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(Chest. 2001;120:209-212.)
© 2001 American College of Chest Physicians

Outcome of Patients With Idiopathic Pulmonary Fibrosis Admitted to the ICU for Respiratory Failure*

Sandra Blivet, MD; François Philit, MD; Jean Michel Sab, MD; Bruno Langevin, MD; Micheline Paret, MD; Claude Guérin, MD and Dominique Robert, MD

* From the Service de Réanimation Médicale, (Drs. Blivet, Philit, Sab, Langevin, Guérin, and Robert), Hôpital de la Croix Rousseand; and Service de Radiologie (Dr. Paret), Hôpital Louis Pradel, Lyon, France.

Correspondence to: François Philit, MD, Service de Réanimation Médicale, Hôpital de la Croix Rousse, 69317 Lyon Cedex 04, France; e-mail: francois.philit{at}chu-lyon.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To analyze the outcome of acute respiratory failure (ARF) in patients with idiopathic pulmonary fibrosis (IPF), and to evaluate the benefits of invasive and noninvasive mechanical ventilation (MV).

Design: Retrospective study.

Setting: University hospital.

Patients: Fifteen consecutive patients with IPF referred to the ICU for ARF between January 1989 and June 1998.

Measurements and results: Fifteen patients (mean ± SD age, 64 ± 10 years) were included. Eight patients had clinical, functional, and radiologic features of IPF, and the remaining seven patients also had biopsy specimen-proven IPF. The mean duration between diagnosis of IPF and admission to the ICU was 26.5 ± 28 months. At the time of ICU admission, mean arterial blood gas levels were as follows: PaO2/fraction of inspired oxygen, 113 ± 95; pH, 7.32 ± 0.10; and PaCO2, 55 ± 21 mm Hg. All patients received MV; 12 patients required tracheal intubation, either at the time of ICU admission (n = 10) or after failure of noninvasive ventilation (NIV; n = 2); and 3 patients only received NIV. Three of the five patients receiving NIV died of respiratory failure. Eleven patients died in the ICU, either from hypoxemia (n = 8) or from septic shock (n = 3). Four patients were discharged alive from the ICU, and two of them died shortly thereafter.

Conclusion: The outcome of patients with IPF referred to the ICU for ARF was very poor and not improved by MV. Without a clearly identified reversible cause of ARF, these patients should not benefit from admission to the ICU.

Key Words: ICU • idiopathic pulmonary fibrosis • interstitial lung disease • respiratory failure


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology with an almost invariably poor prognosis.1 2 3 The mean duration of survival of patients with IPF has been estimated to range from 3 to 6 years.3 4 In most patients, the course of the disease is progressive, and the restrictive ventilatory defect regularly worsens as the result of the extent of fibrosis.5 6 7 This leads to respiratory failure and fatal hypoxemia.3 5 6 The current treatments, including steroids and cytotoxic agents, improve neither the survival nor the quality of life.8 9 10 11 12 13 The occurrence of an acute life-threatening hypoxemia during the course of IPF may require admission to the ICU and ventilatory support. The aim of the present study was to analyze the outcome of patients with IPF referred to the ICU for acute respiratory failure (ARF) and to estimate the benefit of invasive and noninvasive mechanical ventilation (MV) in these patients.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Selection of Patients
We retrospectively studied all consecutive patients with IPF who were referred to the respiratory ICU of Croix-Rousse Hospital, Lyon, France, for ARF, from January 1989 to June 1998. The definition of ARF was as follows: (1) exacerbation of dyspnea within a few days, (2) deterioration of hypoxemia (PaO2/fraction of inspired oxygen < 250), and (3) MV requirement. The diagnosis of IPF was based on a combination of the following criteria: persistent bilateral dry crackles on auscultation; widespread bilateral shadowing on chest radiographs or IPF-related abnormalities on high-resolution CT (HRCT)-scan; pulmonary function test (PFT) results showing a restrictive ventilatory defect and decreased single-breath carbon monoxide diffusing capacity, and/or pathologic criteria on open-lung biopsy specimen. Patients with a clinical history of environmental exposure, drug-induced pulmonary disease, or collagen vascular disease were not included.

Data Collection
From the medical charts, the following information was reviewed: age, gender, smoking history, duration of symptoms, treatment, former PFT results, arterial blood gas levels, BAL, open-lung biopsy results, blood culture, simplified acute physiology score II,14 use of noninvasive ventilation (NIV) or endotracheal MV, and outcome.

