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(Chest. 2006;130:724-729.)
© 2006 American College of Chest Physicians

Etiology and Outcomes of Pulmonary and Extrapulmonary Acute Lung Injury/ARDS in a Respiratory ICU in North India*

Ritesh Agarwal, DM; Ashutosh N. Aggarwal, DM, FCCP; Dheeraj Gupta, DM, FCCP; Digamber Behera, MD, FCCP and Surinder K. Jindal, MD, FCCP

* From the Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Correspondence to: Surinder K. Jindal, MD, FCCP, Professor and Head, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India; e-mail: skjindal{at}indiachest.org

Abstract

Objective: Outcomes in patients with ARDS/acute lung injury (ALI) may be dependent on the underlying cause. We describe the case mix, clinical behavior, and outcomes of patients with ALI/ARDS resulting from pulmonary causes (ALI/ARDSp) and extrapulmonary causes (ALI/ARDSexp).

Design: Retrospective study conducted between January 2001 and June 2005.

Setting: Respiratory ICU (RICU) of a tertiary care hospital in northern India.

Patients: All patients fulfilling the criteria for ALI/ARDS and requiring mechanical ventilation for > 24 h.

Measurements and results: Of the 180 patients (ARDS, 140 patients; ALI, 40 patients), 123 patients had ALI/ARDSp, whereas 57 patients had ALI/ARDSexp. The most common cause of ALI/ARDSp was infective pneumonia, whereas the most common cause of ALI/ARDSexp was sepsis. At ICU admission, although patients with ALI/ARDSexp were sicker than those with ALI/ARDSp, there was no difference between the two groups of patients in the development of new organ dysfunction/failure ({Delta} sequential organ failure assessment [SOFA] scores) or the time to develop the first organ dysfunction/failure (assessed by SOFA scores). The median length of RICU stay was similar in the two groups (5 days [interquartile range (IQR), 6 days] vs 5 days [IQR, 9.5 days], respectively, in patients with ALI/ARDSp and ALI/ARDSexp; p = 0.4). The hospital mortality rate was 47.8% and was not significantly different between the two groups (ALI/ARDSp group, 43.1%; ALI/ARDSexp group, 57.9%; p = 0.06). Multivariate analysis showed the following risk factors for death in the ICU: female gender (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.25 to 0.94); SOFA scores (OR, 1.18; 95% CI, 1.07 to 1.3); and {Delta}SOFA scores (OR, 1.24; 95% CI, 1.09 to 1.41). There was no significant effect of the category of ARDS on outcome (OR, 1.6; 95% CI, 0.8 to 3.2).

Conclusions: Although patients with ALI/ARDSexp are sicker on ICU admission, the underlying cause of ARDS does not affect the length of ICU stay or hospital survival time.

Key Words: acute lung injury • ARDS • etiology • extrapulmonary • outcomes • pulmonary

Acute lung injury (ALI) and ARDS are characterized by refractory hypoxemia that develops secondary to high-permeability pulmonary edema. These syndromes can occur even without primary damage to the lung parenchyma, and thus they are now more often being classified as ALI/ARDS resulting from pulmonary causes (ALI/ARDSp) or extrapulmonary causes (ALI/ARDSexp) according to the mechanism of lung insult.1 Lung injuries of different origins may have possible differences in pathophysiology, lung morphology, radiology, respiratory mechanics, and response to different management strategies.2 Also, this distinction between a direct etiology of lung injury (ie, ALI/ARDSp) and an indirect etiology of lung injury (ie, ALI/ARDSexp) is gaining more attention as a means of better comprehending the pathophysiology of ARDS and possibly for modifying ventilatory management.34 For example, prone positioning and recruitment maneuvers are far more effective in treating patients with ALI/ARDSexp than in treating patients with ALI/ARDSp. Moreover, it has been suggested that the short-term and long-term outcomes of lung injury resulting from pulmonary and extrapulmonary causes are likely to be different.56 Few studies, however, have investigated the prevalence and mortality of ALI/ARDS using the categories ALI/ARDSp and ALI/ARDSexp. Moreover, there are very few data about the impact of the ARDS source from other geographic regions including the developing world. Although the pathophysiologic rationale and clinical characteristics of ALI/ARDSp and ALI/ARDSexp have been extensively detailed, a significant question remains as to the ultimate impact that the etiologic mechanism has on ultimate outcomes. In fact, many authorities doubt that this reductionist etiologic approach is particularly helpful in bettering the understanding of ALI/ARDS.

