Abstract
This retrospective study describes the clinical course of 38 patients with idiopathic pulmonary fibrosis (IPF) admitted to the intensive care unit (ICU). There were 25 males and 13 females who were the mean age of 68.3 ± 11.5 years. Twenty patients were on corticosteroids at the time of admission to the hospital, and 24 had been on home oxygen therapy. The most common reason for ICU admission was respiratory failure. The Acute Physiology and Chronic Health Evaluation III–predicted ICU and hospital mortality rates were 12% and 26%, whereas the actual ICU and hospital mortality rates were 45% and 61%, respectively. We did not find significant differences in pulmonary function or echocardiogram findings between survivors and nonsurvivors. Mechanical ventilation was used in 19 patients (50%). Sepsis developed in nine patients. Multiple organ failure developed in 14% of the survivors and in 43% of the nonsurvivors (p = 0.14). Ninety-two percent of the hospital survivors died at a median of 2 months after discharge. These findings suggest that patients with IPF admitted to the ICU have poor short- and long-term prognosis. Patients with IPF and their families should be informed about the overall outlook when they make decisions about life support and ICU care.
Idiopathic pulmonary fibrosis (IPF) is a form of chronic interstitial lung disease of unknown etiology, usually progressing in a relentless and insidious manner (1–5). At this time, there is no effective therapy for IPF with proven and unequivocal benefit (1, 2). The progressive disease process of IPF and toxicities related to treatment are associated with significant morbidity (1, 4, 6). Recent studies have shown an increase in the mortality rates of pulmonary fibrosis (7, 8). Many patients with IPF develop respiratory failure and other life-threatening complications (4, 6), necessitating admission to the intensive care unit (ICU). Despite the potentially high complication and mortality rates, the clinical course and outcome of critically ill patients with IPF admitted to the ICU have not been well described. This study was aimed to describe the clinical course and outcome of patients with IPF admitted to the ICU.
The study included patients with IPF admitted to the ICU of Mayo Clinic Hospitals, Rochester, MN, between January 1995 and July 2000. The study was approved by the Mayo Institutional Review Board. Patients were identified from the Acute Physiology and Chronic Health Evaluation III database and the diagnoses listed in their medical records (9). Patients were included in the study if they were admitted to the ICU and had IPF based on the following criteria: (1) surgical biopsy showing usual interstitial pneumonitis (UIP); (2) abnormal pulmonary function studies that included evidence of restriction, and/or increased alveolar-arterial oxygen tension gradient at rest or during exercise, or decreased diffusing capacity for carbon monoxide; and (3) chest radiograph or high-resolution computed tomography suggestive of UIP. In the absence of surgical biopsy, patients had to fulfill all of the major criteria and at least three of the four minor criteria of the American Thoracic Society and European Respiratory Society (1). Patients who have known causes of interstitial lung disease, such as collagen vascular disease, drug toxicity, and environmental exposure, were excluded from the study. Patients who were admitted to ICU for electrocardiographic monitoring or postoperative observation after nonthoracic procedures were also excluded.
We collected data including demographics, reason for ICU admission, pulmonary function test measurements, Acute Physiology and Chronic Health Evaluation III scores and predictions, ICU and hospital lengths of stay and mortality rates, use and duration of mechanical ventilation, and the presence of sepsis and organ failure. The last pulmonary function test performed before ICU admission was included for analysis. We reviewed the reports of the histological findings of lung tissues obtained surgically or at autopsy.
The predicted mortality was calculated by the Acute Physiology and Chronic Health Evaluation III prognostic system (9). Sepsis, severe sepsis, and septic shock were defined according the American College of Chest Physicians/Society of Critical Care Medicine consensus conference (10). Liver failure was defined as serum bilirubin of more than 6 mg/dL and a prolongation of the prothrombin time at least 4 seconds greater than control or International Normalized Ratio (INR) of 1.5 or higher. Gastrointestinal failure was defined as gastrointestinal bleeding or obstruction or pancreatitis preventing enteral feeding for at least 24 hours or until death. Cardiovascular, pulmonary, renal, hematologic, and central nervous system failures were defined according to Knaus and colleagues (11). Multiple organ failure was defined as the development of two or more organ failures.
Pneumonia was diagnosed clinically by the presence of radiographic appearance of new or progressive infiltrates, fever, peripheral blood leukocytosis, and purulent tracheal secretions (12). Nosocomial pneumonia was diagnosed if pneumonia developed after 48 hours of hospitalization.
