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Keywords:

  • early intervention;
  • Krebs von den Lungen-6;
  • non-invasive ventilation;
  • rapidly progressive interstitial pneumonia

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background and objective:  Rapidly progressive interstitial pneumonia (RPIP), including acute exacerbations of interstitial pneumonia, is associated with high rates of mortality. The present study was performed to examine the effects of respiratory management using non-invasive ventilation (NIV) in patients with RPIP and to assess the prognostic factors for survival.

Methods:  BiPAP Vision was used for NIV. Clinical data and information on NIV were retrospectively obtained from patient records. Survival at 30 days was evaluated, and biomarkers were measured after initiation of NIV.

Results:  Thirty-eight patients who had been admitted with RPIP and treated by NIV were included in the study. The ratio of PaO2 to fraction of inspired oxygen at initiation of NIV was higher in survivors than in non-survivors (P = 0.0054). The mean duration to initiation of NIV after admission was significantly shorter in survivors than in non-survivors (P = 0.0006). Serum Krebs von den Lungen-6 (KL-6) and LDH levels at the start of NIV were higher in non-survivors than in survivors (KL-6, P = 0.022; LDH, P = 0.044). Bivariate logistic regression analysis showed that early intervention with NIV was a significant predictor of survival at 30 days. In addition, the ratio of PaO2 to fraction of inspired oxygen and both LDH and KL-6 levels at initiation of NIV were significant predictors of survival.

Conclusions:  Early intervention with NIV, mainly continuous positive pressure ventilation, is beneficial for the management of patients with RPIP. A randomized controlled study in a large population is needed to confirm the value of early NIV.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Interstitial lung disease with acute respiratory failure has a poor prognosis and is difficult to treat. These interstitial diseases have various aetiologies and are categorized into various types, such as idiopathic interstitial pneumonia, including acute exacerbations, hypersensitivity pneumonia, sarcoidosis, interstitial pneumonia-related collagen vascular disease (CVD-IP) and drug-induced acute interstitial pneumonia (Drug-IP). Recently, interstitial lung disease with acute respiratory failure has been reported as rapidly progressive interstitial pneumonia (RPIP).1,2 Patients with RPIP show diffuse lung inflammation and develop lung fibrosis in the advanced stages of the disease. The clinical course of the disease shows rapid progression. In general, these patients are treated with corticosteroids and other immunosuppressive agents.1–3 However, patients tend to develop severe acute hypoxaemia, and their prognosis is generally unfavourable. Rapid progression within 1 month is associated with a poor prognosis in patients with amyopathic dermatomyositis.4 In CVD-IP patients, acute exacerbations indicate a poor prognosis.5 There have been no major reviews on Drug-IP, but it has been reported that some drugs induced very severe interstitial pneumonia,6,7 particularly in patients with acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). It was reported that mechanical ventilation was not beneficial in these patients, and the use of mechanical ventilation in patients with IPF is questionable because of their poor prognosis.8,9 The rate of mortality in hospital among patients with AE-IPF is about 90%.10 It has yet to be determined how best to manage respiratory failure in patients with RPIP, including those with AE-IPF.

Non-invasive ventilation (NIV) avoids endotracheal intubation and reduces the risk of complications, such as ventilator-associated pneumonia.11 NIV has been shown to improve survival rates among immunosuppressed patients. In this study, we examined the value of NIV for patients with RPIP who develop acute respiratory failure. Outcomes and factors related to survival after the initiation of NIV were examined.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patients with RPIP, who were treated at Shinshu University Hospital between January 2005 and December 2010, were included in the study. The study protocol was approved by the Human Ethics Review Committee of Shinshu University School of Medicine. Informed consent was obtained from all patients or their families.

