; Div of Respiratory Medicine, Saiseikai Kumamoto Hosp, 5-3-1 Chikami, Kumamoto 861-4193, Japan (K.I., M.S., H. Muranaka); Dept of Radiology, Osaka Univ Graduate School of Medicine, Osaka, Japan (M.T., T.J.); and Pulmonary Div, Kumamoto Chu-oh Hosp, Kumamoto, Japan (N.H., T.Y.). Received Sept 4, 2004; revision requested Nov 3; revision received Dec 29; accepted Feb 1, 2005. Address correspondence to K.I. (e-mail: k-ichikado{at}skh.saiseikai.or.jp).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Purpose: To retrospectively evaluate whether the thin-section computed tomographic (CT) appearance has prognostic value for prediction of mortality, number of ventilator-free days (ie, days without mechanical ventilation), and 28-day risk of barotrauma in patients with a clinically early stage of acute respiratory distress syndrome (ARDS) from diverse causes.

Materials and Methods: Institutional review board approval and informed consent were obtained. Two independent observers who were blinded to patient outcomes retrospectively evaluated the thin-section CT scans obtained within 7 days after clinical ARDS onset in 26 survivors and 18 nonsurvivors. Of 44 patients, there were 37 men and seven women (mean age ± standard deviation, 61.8 years ± 15.6). CT findings were graded on a scale of 1–6 that corresponded with consecutive pathologic phases: score of 1, normal attenuation; score of 2, ground-glass attenuation; score of 3, consolidation; score of 4, ground-glass attenuation associated with traction bronchiolectasis or bronchiectasis; score of 5, consolidation associated with traction bronchiolectasis or bronchiectasis; and score of 6, honeycombing. An overall CT score was obtained by adding the six averaged scores (three zones in each lung). Multivariate regression analysis was used to assess the independent predictive value of the CT score.

Results: The area of increased attenuation associated with traction bronchiolectasis or bronchiectasis (P = .002), as well as the overall CT score (P = .002), was smaller in survivors than in nonsurvivors. Results of multivariate regression analysis revealed that CT score was independently associated with mortality (P = .006). A CT score of less than 230 enabled prediction of survival with 73% sensitivity and 75% specificity and was associated with both a greater number of ventilator-free days (P = .018) and a lower incidence of barotrauma (P = .013) within 28 days after ARDS onset.

Conclusion: Extensive thin-section CT abnormalities indicative of fibroproliferative changes were independently predictive of poor prognosis in patients with a clinically early stage of ARDS.

© RSNA, 2005

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Acute respiratory distress syndrome (ARDS) is characterized by the sudden onset of hypoxemia and the appearance of bilateral opacities on chest radiographs in the absence of clinical evidence of left atrial hypertension. It is the most severe form of a wide spectrum of pathologic conditions designated as acute lung injury (1,2). Although the mortality rate for patients with ARDS is 40%–60% (2,3), the prognosis for affected individuals depends on various background factors and on the general severity of underlying or extrapulmonary disease. Results of multivariate regression analyses have revealed an association of death from ARDS with age (>70 years) (4), underlying liver cirrhosis (5), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and Sequential Organ Failure Assessment (SOFA) score (6). Two pulmonary factors independently associated with mortality are (a) direct lung injury as the cause of ARDS and (b) the extent of oxygenation impairment on day 3 after the onset of ARDS (5,6).

Thin-section computed tomographic (CT) findings have been reported to be of substantial diagnostic value in ARDS (7–12). To our knowledge, however, no study has been performed to evaluate the prognostic implication of thin-section CT findings. Ichikado et al (13,14) previously showed that thin-section CT findings correlated well with pathologic phases of diffuse alveolar damage, the pathologic hallmark of ARDS, and that assessment with thin-section CT was helpful in predicting prognosis in individuals with acute interstitial pneumonia, an idiopathic form of ARDS, regardless of the severity of the physiologic abnormality (15). Thin-section CT scans of acute interstitial pneumonia obtained in nonsurvivors thus showed more extensive areas of increased attenuation associated with traction bronchiectasis, which corresponded to fibroproliferative phases of diffuse alveolar damage, than did those obtained in survivors.