Comparisons between groups were made using Student's t, Mann-Whitney U, chi-square, and Fisher's exact tests. All means are expressed with their standard deviation; p values of less than 0.05 were considered significant. The standardized mortality ratio was defined as the ratio of the observed to predicted mortality rates.
Sixty-one patients with pulmonary fibrosis were admitted to the ICU during the study period. Fourteen patients whose pulmonary fibrosis was secondary to collagen vascular disease or environmental exposure and nine patients with IPF who were admitted to the ICU for only electrocardiographic monitoring or postoperative observation were excluded from the study. The remaining 38 patients fulfilled the inclusion criteria and were included in the analysis.
IPF was documented histologically in 18 (47%) and clinically in 20 (53%). Twenty-five (66%) were male. Thirty-five of the patients (92%) were white, and one each Asian, Hispanic, and Native American Indian. The reasons for ICU admission were respiratory failure in 32 patients (84%), gastrointestinal bleeding in 2 patients, hypotension in 2 patients, and acute abdomen in 2 patients. The median duration of illness from the time of IPF diagnosis to ICU admission was 2 years (range, 6 months to 12 years). Twelve patients (32%) were on corticosteroids, 3 (8%) on colchicine, 8 (21%) on corticosteroids and colchicine, and 15 (39%) on no treatment for IPF at admission to the ICU. Twelve (60%) of the 20 patients who had been on corticosteroid before hospital admission died compared with 11 (61%) of the 18 who had not been on corticosteroids (p > 0.99). Twenty-four (63%) patients had been on long-term oxygen therapy at home before admission to the hospital. Twelve of the patients (50%) who had been on home oxygen died in the hospital compared with 11 of the patients (79%) who had not been on home oxygen (p = 0.10). Twenty-three patients were transferred to the ICU from other units of the same hospital. Four were transferred from other hospitals. Eight were admitted from the emergency department and three from doctors' offices.
Of the 32 patients admitted for respiratory failure, 10 (31%) had pneumonia, 2 (6%) pulmonary embolism, 2 (6%) congestive heart failure, and 2 (6%) pneumothorax. One patient developed acute on chronic respiratory failure following surgery for mitral valve replacement. The remaining 15 (47%) patients with respiratory failure had no immediate precipitating factor, and the worsening respiratory failure was attributed to progression of IPF. Bronchoscopy with bronchoalveolar lavage was performed in 10 patients and showed no evidence of infection in 7. Bronchoalveolar lavage was positive for fungi in two patients, one aspergillus species and another unidentified, and cytomegalovirus in another patient.
Echocardiographic measurements of systolic pulmonary pressure were available in 11 survivors and 10 nonsurvivors, and estimation of left ventricular ejection fraction was available in 11 survivors and 20 nonsurvivors. Total long capacity was measured in 11 survivors and 17 nonsurvivors, spirometry in 13 survivors and 17 nonsurvivors, and diffusing capacity for carbon monoxide in 12 survivors and 15 nonsurvivors. There were no significant differences in echocardiographic and pulmonary function test findings between survivors and nonsurvivors (Table 1)
Survivors (Mean ± SD) | Nonsurvivors (Mean ± SD) | p Value | |
|---|---|---|---|
| Systolic pulmonary artery pressure, mm Hg | 58.4 ± 12.3 | 59.3 ± 12.2 | 0.86 |
| Left ventricular ejection fraction, % | 55.1 ± 18.2 | 61.0 ± 12.8 | 0.30 |
| Total lung capacity, % predicted | 62.3 ± 12.0 | 65.4 ± 16.0 | 0.59 |
| FVC, % predicted | 56.5 ± 19.4 | 59.6 ± 17.3 | 0.66 |
| Diffusing capacity for carbon monoxide, % predicted | 30.0 ± 13.1 | 38.6 ± 20.3 | 0.22 |
| FEV1, L | 1.57 ± 0.74 | 1.82 ± 0.72 | 0.35 |
| FVC, L | 2.05 ± 1.02 | 2.30 ± 1.07 | 0.52 |
| FEV1/FVC, % | 79.0 ± 8.8 | 81.7 ± 7.6 | 0.39 |
The average Acute Physiology and Chronic Health Evaluation III score was 60.2 ± 24.8 (median, 54.0). The predicted hospital and ICU mortality rates were 26% and 12%, and the observed hospital and ICU mortality rates were 61% and 45%, respectively. The standardized hospital and ICU mortality ratios were 2.3 and 3.8, respectively. The median length of hospital stay was 14 days for survivors compared with 11 for nonsurvivors (p = 0.32). Survivors' median length of ICU stay was 3 days compared with 5 of nonsurvivors (p = 0.23). Follow-up mortality information was available in 13 of the 15 patients discharged alive from the hospital. Of these 13 patients, 12 (92%) died at a median of 2 months after discharge from the hospital. One patient, who was admitted to the ICU for respiratory failure after mitral valve replacement, was still alive at 16 months after discharge from the hospital.