In a previous study,7 we showed the factors predicting the outcome of ARDS in our respiratory ICU (RICU). The aim of this study was to describe the etiology, hospital course, and outcomes of patients with ALI/ARDSp compared to patients with ALI/ARDSexp.

Materials and Methods

This was a retrospective study conducted in the RICU of the Postgraduate Institute of Medical Education and Research between January 2001 and June 2005. All data in the RICU are entered prospectively into a computer program that is specifically designed for this purpose, with a continuous process of monitoring its completeness and correcting entries. Data are registered on RICU admission and every 24 h thereafter, using the lowest daily values for all variables of interest. Day 0 is defined as the interval from the time of RICU admission to 8:00 AM on the next day; data from this time period are used to calculate the RICU admission sequential organ failure assessment (SOFA) scores. All remaining days are calendar days from 8:00 AM to 8:00 AM the following day. An informed consent form was obtained from all patients or their relatives as per the RICU protocol. The study was cleared by the institutional ethics committee.

The etiology of ALI/ARDS was ascertained on the basis of medical history and physical examination, radiology, and biochemical and microbiological investigations, and their findings were entered into the database. Direct and indirect insult was defined according to the tabulated distinction made in the published consensus guidelines for the diagnosis of ARDS.8 Patients with ALI and ARDS were classified on the basis of the guidelines of the American-European consensus conference on ARDS.8 Ambiguous cases were assigned after review by two independent clinicians, and patients were excluded from analysis if the ambiguity could not be resolved or if insufficient information was available. All patients received mechanical ventilation (Hamilton Amadeus; Bonaduz, GR, Switzerland) using the protocol followed by the ARDS Network low-tidal volume ventilation strategy using ideal body weight to calculate tidal volumes.9 However, if plateau pressures (Pplat) exceeded 30 cm H2O or if the pH decreased to < 7.3, the tidal volumes were increased or the positive end-expiratory pressure (PEEP) was decreased, as applicable.10 The baseline characteristics such as age and gender, PaO2/fraction of inspire oxygen (FIO2) ratios, serum albumin and creatinine levels, Pplat, static lung compliance (Cstat), and acute physiology and chronic health evaluation (APACHE) II scores were recorded. The severity of the underlying illness was scored using SOFA scores.11

The quantum of the organ dysfunction/failure appearing after RICU admission was calculated using SOFA scores. For purposes of analysis, organ dysfunction was defined as a SOFA score of 1 or 2 points, and organ failure as a score more than that. New-onset organ dysfunction/failure was computed using the {Delta}SOFA, by subtracting the RICU admission SOFA score from the maximum SOFA score during the RICU stay, both for component organ systems score as well as for the aggregate score. The duration of RICU stay and the ultimate hospital outcome were also recorded.

Statistical Analysis
Statistical analyses were performed using a statistical software package (SPSS for Windows, version 10.0; SPSS Inc; Chicago IL). Descriptive frequencies were expressed using the mean (SD) and the median (range and interquartile range [IQR]). Differences between the means of continuous variables were compared using the Mann-Whitney U test, and those of categoric variables were compared with the {chi}2 test. Levels of significance were expressed as p values and odds ratios (ORs) [95% confidence intervals (CIs)].

Stepwise multivariable logistic regression analysis was performed to study the effect of the type of ARDS on RICU mortality. Initially, the variables (ie, age, gender, etiology [ALI/ARDSp vs ALI/ARDSexp], Pplat values, PEEP levels, SOFA scores, and {Delta}SOFA scores) were analyzed using univariate analysis to derive a crude OR. The variables that were found to be significant (ie, p < 0.1) on univariate analysis were then entered in a multivariate logistic regression model to derive the adjusted OR and CIs.

Survival curves were constructed to study the effect of the category of ARDS (ie, pulmonary vs extrapulmonary causes) on RICU stay using Kaplan-Meier analysis. The difference between two survival curves was analyzed using the log-rank test.