Given that acute interstitial pneumonia occurs in previously healthy individuals with no underlying disease, most patients with this condition experience respiratory failure but do not experience any of the other organ failures that are associated with preexisting disease (16,17). It was therefore unclear whether the findings in patients with acute interstitial pneumonia would also apply to those with other forms of ARDS. Thus, the aim of the present study was to retrospectively evaluate whether the thin-section CT appearance has prognostic value in the prediction of mortality, the number of ventilator-free days (ie, days without mechanical ventilation), and the 28-day risk of barotrauma in patients with a clinically early stage of ARDS from diverse causes.

	MATERIALS AND METHODS

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Patients
Cases of 63 patients with ARDS diagnosed according to the American-European Consensus Conference Criteria (1) were recorded at our institutions between January 2001 and December 2002. This study was approved by the institutional review boards at all institutions, and informed consent was obtained either from the participants or from their families if the participants were unable to decide by themselves. At our institutions, informed consent also included permission for future retrospective analyses. Forty-four (70%) of the 63 patients who had undergone thin-section CT within 7 days after the onset of ARDS were included in the present retrospective study. Patients were excluded if they were younger than 16 years of age, if they could not undergo thin-section CT because of unstable clinical status, if they had chronic interstitial pneumonia, or if they had undergone mechanical ventilation for more than 7 days. These 37 men and seven women (age range, 16–83 years; mean age, 61.8 years ± 15.6 [standard deviation]) had acute respiratory failure from various causes and bilateral opacities seen on conventional chest radiographs without clinical evidence of left atrial hypertension. All 44 patients had moderate-to-severe Murray lung injury scores (range, 2.5–4.0; median, 3.5 ± 0.7) (18) and required mechanical ventilation.

The general severity of disease was assigned an APACHE II score (median, 16.0 ± 4.8). The extent of multiple organ failure was evaluated by means of the SOFA score (median, 5.0 ± 3.1). Documented preexisting diseases were recorded, and underlying medical conditions were classified by means of severity according to the criteria of McCabe and Jackson (19) as nonfatal (score of 1), ultimately fatal (score of 2), or fatal (score of 3).

Ventilator management at the time of the thin-section CT examination was designed to limit plateau pressure at 30 cm H₂O or less, with positive end-expiratory pressure of 5–8 cm H₂O. We recorded the number of ventilator-free days, which were defined as days during which the patient was alive and free from mechanical ventilation, during the first 28 days after the onset of ARDS (K.I., H. Muranaka, Y.G., H. Miyakawa, M.T., N.H.). Barotrauma, which was defined as any new pneumothorax, pneumomediastinum, or subcutaneous emphysema, was noted as present or absent on routine chest radiographs during the first 28 days. The information on barotrauma occurrence was obtained from the radiographic reports.

Sepsis surveillance was incorporated into the routine examinations of cultures of blood, urine, and sputum obtained with a sterile intratracheal suction tube. If necessary, bronchoscopy with or without mini-bronchoalveolar lavage was performed.

Although the use of high-dose corticosteroids for the treatment of ARDS is controversial in Japan, it has been shown to be effective (20–22). Two different regimens were used by 21 individual physicians at our institutions, on the basis of their own decisions. Twenty-eight (64%) of 44 patients underwent treatment with high-dose intravenously administered corticosteroids (methylprednisolone, 1–2 grams per day) for 3-day periods, with adequate antibiotic therapy. Ten of the remaining 16 patients were treated with intravenously administered low-dose methylprednisolone (2 mg per kilogram of body weight per day) (23), whereas corticosteroid therapy was contraindicated in the remaining six patients because of gastrointestinal bleeding. In each group of patients treated with methylprednisolone, the dose of corticosteroid was gradually reduced over 1–2 months. Twenty-six (59%) of 44 patients responded to medical treatment and survived, and the remaining 18 patients died of multiorgan failure (n = 13) or respiratory failure (n = 5) within 1 week to 2 months despite intensive treatment.

CT Examination
All patients underwent thin-section CT of the chest once within 7 days (mean, 2.1 days ± 1.5) after the onset of ARDS. CT was performed with various CT scanners. The thin-section CT scans consisted of 1-mm-collimation sections reconstructed with the use of a high-spatial-frequency algorithm. Sections were obtained at 10-mm intervals throughout the chest with the patient in the supine position and without intravenous contrast medium. To avoid degradation of thin-section CT scans by respiratory motion in patients undergoing mechanical ventilation, when CT was performed, full inspiration was sustained by using a respiratory bag with a Jackson-Rees expiration valve (Igarashi Ika-kohgyo, Tokyo, Japan). None of the patients experienced a deterioration in condition as a result of undergoing the CT examination.