Nineteen patients (50%) received mechanical ventilation for an average of 10.5 ± 12.4 (median 5) days. Six patients received invasive as well as noninvasive positive pressure ventilation, whereas one patient received noninvasive positive pressure ventilation only. Fifteen patients (39%) requested not to be resuscitated. Life support was withdrawn from eight patients (21%) at the request of next of kin. Ten of the 19 patients (53%) who did not receive mechanical ventilation died compared with 13 of the 19 patients (68%) who received mechanical ventilation (p = 0.51). There was no significant difference in the duration of mechanical ventilation between survivors and nonsurvivors (median of 4.5 for survivors and of 11.0 for nonsurvivors, p = 0.66).
Data on sepsis and organ failure were available in 37 patients, 14 survivors, and 23 nonsurvivors. Sepsis developed in 3 of the 14 survivors (21%) compared with 6 of the 23 nonsurvivors (26%) (p > 0.99). The stages of sepsis were mild in seven, severe in one, and septic shock in one. The sources of infection were identified as nosocomial pneumonia in five patients, urinary tract infection in two, and sinusitis with bacteremia in one. Thirty-five patients (95%) developed one or more organ failure: one organ failure in 23, two in 7, and three in 5 patients. The types of organ failures were pulmonary in 35 (95%), cardiovascular in 7 (19%), gastrointestinal in 4 (11%), renal in 4 (11%), central nervous system in 1 (3%), and hepatic in 1 (3%). The number of organ failures was 1.07 ± 0.73 (median of 1) in survivors compared with 1.61 ± 0.78 (median of 1) in nonsurvivors (p = 0.06). Multiple organ failure developed in 2 (14%) of the survivors compared with 10 of the 23 nonsurvivors (43%) (p = 0.14).
Lung biopsy results were available in nine patients, immediately before or after ICU admission, by open lung biopsy in seven and autopsy in two patients. In addition to UIP, six of these lung specimens showed features of diffuse alveolar damage and or organizing pneumonia consistent with acute lung injury.
This study describes the clinical course and outcome of 38 patients with IPF treated in the ICU. The majority of the patients were admitted to the ICU for respiratory failure. Progression of the underlying pulmonary fibrosis was the most common cause of the respiratory failure. Most of the patients had been on corticosteroid and oxygen therapy before hospitalization. The hospital and ICU mortality rates were 61% and 45%, respectively. As might be expected for a physiologic scoring tool weighted toward acute illness and assessed at the time of admission, the Acute Physiology and Chronic Health Evaluation III prognostic system underestimated the observed mortality rates. Ninety-two percent of the survivors died at a median of 2 months after hospital discharge. There were no significant differences in systolic pulmonary artery pressure, left ventricular ejection fraction, total long capacity, diffusing capacity for carbon monoxide, and FEV1 between survivors and nonsurvivors. Half of the patients received mechanical ventilation. Septic shock developed only in one patient. Multiple organ failure developed in 14% of the survivors and 43% of the nonsurvivors. The histology of lung tissues showed evidence of acute lung injury in addition to UIP in six of nine patients.
The mean age of 68 years in our patients and the majority being males are consistent with reported characteristics of this disease (1). The median duration of illness of approximately 2 years before the time of ICU admission suggests that our population was relatively late in the course of the disease. Because of our geographic location and referral sources, our patients were almost exclusively whites. Although pulmonary fibrosis has no predilection by race or ethnicity, age-adjusted mortality rate is higher in whites than blacks (8).