Imaging
A radiologist (M.P.) and a pulmonologist (F.P.) carefully reviewed HRCT scans, ignoring clinical data and PFT results. HRCT scans were performed with 1.0-mm-thick sections taken at 1-cm intervals throughout the entire thorax. The overall extent of reticular opacities and honeycombing in lung parenchyma was measured. A score was given according to the relative proportion of fibrotic patterns: reticular opacities and honeycombing involving (1) up to 30%, (2) 30 to 70%, and (3) > 70% of the lungs. The presence of ground-glass attenuation and emphysema was also evaluated.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Characteristics of the Patients
Fifteen patients (11 men) were included (Table 1 ). Eight patients had clinical, functional, and radiologic features of IPF. Seven of them were known to have IPF at the time of admission, whereas in one patient the diagnosis of IPF was made during the ICU stay. In the seven remaining patients, the diagnosis of IPF was established by lung biopsy specimen, in addition to clinical symptoms; the biopsies were performed before ICU admission in six patients, and during ICU stay in one patient. In all patients, the lung biopsy specimens showed histologic features of usual interstitial pneumonia with areas of extensive fibrosis and honeycomb change. The extent of the disease was mainly heterogeneous, and no area of diffuse alveolar damage was seen. The mean duration between the diagnosis of IPF and the ARF leading to ICU admission was 26.5 ± 28 months (range, 1.3 to 81 months). Clinical symptoms of IPF were noticed for < 2 months in two patients, and for > 67 months in three patients. All patients had already received corticosteroid therapy (at 1 mg/kg/d for 10 patients). One patient had also received cyclophosphamide, 3 months after starting corticosteroid treatment. Eleven patients were receiving long-term oxygen therapy before the admission to the ICU.


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  		Table 1. Characteristics of Patients* >

 
PFTs
The results of PFT performed in basal conditions (within the year before ARF) showed a restrictive ventilatory impairment in all patients (Table 1) . Mean FVC of 55 ± 15% and mean total lung capacity of 54 ± 17% of predicted were recorded. Carbon monoxide diffusing capacity per liter of alveolar volume amounted to 55 ± 20% of predicted in eight patients. Two patients also presented with a mild obstructive ventilatory defect related to emphysema.

HRCT Findings
Thirteen patients underwent HRCT just before or during their stay in the ICU. The extent of reticular opacities and honeycombing was between 30% and 70% in four patients, and > 70% in nine patients. None of the patients showed reticular opacities and honeycombing in < 30% of the lung. HRCT showed also ground-glass opacity in 11 patients. The extent of reticular pattern was larger than the extent of ground-glass opacities. No patient exhibited airspace consolidation.

Conditions Associated With ARF in IPF Patients
Conditions associated with the acute exacerbation of IPF were identified in three patients: pneumothorax in two patients and anesthesia for scheduled surgery in one patient. Six patients exhibited a sepsis-like syndrome. Seven patients received antibiotic and/or antifungal treatment, which was unsuccessful in all but one patient. In 6 of the 10 patients who underwent BAL, an infectious pathogen was identified: Streptococcus pneumoniae (n = 1), Staphylococcus aureus (n = 2), influenza A virus (n = 1), and Pneumocystis carinii (n = 2). The mean ± SD BAL cell counts were 67 ± 35% for polymorphonuclear neutrophils, 21 ± 25% for macrophages, 3 ± 4% for lymphocytes, and 0.5 ± 0.3% for eosinophils. Finally, Pseudomonas aeruginosa was identified in blood culture in one patient.

Management and Outcome in the ICU
As shown in Table 2 , patients were markedly hypoxemic and hypercapnic at ICU admission. Five patients were initially treated with noninvasive respiratory support (mean duration, 6.4 ± 4.5 days; Table 3 ). Two patients received pressure-support mode, one patient received assisted-controlled mode, and two patients received continuous positive airway pressure. Afterwards, two of these patients required intubation and died, one patient died during NIV, and the remaining two patients had improved conditions and were discharged from the ICU. Ten patients were intubated and received MV before or soon after admission to the ICU. Eight of these patients died in the ICU, and two patients were discharged alive. Thus, 12 patients in total needed tracheal intubation, either on ICU admission (n = 10) or after failure of NIV (n = 2). Invasive MV lasted an average of 14.7 ± 12 days. Finally, 11 patients died in the ICU, 8 patients from hypoxemia and 3 patients from septic shock. Among the four patients who were discharged from the ICU, two patients died shortly thereafter, one patient was still alive 6 months after discharge, and one patient was unavailable for follow-up. For the survivor, ARF was precipitated by anesthesia and improvement was obtained with NIV alone.


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  		Table 2. Clinical Status of Patients at ICU Admission* >

 

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  		Table 3. Management and Outcome of Patients in the ICU* >

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In our study, the diagnosis of IPF was based on major clinical and radiologic criteria in eight patients10 and was definitely established by open-lung biopsy specimens in the remaining seven patients. Although surgical lung biopsy is the most reliable procedure to provide a definite diagnosis of IPF, it has been demonstrated that HRCT characteristics of IPF in an appropriate clinical context lead to a correct diagnosis in 85 to 90% of cases.5 8 15 The diagnosis of the ARDS could also be excluded because all the 15 patients had preexisting respiratory symptoms within weeks or months before the onset of ARF.