Thin-Section CT Scan Assessment
Thin-section CT scans were evaluated by two independent observers (M.T., T.J.) with more than 10 years of experience in thin-section CT interpretation who were unaware of patient outcome. The observers assessed the presence and extent of areas of ground-glass attenuation, airspace consolidation, traction bronchiectasis, traction bronchiolectasis, and honeycombing. Ground-glass attenuation was defined as an area of hazy increased opacification without obscuration of underlying vascular markings. Airspace consolidation was considered present when the vascular markings were obscured. When bronchi were irregular in contour, the dilated bronchus within areas of parenchymal abnormality was recognized as traction bronchiectasis. Traction bronchiolectasis was identified by means of the presence of dilated bronchioles within areas with parenchymal abnormality. Architectural distortion was defined as the presence of displacement or distortion of interlobar fissures, interlobular septa, bronchi, or vessels. Interlobular septal thickening was recognized as abnormal thickening of interlobular septa. Intralobular interstitial thickening was identified by means of a fine reticular, or meshlike, appearance to the lung parenchyma. Honeycombing was defined as the presence of cystic air spaces measuring 2–10 mm in diameter with well-defined walls.

Scoring of Thin-Section CT Findings
The thin-section CT findings were graded on a scale of 1–6 on the basis of the classification system previously described (15): score of 1, normal attenuation; score of 2, ground-glass attenuation; score of 3, consolidation; score of 4, ground-glass attenuation with traction bronchiolectasis or bronchiectasis; score of 5, consolidation with traction bronchiolectasis or bronchiectasis; and score of 6, honeycombing. The presence of each of these six abnormalities was assessed independently in three (upper, middle, and lower) zones of each lung. The upper zone was defined as the area above the level of the carina, the middle zone as the area between the level of the carina and the level of infrapulmonary vein, and the lower zone as the area below the level of infrapulmonary vein. The extent of each abnormality was determined by visually estimating the percentage (to the nearest 10%) of the affected lung parenchyma in each zone. The assessments of the two observers were averaged. The abnormality score for each zone was calculated by multiplying the percentage area by the point value (the score of 1–6). The six zone scores were averaged to determine the total score for each abnormality in each patient. The overall CT score for each patient was obtained by adding the six averaged scores.

Statistical Analysis
Data are expressed as mean ± standard deviation, unless indicated otherwise. Interobserver variability in identification of parenchymal abnormalities on the CT scans was assessed with the statistic. Interobserver variability in estimation of the extent of each finding was assessed with the Spearman rank correlation coefficient. Differences in CT findings between survivors and nonsurvivors were analyzed by using the ² test or the Fisher exact test. Comparison of CT score between survivors and nonsurvivors was evaluated by means of the Mann-Whitney U test.

To analyze the CT score as a predictor of survival, of the failure of ventilator weaning, or of the occurrence of barotrauma within 28 days after the onset of ARDS, we used receiver operator characteristic (ROC) curves to determine the cutoff value of the CT score that yielded the highest sensitivity and specificity (24). We also evaluated the relation between the cutoff CT score and the number of ventilator-free days within 28 days after the onset of ARDS. Analyses of the ROC were computed with a computer program (LABROC4, IBM compatible version, 1999; C. E. Metz, University of Chicago, Chicago, Ill). Multivariate regression analysis was used to assess the independent predictive value of the CT score.

To evaluate whether the number of days from the onset of ARDS really correlated with the histopathologic stages of ARDS, the relation between the thin-section CT score and the disease duration of ARDS was assessed with the Spearman rank correlation coefficient. Statistical analyses were performed by using a commercially available software package (SPSS, version 12.0J; SPSS, Chicago, Ill). For all statistical analyses, P < .05 was considered to indicate a significant difference.

	RESULTS

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Baseline Clinical Characteristics
The demographic data, causes of ARDS, and clinical variables on the day of thin-section CT scanning for all 44 study patients, as well as those of the survivors and nonsurvivors, are shown in Table 1. Survivors tended to be younger and to have more favorable prognoses of underlying diseases, as shown by smaller McCabe scores, than did nonsurvivors, but no significant differences were seen between the two groups.