Patients

The following criteria for a diagnosis of RPIP were fulfilled: (i) development or unexplained worsening of dyspnoea within the preceding 30 days; (ii) new bilateral ground-glass opacities and/or consolidations on high-resolution CT; (iii) PaO2/inspiratory oxygen fraction (FIO2) (P/F) ratio <300 mm Hg; and (iv) absence of apparent infection, pneumothorax, pulmonary thromboembolism, heart failure or alternative causes of acute lung injury, such as trauma, blood infusion or toxic inhalation.2

The patients with RPIP were finally diagnosed as having AE-IPF, acute interstitial pneumonia (AIP) of unknown origin, CVD-IP or Drug-IP. The diagnosis of AE-IPF was based on the criteria proposed by Kondoh et al.12 Patients with AIP were diagnosed on the basis of an acute onset without infection or other disease. Patients with CVD-IP were diagnosed with RPIP based on the presence of collagen vascular disease. The presence of collagen vascular disease was inferred from detailed clinical histories, clinical examinations and data on serum analyses, including antineutrophil cytoplasmic antibody, anti-nuclear and anti-DNA antibodies, and rheumatoid factor. Drug-IP was diagnosed on the basis of clinical features and whether or not exposure to the drug coincided with the development of respiratory signs and clinical symptoms.

Examinations and treatments

Clinical data were obtained retrospectively from patient records. Survival at 30 days after the initiation of NIV was evaluated. NIV settings, treatments, laboratory findings and respiratory management at initiation of NIV were assessed. Information on the introduction of NIV, and settings, duration and management of NIV were collected retrospectively from patient records. The P/F ratio was determined at admission and at the initiation of NIV. Circulating white blood cell count (WBC), neutrophil count, serum LDH (normal range 114–220 IU/L), CRP (normal range 0.00–1.0 mg/L) and serum Krebs von den Lungen-6 (KL-6) (normal range 105–435 U/mL) levels were also determined at admission and at the initiation of NIV.

Standard microbiological investigations (e.g. blood and sputum cultures) were performed before the start of antibiotic therapy to exclude pulmonary infection. Broad-spectrum antibiotics were administered until the offending pathogen was identified. BAL was performed at admission except in patients with refractory hypoxaemia despite sufficient mechanical ventilation, those with haemodynamic instability and those who rejected BAL. BAL fluid was assessed to exclude infectious disease. Echocardiography was performed to exclude congestive heart failure.

High-dose corticosteroid (methylprednisolone 1 g/day for 3 days) was administered as a general therapy for RPIP. Other immunosuppressive therapies, including cyclophosphamide or cyclosporin A, were administered to patients in whom high-dose corticosteroid therapy was ineffective. The criterion for administration of immunosuppressive therapy was a decrease in the P/F ratio of more than 10 mm Hg from baseline, despite administration of high-dose corticosteroid therapy. For patients with idiopathic interstitial pneumonia (AE-IPF and AIP), combined therapy, including cyclophosphamide (500 mg/m2, every 3 weeks), was administered. For patients with CVD-IP or Drug-IP, cyclophosphamide or cyclosporin was added on a case-by-case basis. Drug-IP was treated by discontinuing the causative agent. In this study, NIV was initiated for Drug-IP patients who experienced no improvement in their respiratory function with standard treatment. Drug-IP patients who improved after receiving immunosuppressive treatment were excluded from this study.

NIV

Initiation of NIV was based on the judgment of individual physicians after patients with severe respiratory failure did not respond to conventional oxygen therapy by nasal cannula or face mask. BiPAP Vision (Respironics Inc., Murrysville, PA, USA) was used for NIV. The initial ventilator setting was CPAP mode, and the CPAP level was increased gradually from 4 cmH2O.13 Pressure support was provided for patients with high respiratory frequencies or respiratory acidosis. FIO2 was set at 100% and was decreased so as to maintain PaO2 at >60 mm Hg.

Endotracheal intubation was performed in patients with decreased alertness or major agitation requiring sedation, those with clinical signs of exhaustion (active contraction of the accessory respiratory muscles with paradoxical abdominal or thoracic motion), those with haemodynamic instability, cardiac arrest or refractory hypoxaemia, and those with a P/F ratio <100 after treatment by NIV.

Evaluation of clinical outcomes

Clinical data were obtained retrospectively from patient records. The patients' physical status (age, BMI, smoking history, acute physiology and chronic health evaluation [APACHE] II score), laboratory data, respiratory management by NIV, P/F ratio at admission and at initiation of NIV, and survival at 30 days after the introduction of NIV were analysed.