Patients in our study exhibited high-gravity HRCT findings, such as a large extent of honeycombing and septal thickening that exceeded 70% of the lungs in nine patients. The clinical significance of the high rate of polymorphonuclear neutrophils observed in the BAL fluid is unclear. Although it could be considered as a marker of poor prognosis in IPF, it could also suggest the presence of lung infection in our patients.

Of our patients, two patients had a marked rapidly progressive form of IPF. Diagnosis was made < 2 months before ICU admission, with HRCT in both patients and with lung biopsy specimens in one patient. According to the acuteness of their deterioration, acute interstitial pneumonia could also be discussed. However, HRCT findings in these two patients (honeycombing and septal thickness) were more suggestive of usual interstitial pneumonia.5 8

A possible cause of acute exacerbation was found in 9 of the 15 patients: infection (n = 6), pneumothorax (n = 2), and complications of anesthesia (n = 1). Among the four patients discharged alive from the ICU, the precipitating cause of ARF was reversible in three patients (two pneumothoraces and one general anesthesia). On the contrary, infection was commonly suspected, as suggested by the high level of BAL neutrophils, and was responsible for sepsis-like syndrome in six patients. Despite the treatment of microorganisms identified by BAL, a fatal outcome eventually occurred in five patients. Therefore, our study suggests that early diagnosis and treatment of common infection in IPF patients do not really change the outcome at this stage of the disease.16 Of the two patients in whom pneumocystosis was diagnosed by BAL, only one patient’s condition improved with antifungal therapy.

In our study, management of IPF with either NIV or invasive MV was highly unsuccessful. The rate of mortality was indeed about 73%. A significant benefit of NIV has been demonstrated in acute exacerbations of COPD, reducing the need of endotracheal intubation, the length of hospital stay, and the in-hospital mortality rate.17 In our patients, intubation was avoided by NIV in only one patient. Our series is, however, too small to raise definite conclusions about this kind of treatment. Invasive MV did also not improve the prognosis of IPF patients, even though a potential cause of ARF was identified in nine patients. Lewis et al18 reported a quite similar poor prognosis in 16 patients with IPF who required ventilation for ARF. In this study, only two patients survived and one was able to receive a lung transplantation.18 Lung transplantation could be considered in those patients with end-stage IPF. However, once the patients are intubated, the too-short duration of survival in ICU does not allow waiting until a lung transplant is available.

Reasons for the inefficacy of ventilation in patients with end-stage IPF have been pointed out by Nava and Rubini,19 who measured the respiratory mechanics during MV in seven patients with IPF.19 They found that the elastance and the resistance of the respiratory system were markedly increased and correlated with the degree of hypercapnia. These phenomena may contribute to the absence of respiratory improvement with MV.

In conclusion, in the absence of identifiable reversible etiology, the prognosis of ARF in IPF patients is very poor, even with MV and treatment of current infections. In those conditions, we would not systematically recommend admission to the ICU.


   Footnotes
 
Abbreviations: ARF = acute respiratory failure; HRCT = high-resolution CT; IPF = idiopathic pulmonary fibrosis; MV = mechanical ventilation; NIV = noninvasive ventilation; PFT = pulmonary function test

Received for publication April 19, 2000. Accepted for publication November 20, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Bjoraker, JA, Ryu, JH, Edwin, MK, et al (1998) Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 157,199-203
  2. Turner-Warwick, M, Burrows, B, Johnson, A (1980) Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax 35,171-180[ISI][Medline]
  3. Wells, AU, du Bois, RM (1994) Prediction of disease progression in idiopathic pulmonary fibrosis. Eur Respir J 7,637-639[CrossRef][ISI][Medline]
  4. Hubbard, R, Johnston, I, Britton, J (1998) Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study. Chest 113,396-400[Abstract/Free Full Text]
  5. Ryu, JH, Colby, TV, Hartman, TE (1998) Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc 73,1085-1101[ISI][Medline]
  6. Panos, RJ, Mortenson, RL, Niccoli, SA, et al (1990) Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 88,396-404[CrossRef][ISI][Medline]
  7. Erbes, R, Schaberg, T, Loddenkemper, R (1997) Lung function tests in patients with idiopathic pulmonary fibrosis: are they helpful for predicting outcome? Chest 111,51-57[Abstract/Free Full Text]
  8. Katzenstein, AL, Myers, JL (1998) Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 157,1301-1315[Free Full Text]
  9. Gay, SE, Kazerooni, EA, Toews, GB, et al (1998) Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 157,1063-1072[Abstract/Free Full Text]
  10. Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement. Am J Respir Crit Care Med 2000; 161:646–664
  11. Selman, M, Carrillo, G, Salas, J, et al (1998) Colchicine, D-penicillamine and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Chest 114,507-512[Abstract/Free Full Text]
  12. Raghu, G, Depaso, WJ, Cain, K, et al (1991) Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blinded, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 144,291-296[ISI][Medline]
  13. Johnson, MA, Kwan, S, Snell, NJ, et al (1989) Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 44,280-288[Abstract]
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