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   Figure 1: Thin-section CT scans at the level of the carina obtained in a 76-year-old man on the day of ARDS onset from viral pneumonia (PAO2/FIO2 score, 121 mm Hg). Scan shows ground-glass attenuation associated with traction bronchiectasis (arrows) and fine reticular opacities. Overall thin-section CT score is 311. This patient needed ventilator assistance for more than 28 days.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Thin-section CT scan at the level of the right infrapulmonary vein obtained in a 51-year-old woman on the day of ARDS onset from bacterial pneumonia (PAO2/FIO2 score, 123 mm Hg). Scan shows extensive airspace consolidation without traction bronchiectasis. Bronchial walls are smooth and not dilated, as indicated by regularity along the wall length. Pleural effusion is not apparent. Overall thin-section CT score is 217. This patient was weaned from mechanical ventilation 11 days after onset of ARDS.

View larger version (26K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Graph compares thin-section CT scores between survivors and nonsurvivors of ARDS. CT score was significantly lower in patients who survived than in those who died (P = .002).

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 4: ROC curve of prognostic value of the CT score identified the optimal cutoff value of 230 for prediction of survival, with 73% sensitivity and 75% specificity. Area under the ROC curve (Az) indicates an index of discrimination performance for survival is 0.808.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 5: ROC curve for the prediction of the onset of barotrauma from CT score identified the optimal cutoff value of 247 for prediction of barotrauma onset with 66% sensitivity and 75% specificity. Area under the ROC curve (Az) indicates an index of discrimination performance for the occurrence of barotrauma is 0.769.

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 6: Graph shows correlation between CT score and number of days elapsed since onset of ARDS in the 44 patients. CT score was significantly but weakly correlated with number of days since onset of ARDS. Note that high CT scores were observed in some cases even on the day of ARDS onset.

	DISCUSSION

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In contrast to acute interstitial pneumonia, which affects previously healthy individuals, has an unknown cause, and is a "pure" form of acute respiratory failure, ARDS is generally associated with a variety of causes and is often associated with the failure of other organs that results from various underlying diseases (5,6,16,17). Multivariate regression analyses of baseline risk factors for survival have shown that an age older than 70 years (4), the presence of liver cirrhosis as an underlying disease (5), a high McCabe score for prognosis of the underlying disease, and a high APACHE II score are independently associated with mortality. The SOFA score is also an important predictor of survival (5,6). As far as we are aware, however, few pulmonary factors have been associated with ARDS mortality; those factors so associated include direct lung injury as the cause of ARDS and the extent of oxygenation impairment on day 3 after the onset of ARDS (5). Our present data suggest that the thin-section CT score defined herein provides information about the histopathologic stage of ARDS and that this score might be informative with regard to the response to treatment. However, in contrast to the high specificity and sensitivity (for prediction of survival with the optimal cutoff CT score) in acute interstitial pneumonia (15), the low specificity (75%) and sensitivity (73%) values for prediction of survival with the optimal cutoff CT score of 230 suggest that extrapulmonary or multi-organ disease factors affect prognosis even in individuals with a high CT score.

In a previous study (25) of 45 cases of ARDS confirmed at biopsy, patients whose condition was shown histologically to be in the acute exudative phase had a better prognosis than did those whose condition was shown to be in more advanced phases. Authors of other studies that have involved histologic analysis of specimens obtained by means of open lung biopsy have suggested that low-dose and prolonged corticosteroid treatment improves survival, especially when administered in the early proliferative phase of ARDS (23,26–28). In the present study, the group of patients who had mostly exudative lesions and limited areas of thin-section CT abnormalities indicative of the fibroproliferative phase (CT score, <230) had a lower mortality than did both the patients who had more extensive areas of fibroproliferation (CT score, 230). These results suggest a possible relationship between the pathologic stage of diffuse alveolar damage and responsiveness to corticosteroid treatment. Prospective studies with a larger number of patients are required to confirm such a relation.

In the present study, traction bronchiolectasis or bronchiectasis was already apparent on thin-section CT scans obtained within a few days of ARDS onset in 28 (64%) of 44 patients. Howling et al (29), on the basis of a review of thin-section CT findings in 16 patients with early phase ARDS, reported that bronchiectasis associated with ground-glass attenuation was a frequent observation that tended to persist at follow-up and was usually accompanied by the CT finding of supervening fibroproliferation. The CT score in our patients was weakly correlated with time elapsed since ARDS onset. A clinically early time point therefore does not necessarily correspond to a pathologically early phase of ARDS.