The degree of abnormality in pulmonary function values has not been uniformly shown to influence long-term survival in patients with IPF. An earlier study had shown a shorter survival period in patients with lower diffusing capacity for carbon monoxide (13). However, a more recent study using multivariate analysis has not confirmed this finding (14). In an article published approximately 3 decades ago, Stack and colleagues reported that 8 of 10 patients (80%) with IPF and vital capacity of 60% or less of predicted died within 2 years compared with 8 of 19 of those (42%) with a vital capacity higher than 60% (15). However, the difference was not statistically significant, and more recent studies have not shown significant association between long-term prognosis and FEV1, FVC, or total lung capacity (13, 14, 16). We are not aware of previous studies addressing the association of hospital mortality and pulmonary function abnormalities in patients with IPF admitted to the ICU. In this study, we did not find significant differences in pulmonary function test and echocardiogram findings between survivors and nonsurvivors. Our observations were limited by incompleteness of data and the variable time intervals between pulmonary function test and ICU admission dates.
Over 80% of the patients in this study were admitted to the ICU for respiratory failure, and the immediate cause of the respiratory failure was progression of the pulmonary fibrosis in approximately half. In addition to progression of the pulmonary fibrosis leading to respiratory failure, the clinical course of patients with IPF is complicated by pulmonary infections, bronchogenic carcinoma, heart failure, ischemic heart disease, stroke, pulmonary embolism, and nonpulmonary infections (4). Pneumonia was the second most common cause of respiratory failure in our patients. However, the clinical criteria that we used for the diagnosis of pneumonia may have underestimated or overestimated the true occurrence of pneumonia. It is difficult to detect new radiographic changes in IPF, and new radiographic changes cannot be used to differentiate between an infectious process and progression of the IPF. Purulent secretions are nonspecific, and fever may not be present in the older patients and in patients on corticosteroid therapy.
We often resort to invasive procedures, including bronchoscopy and open lung biopsy, to identify reversible causes of respiratory failure in patients with IPF, especially if they are on corticosteroids and other immunosuppressants. However, neither bronchoscopy nor open lung biopsy was of benefit in identifying treatable conditions in most of the patients in this study. Although aspergillus and cytomegalovirus were detected in the bronchoalveolar lavage of two patients, a causative role could not be ascertained. Opportunistic infections are rare in patients with IPF (4). Among nine of our patients who had lung tissues examined, all had histologic evidence of UIP, and six of them had evidence of acute lung injury. Similar histologic findings were described in a previous study of three patients with acute exacerbation of IPF (17). Although we cannot make any definite conclusions based on our small sample size, the role of invasive diagnostic methods in critically ill patients with IPF needs to be questioned.
The development of sepsis and multiple organ failure is associated with increased mortality in critically ill patients (10, 11). Sepsis develops in 5–49% of ICU patients, and mortality increases with progression to severe sepsis and septic shock (18). In this study, sepsis developed in 24% of the patients, and only one patient each developed severe sepsis and septic shock. Because of our small sample size, we did not notice significant differences in the rates of sepsis and multiple organ failure between survivors and nonsurvivors.
The overall long-term prognosis of IPF is known to be poor (4). However, studies addressing the outcome of patients with IPF requiring ICU admissions are scarce. In one study of seven patients with IPF admitted to the ICU and required invasive mechanical ventilation, multiple organ failure developed in two patients, and six died after 3.2 ± 4 days of ventilation (19). The hospital mortality rate was similarly high in our study. Moreover, over 90% of the survivors died within a few months after hospital discharge. The only known long-term survivor in our study was admitted to the ICU for postoperative respiratory failure. Reflecting the perception among clinicians and patients that IPF is associated with poor prognosis, the majority of our patients either refused resuscitation or had life support withdrawn from them. This treatment bias may have contributed to the high mortality in this study. However, because the outcome of the patients who received full resuscitation and life support was also poor and there has been no new development with positive impact on survival, the treatment bias is unlikely to have played a major role. The nature of our referral center may also have contributed to a patient population with advanced disease. Nonetheless, clinicians commonly face decisions regarding treatment of late stages of IPF, and such data regarding near-term outlook after ICU admission may be relevant.
Our study has several potential shortcomings. The data were retrospectively collected, and the study was limited to one medical center. Data collection was incomplete in some patients. The clinical definition of pneumonia is likely to have overestimated its incidence. The selection bias may have contributed to the observed high mortality rate. The diagnosis of IPF was not confirmed histologically in the majority. The small sample size weakens the power of the study.
In conclusion, we found that most patients with IPF are admitted to the ICU for respiratory failure. Both the hospital and long-term mortality rates of patients with IPF admitted to the ICU are high. Based on these observations and previously published studies addressing long-term prognosis, clinicians should be prepared to discuss the value of life support compared with comfort and palliative measures for patients with IPF. Prospective multicenter studies are needed to assess further the clinical course, prognostic factors, and outcomes of patients with IPF admitted to ICU.
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