Results

During the study period, a total of 209 patients were admitted to the RICU with a diagnosis of ALI/ARDS; 180 patients (ARDS, 140 patients; ALI, 40 patients; ALI/ARDSp, 123 patients; ALI/ARDSexp, 57 patients) were included for further analysis. Twenty-nine patients were excluded from the analysis for one of the following reasons: survival for < 24 h; ambiguity in the diagnosis and etiology of lung injury; and the presence of insufficient information. The most common cause of ALI/ARDSp was infective pneumonia, whereas the most common cause of extrapulmonary ALI/ARDSexp was sepsis (Table 1 ). There were 103 men and 77 women in the study, with a mean age of 43 years (SD, 19 years). At RICU admission, patients with ALI/ARDSexp were younger, had lower serum albumin levels and Pplat values, and were sicker than those with ALI/ARDSp (higher SOFA scores); there was no difference, however, in gender, hypoxia scores (ie, PaO2/FIO2 ratio), serum creatinine levels, and Cstat (Table 2 ). Patients with ALI/ARDSexp had higher maximum SOFA scores, but the {Delta}SOFA (signifying the new-onset organ dysfunction and/or organ failure) scores were similar in the two groups (Table 2). Similarly, there was no difference between the two groups in terms of the length of time to the first development of nonpulmonary organ dysfunction and organ failure (Table 2).


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  		Table 1. Etiology of Patients With ALI/ARDSp and ALI/ARDSexp Admitted to the RICU (n = 180)

 

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  		Table 2. Baseline Characteristics, Hospital Course, and Outcome of Patients With ALI/ARDSp and ALI/ARDSexp Admitted to the RICU*

 
Figure 1 shows the PaO2/FIO2 scores and PEEP levels, and Figure 2 shows Cstat and Pplat values over the course of the hospital stay. Although the initial Pplat values (ie, day 0 to day 3) were higher in ALI/ARDSp patients than in ALI/ARDSexp patients, there were no significant differences in the progression of lung mechanics and gas exchange variables over time.


Figure 1
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  		Figure 1. Time course of PEEP levels (top) and PaO2/FIO2 scores (bottom) from baseline to day 7 in the two groups of patients. There were no significant differences in the two groups. Circles = mean values; error bar = SD.

 

Figure 2
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  		Figure 2. Time course of Cstat scores and Pplat levels from baseline to day 7 in the two groups of patients. Although the Pplat levels were higher in patients in the pulmonary ARDS group than in those in the extrapulmonary ARDS group, these levels were not significant over time. Circles = mean; error bar = SD.

 
Ninety-four of the 180 patients with ALI/ARDS were discharged from the hospital; there was no difference in hospital survival between the two categories of ARDS patients (ALI/ARDSp, 70 of 123 [56.9%]; ALI/ARDSexp, 24 of 57 [42.1%]). Logistic regression analysis was performed to study the effect of the category of ALI/ARDS on ultimate hospital survival. In the univariate model, the factors that predicted survival included female gender, ALI/ARDSexp, SOFA score, and {Delta}SOFA score (Table 3 ). However, in the multivariate model, after adjustment, the only variables that predicted outcome were female gender, baseline SOFA scores, and {Delta}SOFA scores (Table 3); although there was a trend toward decreased hospital survival with ALI/ARDSexp, this was not statistically significant (OR, 1.6; 95% CI, 0.8 to 3.2).


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  		Table 3. Risk Factors Affecting Outcome of ALI/ARDS Patients in the RICU (Multivariate Logistic Regression Model)

 
Survival curves were plotted for patients with ALI/ARDSp and ALI/ARDSexp vis-à-vis the RICU stay (Fig 3 ). The median RICU stay in patients with ALI/ARDSp was 5 days (IQR, 6 days; range, 1 to 53 days) vs 5 days in patients without ALI/ARDSexp (IQR, 9.5 days; range, 1 to 64 days). The difference between the curves was analyzed using the log-rank test and was found to be statistically insignificant (p = 0.4) [Fig 3].


Figure 3
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  		Figure 3. Timing of hospital discharge in patients with ALI/ARDSp and ALI/ARDSexp (Kaplan-Meier analysis). There was no difference in length of RICU stay with ALI/ARDSp or ALI/ARDSexp (log-rank test).