Johkoh et al (30), on the basis of their evaluation of 36 patients with idiopathic ARDS, or acute interstitial pneumonia, reported that the extent of traction bronchiectasis, which evolved from bronchioles to central bronchi with the extent of fibroproliferation, was weakly correlated with disease duration and suggested that difficulty in determination of the onset of injury might explain the weak correlation between them. Given that no significant difference in the cause of ARDS was apparent between the survivors and nonsurvivors in the present study, the weakness of the correlation between the CT score and the clinical duration of ARDS may also be attributable to differences in individual sensitivity to lung injury and in the intensity of the consequent exaggerated inflammation that occurs between the onset of lung injury and progression to ARDS. In the present study, if only the parameter of time elapsed since onset of ARDS was used to identify disease stage, some patients with fibroproliferative changes would be diagnosed with early ARDS (Fig 6). Such a situation might explain the discrepancy in the effectiveness of treatment between patients with "clinically" early phases of ARDS and those with "pathologically" early phases of ARDS.

In the current study, the thin-section CT score showed a significant inverse association with the number of ventilator-free days. Prolonged ventilation has been found to contribute to systemic inflammation and multiple organ failure in patients with ARDS (29). In our study, the death of 13 of the 18 nonsurvivors with ARDS, who required prolonged ventilation, was associated with multiple organ failure. A reduction in the duration of ventilation should therefore result in a reduction in ventilator-associated lung injury and thereby improve survival (31,32). Given that the patients in our study with lower CT scores needed less ventilator assistance than did those with higher CT scores, the former individuals may have experienced a reduced extent of ventilator-induced lung injury and therefore had an improved survival rate.

Barotrauma was more frequent in patients with a higher CT score (score 230) than in those with a lower CT score (score < 230) during the first 28 days after the onset of ARDS. Barotrauma occurred more than 14 days after ARDS onset. Most barotrauma events have also previously been shown to occur late in the course of ARDS and to be related to lung structural changes, such as emphysemalike or fibroproliferative lesions that develop over time (33). Desai et al (7) also reported that a coarse reticular pattern with distortion of lung parenchyma on the follow-up thin-section CT scans correlated well with the total duration of mechanical ventilation. Given that a higher CT score at presentation is indicative of more advanced fibroproliferative changes, our data may support those of these previous studies and suggest that thin-section CT findings might be used as a predictor of barotrauma in the development of therapeutic strategies for lung protection.

There were some potential limitations in the present study. Our study was retrospective and included only 44 patients who had undergone thin-section CT scanning within 7 days after the onset of ARDS; thus, although it included 70% of the patients with ARDS at our institutions during the allotted time period, our study may have a case selection bias and may not sufficiently reflect all forms of ARDS. Furthermore, in the present study, no correlation was provided with either physiologic parameters or pathologic correlation. Further prospective evaluation of thin-section CT findings in patients with ARDS will be necessary not only to clarify their prognostic implications but also to assess their potential application in the development of treatment strategies based on pathologic stage. Ideally, such investigations would also help determine the most appropriate time for administration of pharmacologic agents, such as corticosteroids.

In summary, thin-section CT findings suggestive of extensive fibroproliferative changes are independently predictive of poor prognosis in patients with clinically early ARDS. Such findings also are associated with a longer duration of ventilator assistance and a higher frequency of barotrauma during the first 28 days after the onset of ARDS. We conclude that the accurate determination of disease stage by means of thin-section CT assessment is informative with regard to the potential for ventilator-induced lung injury and the response to treatment in individuals with ARDS.

	ACKNOWLEDGMENTS

 
We thank Shigehiko Katsuragawa, MD, PhD, Kumamoto University School of Health Sciences, for suggestions on statistical methodology.

	FOOTNOTES

 

Abbreviations: APACHE II = Acute Physiology and Chronic Health Evaluation II • ARDS = acute respiratory distress syndrome • ROC = receiver operating characteristic • SOFA = Sequential Organ Failure Assessment

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, M.S., T.J., Y.K., Y.Y.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, K.I., M.T., N.H.; clinical studies, K.I., H. Muranaka, Y.G., H. Miyakawa, M.T., N.H., T.Y., Y.K.; statistical analysis, K.I.; and manuscript editing, K.I., M.S., T.J., T.Y., Y.Y., Y.S.

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