Statistical analysis

Data for all patients were included in the statistical analysis. Normally distributed parameters are presented as means ± SD. Differences between survivors and non-survivors were assessed for statistical significance using the Mann–Whitney U-test and Fisher's exact probability test. Correlations were assessed by the Wilcoxon signed-rank test. Bivariate logistic regression analysis was performed, with the dependent variable being 30-day survival. In all analyses, P < 0.05 was taken to indicate statistical significance. StatView® 5.0 (SAS Institute Inc., Cary, NC, USA) was used for all analyses.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patient characteristics

Thirty-eight patients (29 men and 9 women; mean age 68.8 ± 10.1 years) were included in the study. The diagnoses were AE-IPF (n = 16), AIP (n = 4), CVD-IP (n = 6) and Drug-IP (n = 12). The six patients with CVD-IP included three with AIP due to dermatomyositis and three with acute exacerbations of chronic interstitial pneumonia due to collagen vascular disease (one with polymyositis, one with systemic sclerosis and one with rheumatoid arthritis). The underlying cause of RPIP was not significantly related to survival (data not shown). NIV was not offered to another 26 patients during the same period (AE-IPF, n = 5; Drug-IP, n = 21), and these patients were excluded because their respiratory function improved immediately with standard treatment such as corticosteroid therapy.

Standard baseline microbiological investigations on admission showed no evidence of infectious disease. Blood cultures were negative in all patients, as were the results for Gram staining and culture of sputum. BAL was performed at admission for 21 of the 38 patients included in this study. In all patients, the BAL fluid revealed no evidence of infection. BAL was not performed on the other patients because of their severe hypoxaemia.

Characeristics of the patients who did or did not survive

The baseline characteristics of the patients who did or did not survive to 30 days are shown in Table 1. There were no major complications after initiation of NIV. In all patients, NIV was initially set to CPAP mode and was administered for a mean of 11.0 ± 13.9 days. There was no significant difference in the highest CPAP level between survivors (8.1 ± 2.7 cmH2O) and non-survivors (8.1 ± 3.3 cmH2O). Bi-level pressure support was required for three patients because of elevated PaCO2 levels. However, all three patients died within 30 days. All patients were treated by NIV for as many hours per day as possible, except at mealtimes.

Table 1.  Comparison of demographic and clinical parameters between patients who did or did not survive to 30 days
VariableSurvivorsNon-survivorsP value
  1. Data are mean ± SD or number (%) of patients.

  2. APACHE, acute physiology and chronic health evaluation; FIO2, inspiratory oxygen fraction; NIV, non-invasive ventilation; PSV, pressure support ventilation; PS, pressure support.

Number (males/females)26 (20/6)12 (9/2)>0.999
Age, years67.3 ± 8.072.1 ± 13.30.039
BMI, kg/m222.6 ± 2.822.4 ± 3.70.688
Smoking history, n (%)13 (50)6 (50.0)0.734
Pack years18.6 ± 24.99.8 ± 14.70.434
APACHE II score9.5 ± 3.111.4 ± 3.20.056
FIO2 for conventional oxygen therapy before starting NIV, %61.8 ± 26.180.3 ± 24.20.0336
Time to initiation of NIV, days2.3 ± 2.94.4 ± 3.10.0006
Intervention with NIV within the first hospital day, n (%)20 (76.9)1 (8.3)<0.0001
NIV settings   
 Mode   
  CPAP, n (%)26 (100)9 (75)0.0261
  PSV, n (%)0 (0)3 (25)0.0261
  PEEP, cmH2O8.1 ± 2.78.1 ± 3.30.8716
  PS, cmH2O0.0 ± 0.00.8 ± 1.50.0088
Duration of NIV, days11.8 ± 16.29.3 ± 7.40.717
Endotracheal intubation, n (%)8 (30.8)4 (33.3)>0.999

Eighteen of the 38 patients (47.4%) did not require endotracheal intubation and survived for over 30 days after the initiation of NIV (Fig. 1). Sixteen of the 18 patients were discharged, having survived without mechanical ventilation. Although respiratory failure deteriorated after the 30th hospital day in two of the 18 patients, these two patients refused endotracheal intubation and died in hospital.

image

Figure 1. Flow diagram showing the process for enrolment of patients with rapidly progressive interstitial pneumonia. The figure shows survival to 30 days and rate of survival in hospital. NIV, non-invasive ventilation.