 
Discussion

Only a few studies have investigated the prevalence of ALI/ARDSp and ALI/ARDSexp and the mortality of patients with those conditions. However, in the majority of available studies, as in the present study, the prevalence of ARDSp was higher compared to ARDSexp,31213 although, in the most recent retrospective analysis of patients enrolled in the ARDS Network trial14 of low-tidal volume ventilation, roughly an equal proportion of ARDSp and ARDSexp patients were identified. In two studies,1516 patients with pulmonary trauma were reported to have a higher survival rate, whereas patients with opportunistic pneumonia, but not aspiration pneumonia, had a lower survival rate. However, the reported mortality rate in patients with ARDS that is attributable to pulmonary and extrapulmonary causes varies considerably, with one study5 suggesting increased mortality with direct pulmonary insult triggering ARDS, and another study14 finding no relationship between direct pulmonary insults and increased mortality.

In our study, although patients with ALI/ARDSexp were younger and sicker (ie, higher baseline and maximum SOFA scores) than their ALI/ARDSp counterparts, we found no difference in the occurrence of new organ dysfunction/failure (ie, {Delta}SOFA scores), time to the development of the first organ dysfunction/organ failure, the duration of RICU stay, and length of hospital survival between the two categories of patients. Moreover, the classification of ARDS had no impact on the ultimate length of hospital survival after adjusting for various other risk factors like gender, baseline disease severity (ie, baseline SOFA scores), and the occurrence of new-onset organ dysfunction (ie, {Delta}SOFA scores). The lack of agreement among various studies can be explained by differences in baseline status, the prevalence of the disease precipitating ARDS in each center, the impact of therapy, and the overall distribution of these factors in the studied population. Another reason for the lack of agreement is probably the fact that the differentiation between direct and indirect insult is often straightforward only in patients with pneumonia or ARDS originating from intraabdominal sepsis, but a precise identification of the pathogenetic pathway is somewhat difficult to ascertain in other situations.

In our study, one interesting feature was the fact that women with ALI/ARDS had longer survival times, irrespective of the category or severity of the ARDS. A few studies171819 have described gender differences in the occurrence of sepsis and ARDS and in the outcomes of patients with those conditions, with a higher incidence and poorer outcomes in men compared to women. Sex steroids probably play an important modulatory role in the regulation of immune function, and reports20 have shown that female sex hormones are immunostimulatory, whereas male sex hormones are immunosuppressive.

Although some more recent studies2122 have shown that mortality secondary to ARDS has decreased, the mortality rate in this study was 48%; the reasons for higher mortality can probably be attributed to obvious differences in case mix, delays in the transfer of critically ill patients from the emergency department to the ICU because of the limited availability of beds, possible selection bias as sickest patients with multiple organ failure are admitted to the ICU, and other logistical reasons.2122

The strengths of this study include outcome analysis by the characterization of lung injury into pulmonary and extrapulmonary subsets, and the fact that the data from the developing world are sparse on this subject. The major limitations of our study include its retrospective nature and the small numbers of patients in each group. Also, there were significant differences in baseline characteristics between the two groups. Finally, because of the retrospective nature of the study, there were limitations in the collection of data set.

In conclusion, within the limitations of this study, the major factors that affect patient outcome were female gender, baseline disease severity, and the fresh development of organ dysfunction/failure in hospital. The category of lung injury (ie, from pulmonary or direct causes vs extrapulmonary or indirect causes) did not influence the length of ICU stay or the ultimate length of hospital survival time.

Footnotes

Abbreviations: ALI = acute lung injury; ALI/ARDSexp = acute lung injury/ARDS resulting from extrapulmonary causes; ALI/ARDSp = acute lung injury/ARDS resulting from pulmonary causes; APACHE = acute physiology and chronic health evaluation; CI = confidence interval; Cstat = static lung compliance; FIO2 = fraction of inspired oxygen; IQR = interquartile ratio; OR = odds ratio; PEEP = positive end-expiratory pressure; Pplat = plateau pressure; RICU = respiratory ICU; SOFA = sequential organ failure assessment

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication April 3, 2006. Accepted for publication June 1, 2006.

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