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Eight of 38 patients developed respiratory failure within 30 days while in hospital. However, these eight patients refused endotracheal intubation and died in hospital while receiving NIV.

Twelve of the 38 patients (31.6%) were intubated and mechanically ventilated due to progression of hypoxaemia. The median time from initiation of NIV to intubation was 8.8 ± 10.0 days. Eight of the 12 intubated patients survived to 30 days after the initiation of NIV, and the remaining four died of respiratory failure within 30 days. Only four of eight intubated patients survived and were discharged, but two of four intubated patients were discharged after mechanical ventilation, and four of the eight finally died in hospital. The mean rate of survival to 30 days after the initiation of NIV for all 38 patients was 70.3%. Overall, 20 patients survived and were discharged, and the rate of mortality in hospital for all patients was 54.1%. There were no significant differences in survival among the different groups of patients (Fig. 2).

image

Figure 2. Survival curves for patients with different types of interstitial lung disease. AE-IPF: acute exacerbation of idiopathic pulmonary fibrosis; AIP, acute interstitial pneumonia; CVD-IP, acute interstitial pneumonia-related collagen vascular disease; Drug-IP, drug-induced acute interstitial pneumonia; NS, not significant.

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Early initiation of NIV was associated with survival

As shown in Table 1, there were no significant differences in gender, BMI or smoking history between survivors and non-survivors. Survivors were significantly younger than non-survivors (P = 0.039). APACHE II scores were not significantly different between the two groups. The mean time to initiation of NIV after onset of respiratory failure was significantly shorter in survivors than in non-survivors (2.3 ± 2.9 days vs 4.4 ± 3.1 days; P = 0.0006).

All patients received conventional oxygen therapy because of hypoxaemia at admission. The use of conventional oxygen therapy before initiation of NIV differed between survivors and non-survivors, as shown in Table 1. The FIO2 during oxygen therapy was higher in non-survivors than in survivors (P = 0.0336).

P/F ratio at the start of NIV was higher in survivors

The P/F ratio was significantly decreased from baseline to initiation of NIV in both groups. As shown in Table 2, there was no significant difference in the baseline P/F ratio between survivors and non-survivors. However, the P/F ratio at initiation of NIV was higher in survivors than in non-survivors (P = 0.0054).

Table 2.  Comparison of laboratory data for survivors and non-survivors
Variable SurvivorsNon-survivorsP value
  • Significant difference between admission and start of NIV (Wilcoxon signed-rank test, P < 0.05). P values shown are for comparison between survivors and non-survivors at admission and start of NIV.

  • Data are mean ± SD.

  • FIO2, inspiratory oxygen fraction; KL-6, Krebs von den Lungen-6; Neu, neutrophils; NIV, non-invasive ventilation; WBC, white blood cell count.

PaO2/FIO2Admission195.6 ± 75.8184.0 ± 71.60.851
Start of NIV164.5 ± 53.6*110.4 ± 50.5*0.005
WBC (×109/L)Admission11.2 ± 4.48.8 ± 3.30.084
Start of NIV12.3 ± 4.5*14.2 ± 6.7*0.445
Neu (×109/L)Admission9.3 ± 4.37.6 ± 3.10.388
Start of NIV10.5 ± 4.6*13.5 ± 6.5*0.180
CRP (mg/L)Admission105 ± 6481 ± 680.203
Start of NIV91 ± 6965 ± 850.131
LDH (IU/L)Admission420.2 ± 126.9486.3 ± 330.70.778
Start of NIV416.8 ± 118.2650.7 ± 360.0*0.044
KL-6 (U/mL)Admission1448.2 ± 810.91942.1 ± 1309.10.414
Start of NIV1515.7 ± 837.3*3015.4 ± 1854.2*0.022

In non-survivors, serum KL-6 levels increased before initiation of NIV

As shown in Table 2, there were no significant differences in baseline circulating WBC, neutrophil count, serum KL-6, LDH and CRP levels between survivors and non-survivors. However, serum KL-6 and LDH levels at initiation of NIV were higher in non-survivors compared with survivors (P = 0.022 and P = 0.044, respectively). KL-6 and LDH levels were significantly increased in the non-survivors. However, in survivors, the change in LDH levels was not significant, and the change in KL-6 levels was modest. Based on the LDH and KL-6 levels, interstitial inflammation and lung fibrosis were milder in the survivors than in the non-survivors. NIV was initiated earlier in the survivors than in the non-survivors (Fig. 3).

image

Figure 3. Changes in PaO2/FIO2 from admission to initiation of non-invasive ventilation (NIV) in survivors and non-survivors. ANOVA, analysis of variance; FIO2, inspiratory oxygen fraction.

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Early intervention with NIV improved survival

All patients received conventional oxygen therapy from the time of admission. Twenty-one patients were treated by NIV on the first hospital day. Twenty of these 21 patients were still alive on the 30th hospital day. Initiation of NIV within the first hospital day was defined as early intervention with NIV. Kaplan–Meier curves were used to compare survival between the groups that received early or late intervention with NIV. There was a significant difference between these two groups (log rank P = 0.0016), as shown in Figure 4. There was no difference in intubation rates between the two groups.

image

Figure 4. Survival curves for patients who received early or late intervention with non-invasive ventilation (NIV). Early NIV intervention: time from admission to start of NIV <24 h; late NIV intervention: time from admission to start of NIV >24 h.

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Bivariate logistic regression analysis

Bivariate logistic regression analysis was performed to evaluate the prognostic value of clinical variables and laboratory findings for survival to 30 days (Table 3). Age was not a significant predictor in this analysis, although survivors were significantly younger than non-survivors. Early intervention with NIV was a significant predictor of survival to 30 days. P/F ratio, as well as LDH and KL-6 levels, at initiation of NIV was significant predictors of survival to 30 days, whereas the values for these parameters at admission were not. The underlying cause of RPIP was not a significant predictor of survival to 30 days (data not shown).

Table 3.  Bivariate logistic regression analysis for factors predicting survival to 30 days
ParameterOdds ratioConfidence intervalP value
  1. APACHE, acute physiology and chronic health evaluation; FIO2, inspiratory oxygen fraction; KL-6, Krebs von den Lungen-6; NIV, non-invasive ventilation.

Age0.9430.865–1.0280.186
Male gender1.110.226–5.4690.897
BMI1.020.805–1.2970.861
Smoking history1.4000.352–5.5730.633
APACHE II score0.8160.645–1.0340.092
Endotracheal intubation0.8890.206–3.8310.874
Early intervention with NIV37.040.003–0.2570.002
Clinical/laboratory findings at admission   
 PaO2/FIO2, log change2.730.056–132.0100.613
 LDH, log change0.3570.005–26.4800.640
 KL-6, log change0.2130.016–2.8140.240
Clinical/laboratory findings at start of NIV   
 PaO2/FIO2, log change912.26.129–135 773.1470.008
 LDH, log change0.0090.001–0.8080.040
 KL-6, log change0.0310.001–0.7380.032

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The clinical usefulness of NIV for RPIP, including AE-IPF, AIP, CVD-IP and Drug-IP, was evaluated. Previous studies have indicated that endotracheal intubation9 or admission to an intensive care unit14 provided no survival advantage in patients with RPIP, including those with AE-IPF. A recent review of nine reports indicated that AE-IPF has a very poor prognosis (87.4% hospital mortality and 94.1% overall mortality).10 Furthermore, AIP was reported to have a high rate of mortality (67.7%).15 However, the present data suggested that early treatment by NIV conferred a survival advantage in patients with RPIP. In this study, patients who survived to 30 days tended to receive NIV earlier than non-survivors. In non-survivors, the P/F ratio decreased significantly between baseline and the initiation of NIV. A delay in the initiation of NIV increased the severity of respiratory failure in non-survivors as compared with survivors.

In general, patients with interstitial pneumonia are treated with corticosteroids and immunosuppressive agents.1–3 Hilbert et al. demonstrated that in selected immunosuppressed patients with pneumonitis and acute respiratory failure, early initiation of NIV was associated with significant reductions in the rates of endotracheal intubation and serious complications, as well as an improved likelihood of survival to hospital discharge.11 These findings suggest that NIV may be more effective than intubation and mechanical ventilation in immunocompromised patients with RPIP. Some previous studies indicated that NIV was potentially beneficial for patients with RPIP.16,17 We previously reported that NIV was a viable option for management of respiratory failure in patients with AE-IPF, considering their extremely poor prognosis.17 However, there have been no good controlled randomized studies investigating this option.

In comparison with conventional oxygen therapy, little is known about the effects of NIV. Patients with interstitial pneumonia have unstable ventilation/perfusion ratios due to dead space in the lungs as a consequence of the progression of lung fibrosis and inflammation. Therefore, adequate oxygen supplementation is important for stabilizing respiratory function in these patients. FIO2 also fluctuates during conventional oxygen therapy, depending on adequate and effective alveolar ventilation. With NIV, FIO2 remains stable regardless of fluctuations in ventilation.

Furthermore, because PEEP can reduce dead space in the lungs, it may improve oxygenation and avoid the need for high FIO2. Prolonged use of high FIO2 during conventional oxygen therapy (without NIV and PEEP) may result in oxygen toxicity due to free radical-induced lung injury;18,19 therefore earlier initiation of NIV may reduce oxygen toxicity and additional lung injury. In this study, non-survivors had been treated with a higher FIO2 during oxygen therapy before initiation of NIV. The survivors may have been protected from oxygen toxicity because of the beneficial effects of PEEP.

In this study, early intervention with NIV was found to be more effective in prolonging survival. Early initiation of NIV improved the survival rate in comparison with conventional oxygen therapy. Bivariate regression analysis showed that early initiation of NIV was an important predictor of survival to 30 days.

In a multicentre survey of the use of NIV in patients with ARDS, Antonelli et al. found that successful NIV was associated with low simplified acute physiology scores, less severe disease and improvement in the P/F ratio within 2 h of the initiation of NIV.20 In the present study, bivariate regression analysis indicated that the P/F ratio, as well as serum KL-6 and LDH levels at initiation of NIV, was significant predictors of survival to 30 days, although the values of these parameters at admission were not. The data suggested that early initiation of NIV was more important in the early phase of lung injury, when there is alveolar inflammation and pulmonary oedema, rather than in the late phase, which is characterized mainly by fibrosis. In the early phase, positive pressure ventilation may protect against microatelectasis of alveoli and improve hypoxaemia. In the present study, late initiation of NIV was associated with worsening of hypoxaemia in patients who subsequently died. Markers of lung fibrosis, such as serum KL-6 and LDH levels, did not differ significantly between survivors and non-survivors at admission. However, KL-6 and LDH levels had deteriorated more in non-survivors than in survivors at initiation of NIV. This suggested that fibrosis had progressed to a greater degree in the non-survivors at initiation of NIV. Positive pressure ventilation is not beneficial for fibrosis in late-stage disease. It is therefore important to initiate NIV at an early phase when the patient's respiratory function is better.

Comparison of data for survivors and non-survivors demonstrated the importance of early initiation of NIV. However, the present study had important limitations. As it was a retrospective investigation, the time of initiation of NIV varied. NIV was initiated in some patients with only mild hypoxaemia, whereas this was not the case in other patients. The initiation of NIV was delayed for various reasons based on the physicians' decisions because the criteria for initiation of NIV were not predetermined. The physician in charge may have doubted the efficacy of early NIV for some patients. Therefore, a well-controlled randomized study should be performed.

The use of bi-level support ventilation was not evaluated in the present study because all patients initially received CPAP without bi-level pressure support. Only three patients received pressure support ventilation because of elevation of PaCO2 due to disease progression. The effects of ventilation mode on survival were not assessed.

In conclusion, early intervention with NIV, mainly continuous positive pressure ventilation, may be a beneficial option in the management of RPIP and can potentially improve patient outcomes. A randomized controlled study is required to confirm the usefulness of early intervention with NIV.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES