Effectiveness of NIV vs. IMV in AECOPD

Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States,[1] and its rising mortality trend is unique among the top 5 causes of death.[2] Acute exacerbations of COPD (AECOPD) are important events in the natural history of COPD, accounting for 1.5 million emergency department (ED) visits and 726,000 hospitalizations each year in the United States.[3, 4] Given the significant morbidity and mortality from AECOPD, Healthy People 2020 lists reducing deaths, hospitalizations, and ED visits as the key objectives for COPD.[5]

Over the past 2 decades, noninvasive ventilation (NIV) has emerged as a potentially useful treatment modality in AECOPD patients with acute respiratory failure. Noninvasive ventilation commonly refers to positive‐pressure ventilatory support delivered through a nasal or full‐face mask, such as bilevel positive airway pressure.[6] A number of randomized controlled trials[7, 8, 9] and meta‐analyses[10] have suggested a mortality‐reduction benefit with NIV use compared with standard medical care in AECOPD. To our knowledge, however, very few small randomized controlled trials compared NIV vs invasive mechanical ventilation (IMV) head‐to‐head,[11, 12, 13] and a recent evidence review found only 5 studies (405 subjects) on this topic.[14] Collectively, the limited evidence from randomized trials showed that NIV use resulted in similar intensive care unit (ICU) and in‐hospital mortality, fewer complications (eg, ventilator‐associated pneumonia and sepsis), and shorter hospital length of stays (LOS). Given that these trials have a smaller sample size and tend to exclude older patient (age >75 years) or patients with multiple comorbidities, there is a need to better understand the adoption and effectiveness of NIV treatment for AECOPD in a much larger patient population in the real‐world setting using observational data.

To address these knowledge gaps in the literature, we analyzed data from a large, nationally representative ED and inpatient sample. The objective of the present analysis was 2‐fold: (1) to characterize the use of NIV and IMV in AECOPD patients with acute respiratory failure at a national level; and (2) to compare the effectiveness of NIV vs IMV in the real‐world setting.

METHODS

RESULTS

Patient and ED Characteristics

The 20062008 NEDS sample contained 67,651 ED visits for AECOPD with acute respiratory failure from 1594 US EDs. After the weighting procedure, there were an estimated 101,000 visits annually for AECOPD with acute respiratory failure from approximately 4700 US EDs. In the weighted analysis, the mean patient age of these visits was 68 years, and 56% were made by women. Ninety‐six percent were admitted to the hospital. Of these, the mortality rate was 9% and the mean hospital LOS was 7 days. Figure 1 shows the secular trends in NIV, IMV, and the combined use over the 3‐year study period. Use of IMV decreased from 28% in 2006 to 19% in 2008 (P<0.001), whereas NIV use increased slightly from 14% in 2006 to 16% in 2008 (P=0.049); the combined use of both ventilation modalities remained stable (4%). Inpatient mortality decreased from 10% in 2006 to 7% in 2008 (P<0.001).

Figure 1

Figure 2 shows that the frequency of NIV use (including combined use of NIV and IMV) varied widely between hospitals, ranging from 0% to 100% with a median of 11%. In the unweighted cohort of AECOPD with acute respiratory failure, 43% received some forms of ventilatory support. Table 1 shows the patient and hospital characteristics of the patients receiving ventilatory support: 36% received NIV, 56% received IMV, and 8% received combined use. In general, patients receiving combined use of NIV and IMV tended to have more comorbidities (eg, congestive heart failure and pneumonia) compared with the NIV‐alone or IMV‐alone groups. With respect to hospital characteristics, NIV was used more often in hospitals with higher volumes of COPD exacerbation and respiratory failure, in nonmetropolitan hospitals, and in hospitals in the Northeast.

Figure 2

Table 1.Patient and Hospital Characteristics According to Ventilatory Mode

	NIV Alone (A) (n=10,032)	IMV Alone (B) (n=15,427)	Combined Use (C) (n=2311)	P Value, A vs B	P Value, B vs C
NOTE: Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; ED, emergency department; IMV, invasive mechanical ventilation; IQR, interquartile range; NIV, noninvasive ventilation.
Patient characteristics
Age, y,				<0.001	0.64
4049	5	5	5
5059	17	18	19
6069	31	33	33
7079	30	29	29
80	17	15	13
Female sex, %	57	53	54	<0.001	0.87
Quartile for median household income of patient ZIP code, $, %				<0.001	<0.001
138,999	30	34	29
39,00047,999	28	28	28
48,00062,999	24	22	24
63,000	18	15	19
Weekend admission, %	27	28	28	0.07	0.80
Insurance status, %				<0.001	0.91
Medicare	74	70	70
Medicaid	9	12	12
Private	12	13	13
Self‐pay	2	3	2
Other	2	2	2
Season, %				<0.001	0.16
Winter (January 1March 31)	29	32	31
Spring (April 1June 30)	24	25	26
Summer (July 1September 30)	22	20	19
Fall (October 1December 31)	25	22	24
No. of comorbidities, median (IQR)	4 (35)	4 (35)	4 (36)	<0.001	<0.001
Selected comorbidities, %
Hypertension	56	55	55	0.01	0.65
CHF	38	40	44	0.001	<0.001
Fluid and electrolyte disorders	37	44	49	<0.001	<0.001
Diabetes, uncomplicated	27	26	29	0.04	0.002
Pneumonia	19	34	39	<0.001	<0.001
Deficiency anemia	16	19	19	<0.001	0.39
Obesity	18	12	17	<0.001	<0.001
Depression	15	11	11	<0.001	0.54
Pulmonary circulatory diseases	15	11	14	<0.001	<0.001
Hospital characteristics
Annual ED visit volume, median (IQR)	42,704 (29,50562,470)	44,119 (29,89564,097)	46,695 (31,29866,235)	0.02	0.0003
Annual ED volume of COPD exacerbation with respiratory failure, median (IQR)	45 (2672)	42 (2368)	38 (2364)	<0.001	<0.001
Urban/rural and teaching status, %				<0.001	<0.001
Metropolitan nonteaching	53	52	47
Metropolitan teaching	31	35	39
Nonmetropolitan	16	13	13
US region, %				<0.001	<0.001
Northeast	28	16	36
Midwest	17	22	15
South	41	45	32
West	14	17	17

The unadjusted differences in outcomes are shown in Table 2. The combined‐use group had the highest inpatient mortality, longest LOS, and highest charges, followed by the IMV and NIV groups. In general, complications were few across all 3 groups, but the rate of iatrogenic pneumothorax was notably lower in the NIV group. Table 3 details the statistically significant predictors of NIV use in the propensity score model. Similar to the unadjusted analysis, older age, high‐income neighborhoods, Medicare insurance, and some comorbidities were positively associated with NIV use (eg, pulmonary circulatory disorders and liver disease), whereas a few comorbidities were negatively associated with NIV use (eg, pneumonia, and alcohol and drug abuse). With respect to hospital characteristics, higher case volumes of COPD exacerbation/respiratory failure, Northeastern and nonmetropolitan hospitals, and more recent years were associated with NIV use.

Table 2.Clinical Outcomes Among COPD Patients With Acute Respiratory Failure According to Ventilatory Mode

Outcome	NIV Alone (A) (n=10,032)	IMV Alone (B) (n=15,427)	Combined Use (C) (n=2311)	P Value. A vs B	P Value, B vs C
NOTE: Abbreviations: COPD, chronic obstructive pulmonary disease; IMV, invasive mechanical ventilation; IQR, interquartile range; NIV, noninvasive ventilation. *For privacy protection, we are not able to report cells in the tables 10 individual records.
Inpatient mortality, n (%)	825 (8)	2,454 (16)	407 (18)	<0.001	0.04
Hospital length of stay, median (IQR), d	5 (48)	8 (513)	10 (716)	<0.001	<0.001
Hospital charge per visit, median (IQR), $	26,002 (15,74744,638)	53,432 (31,99892,664)	64,585 (39,024110,336)	<0.001	<0.001
Complications*
Ventilator‐associated pneumonia, n (%)	10 (0.1)	10 (0.1)	10 (0.5)	0.09	1.00
Facial injury, n (%)	10 (0.1)	10 (0.1)	10 (0.5)	0.26	1.00
Iatrogenic pneumothorax, n (%)	10 (0.1)	90 (0.6)	14 (0.6)	<0.001	0.90

Table 3.Statistically Significant Predictors of NIV Use Alone

Patient Characteristics	Adjusted OR (95% CI)*	P Value
NOTE: Abbreviations: AIDS, acquired immune deficiency syndrome; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ED, emergency department; NIV, noninvasive ventilation; OR, odds ratio; RA, rheumatoid arthritis. *Propensity score model included the following patient and hospital characteristics: age, sex, median household income, insurance status, weekend admission, season, comorbid conditions, US region, urban/rural and teaching status, annual ED volume, annual ED volume of COPD with respiratory failure, and calendar year. Nonsignificant predictors that are not reported in the table include sex, weekend admission, and the following comorbid conditions: peripheral vascular disorders, paralysis, uncomplicated diabetes, hypothyroidism, renal failure, peptic ulcer disease excluding bleeding, hypertension, lymphoma, AIDS, solid tumor without metastasis, and metastatic cancer.
Age, y
4049	1.00 (Reference)
5059	0.96 (0.84‐1.11)	0.61
6069	0.96 (0.84‐1.10)	0.56
7079	1.09 (0.94‐1.25)	0.25
80	1.30 (1.12‐1.52)	0.001
Quartile for median household income of patient ZIP code, $
138,999	1.00 (Reference)
39,00047,999	1.13 (1.05‐1.21)	0.001
48,00062,999	1.21 (1.12‐1.30)	<0.001
63,000	1.21 (1.11‐1.32)	<0.001
Insurance status
Medicare	1.00 (Reference)
Medicaid	0.79 (0.72‐0.88)	<0.001
Private	0.88 (0.81‐0.96)	0.004
Self‐pay	0.68 (0.56‐0.82)	<0.001
Other	0.88 (0.73‐1.07)	0.22
Season
Winter (January 1March 31)	1.00 (Reference)
Spring (April 1June 30)	1.06 (0.99‐1.14)	0.11
Summer (July 1September 30)	1.17 (1.08‐1.26)	<0.001
Fall (October 1December 31)	1.24 (1.15‐1.33)	<0.001
Comorbidity
CHF	0.90 (0.85‐0.95)	<0.001
Pulmonary circulatory disorders	1.40 (1.29‐1.52)	<0.001
Diabetes, complicated	1.25 (1.08‐1.44)	0.002
Liver disease	1.79 (1.40‐2.28)	<0.001
Coagulopathy	0.54 (0.46‐0.63)	<0.001
Obesity	1.52 (1.41‐1.65)	<0.001
Weight loss	0.50 (0.44‐0.57)	<0.001
Fluid and electrolyte disorders	0.84 (0.80‐0.89)	<0.001
Deficiency anemia	0.83 (0.78‐0.90)	<0.001
Alcohol abuse	0.66 (0.58‐0.76)	<0.001
Drug abuse	0.74 (0.62‐0.88)	0.001
Psychoses	1.22 (1.10‐1.37)	<0.001
Depression	1.45 (1.34‐1.57)	<0.001
Pneumonia	0.48 (0.45‐0.51)	<0.001
Valvular heart disease	0.87 (0.77‐0.97)	0.01
Neurological disorders	0.89 (0.80‐0.98)	0.02
RA/collagen vascular diseases	1.25 (1.02‐1.53)	0.04
Blood‐loss anemia	0.72 (0.53‐0.97)	0.03
Hospital characteristics
Annual ED visit volume, per 1000‐visit increase	0.997 (0.996‐0.998)	<0.001
Annual ED volume of COPD exacerbation with respiratory failure, per 10‐visit increase	1.03 (1.02‐1.03)	<0.001
Urban/rural and teaching status
Metropolitan nonteaching	1.00 (Reference)
Metropolitan teaching	0.91 (0.85‐0.97)	0.006
Nonmetropolitan	1.30 (1.20‐1.42)	<0.001
US region
Northeast	1.00 (Reference)
Midwest	0.44 (0.40‐0.48)	<0.001
South	0.54 (0.50‐0.58)	<0.001
West	0.51 (0.46‐0.56)	<0.001
Calendar year
2006	1.00 (Reference)
2007	1.30 (1.22‐1.39)	<0.001
2008	1.65 (1.54‐1.76)	<0.001

In terms of propensity score distributions (see Supporting Information, Figure E1, in the online version of this article), there was sufficient overlap of the NIV and IMV groups. After matching on propensity score for the NIV and IMV groups, the differences in baseline characteristics were all balanced (see Supporting Information, Table E1, in the online version of this article), as indicated by <10% standardized differences in all covariates between the 2 groups. Finally, in the propensity scorematched cohort (see Supporting Information, Table E2, in the online version of this article), NIV use remained associated with significantly lower inpatient mortality (risk ratio: 0.54; 95% CI: 0.50‐0.59, P<0.001), a shorter hospital LOS (mean difference, 3.2 days; 95% CI: 3.4 to 2.9 days, P<0.001), and lower hospital charges (mean difference, P<$35,012; 95% CI: $36,848 to $33,176, P<0.001), compared with IMV use. Use of NIV also was associated with a lower rate of iatrogenic pneumothorax than IMV use (0.05% vs 0.5%, P<0.001).

Using hospital preference for NIV vs IMV as an instrument, the instrumental analysis confirmed the benefits of NIV use, with a 5% reduction in inpatient mortality in the NIV‐preferring hospitals (risk difference, P<5%; 95% CI: P<1.8% to P<8.3%).

In the sensitivity analysis to assess the impact of an unmeasured confounder, the confounder would have had to have a very strong impact on outcome (risk ratio: 5) and a severe exposure‐confounder imbalance (odds ratio of exposure on confounder: 5) to reduce the observed association to 1.0. In other words, an individual unmeasured confounder is unlikely to explain the observed association.

DISCUSSION

In this nationally representative sample of 67,651 ED visits for AECOPD with acute respiratory failure, we found that NIV use was increasing from 2006 to 2008. However, the utilization of NIV remained low (16% in 2008) and varied widely by patient and hospital characteristic. As with all observational studies, causality cannot be inferred definitely; however, our study suggests that, NIV usecompared with IMV usewas associated with potentially important benefits: a reduction of inpatient mortality by 46%, shortened hospital LOS by 3 days, reduced hospital charges by approximately $35,000 per visit, and modestly reduced risk of iatrogenic pneumothorax.

A recent analysis using the US Nationwide Inpatient Sample has shown increasing use of NIV and concomitant decreasing mortality in AECOPD over time.[28] Our analysis confirmed these favorable trends in the United States using a much larger NEDS sample (28 million visits in the NEDS vs 8 million visits in the Nationwide Inpatient Sample per year). Despite these favorable trends, NIV was still underutilized for AECOPD with respiratory failure in the United States (16% in 2008) compared with major European countries (40%).[29] Although our study lacked clinical details to arrive at the optimal rate of NIV use, the low rate of NIV use is concerning and suggests room for improvement in NIV use in appropriate patients as outlined by the current COPD guidelines.[18, 30] Why is NIV not widely adopted, given its demonstrated efficacy? Previous surveys have identified several perceived reasons for low NIV use, including lack of physician knowledge, insufficient respiratory therapist training, inadequate equipment, and time required for setting up NIV.[29, 31, 32] Our study adds to the literature by showing the actual predictors of NIV use in the real world. Our data showed that the early adopters were hospitals with higher case volumes, and hospitals in the Northeast and in nonmetropolitan areas. A higher case volume has been linked with lower mortality in AECOPD (ie, practice makes perfect),[33] and frequent NIV use could explain the lower AECOPD mortality in highcase volume centers. Alternatively, smaller hospitals tend to have moonlighters working in EDs who may not be board certified in emergency medicine. Perhaps the logical next step is to conduct a qualitative study to understand the specifics of best practices and provider characteristics in these Northeastern, highercase volume centers. Another incentive to promote NIV use in clinical practice is the cost‐effectiveness associated with this intervention, as previous studies have shown that, compared with usual care, receiving NIV was associated with a reduction in costs, mainly through reduced use of the ICU.[34, 35]

Some patient factors associated with NIV use may be well justified. For example, older AECOPD patients may have an advance directive describing their treatment wishes (eg, do‐not‐intubate order),[36] and therefore NIV was preferred to IMV. Also, our data suggested AECOPD patients with a suspected pneumonia component were less likely to be placed on NIV, which is consistent with COPD guideline recommendations.[18, 30] As outlined in the current guidelines, the major contraindications to NIV include impending respiratory arrest, excessive respiratory secretions, massive gastrointestinal bleeding, recent facial trauma, or altered mental status.[18, 30] By contrast, some factors associated with NIV use may be targeted for intervention, such as lower rates of NIV use in the uninsured, patients who live in low‐income neighborhoods, and hospitals in US regions other than the Northeast.

Current guidelines recommend using NIV in AECOPD patients with early signs of respiratory failure, such as arterial pH of 7.257.35 or pCO₂ 45 mm Hg.[18, 30] When NIV is considered as the modality of ventilatory support, it should probably be used as early as possible,[37] because evidence suggests that delayed use of NIV may lead to severe respiratory acidosis and increased mortality.[38] Other than in ICUs, NIV can be used on general wards and in EDs that have adequate staff training and experience, because the success rates of NIV in these settings are similar to those reported in ICU studies.[8, 36, 39] In addition, NIV is more cost‐effective when performed outside the ICU.[35] In fact, studies have found a substantial portion of patients had NIV started in the ED (one‐fourth) and on the general ward (one‐fourth).[31, 40] Given the shortage of intensivists in the United States, hospitalists begin to play an important role in provision of critical care outside the ICU.[41] Once NIV is used, it is important to ensure that it is delivered effectively and monitored closely because NIV failure has been shown to be associated with high mortality.[28, 42]

This study has some potential limitations. First, we used administrative claims that lack clinical details such as data on arterial blood gases and severity scores, and thus potential residual confounding may exist. In our study, the IMV group may be sicker than the NIV group, which could partially explain the increased mortality with IMV. However, the propensity scores overlap to a great extent between the 2 study groups, suggesting that a strong confounding bias is less likely, given the observed covariates. Furthermore, the instrumental variable and sensitivity analyses taking into account unmeasured confounders still suggested the benefits of NIV. Second, the NEDS does not contain data on the location where NIV was initiated (eg, ED, ward, or ICU) or the timing of initiating NIV or IMV. As a result, for the combined‐use group, we could not further distinguish the group switching from NIV to IMV (ie, NIV failure)[42] or from IMV to NIV (ie, NIV as a weaning strategy).[43] Accordingly, we chose to focus on the comparativeness effectiveness of NIV vs IMV. Third, although the NEDS data have undergone quality‐control procedures,[44] some misclassification may exist in identifying patient population and interventions. Finally, the analysis may not reflect the most recent trend in NIV use, as the 2010 NEDS data have just been released. In addition, although the study is the largest to date on this topic, our findings may not be generalizable to EDs that were not part of the NEDS.

In summary, in this nationally representative ED and inpatient database, NIV use is increasing for AECOPD with acute respiratory failure; however, its adoption remains low and varies widely between US hospitals. Our observational study suggests that NIV appears to be more effective and safer than IMV in the real‐world setting. There is an opportunity to increase the use of NIV as recommended in guidelines and to promote the use NIV in replacement of IMV in patients with severe AECOPD. Given the increasing mortality burden of COPD, such a strategy may help reduce COPD mortality at the population level, thereby fulfilling the objectives of Healthy People 2020.

Disclosure

Partial results from this study were presented at the 2012 Society for Academic Emergency Medicine Annual Meeting, Chicago, Illinois, May 912, 2012. This project was supported by grant number R03HS020722 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The authors have no conflicts of interest to disclose.

Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States,[1] and its rising mortality trend is unique among the top 5 causes of death.[2] Acute exacerbations of COPD (AECOPD) are important events in the natural history of COPD, accounting for 1.5 million emergency department (ED) visits and 726,000 hospitalizations each year in the United States.[3, 4] Given the significant morbidity and mortality from AECOPD, Healthy People 2020 lists reducing deaths, hospitalizations, and ED visits as the key objectives for COPD.[5]

Over the past 2 decades, noninvasive ventilation (NIV) has emerged as a potentially useful treatment modality in AECOPD patients with acute respiratory failure. Noninvasive ventilation commonly refers to positive‐pressure ventilatory support delivered through a nasal or full‐face mask, such as bilevel positive airway pressure.[6] A number of randomized controlled trials[7, 8, 9] and meta‐analyses[10] have suggested a mortality‐reduction benefit with NIV use compared with standard medical care in AECOPD. To our knowledge, however, very few small randomized controlled trials compared NIV vs invasive mechanical ventilation (IMV) head‐to‐head,[11, 12, 13] and a recent evidence review found only 5 studies (405 subjects) on this topic.[14] Collectively, the limited evidence from randomized trials showed that NIV use resulted in similar intensive care unit (ICU) and in‐hospital mortality, fewer complications (eg, ventilator‐associated pneumonia and sepsis), and shorter hospital length of stays (LOS). Given that these trials have a smaller sample size and tend to exclude older patient (age >75 years) or patients with multiple comorbidities, there is a need to better understand the adoption and effectiveness of NIV treatment for AECOPD in a much larger patient population in the real‐world setting using observational data.

To address these knowledge gaps in the literature, we analyzed data from a large, nationally representative ED and inpatient sample. The objective of the present analysis was 2‐fold: (1) to characterize the use of NIV and IMV in AECOPD patients with acute respiratory failure at a national level; and (2) to compare the effectiveness of NIV vs IMV in the real‐world setting.

METHODS

RESULTS

Patient and ED Characteristics

The 20062008 NEDS sample contained 67,651 ED visits for AECOPD with acute respiratory failure from 1594 US EDs. After the weighting procedure, there were an estimated 101,000 visits annually for AECOPD with acute respiratory failure from approximately 4700 US EDs. In the weighted analysis, the mean patient age of these visits was 68 years, and 56% were made by women. Ninety‐six percent were admitted to the hospital. Of these, the mortality rate was 9% and the mean hospital LOS was 7 days. Figure 1 shows the secular trends in NIV, IMV, and the combined use over the 3‐year study period. Use of IMV decreased from 28% in 2006 to 19% in 2008 (P<0.001), whereas NIV use increased slightly from 14% in 2006 to 16% in 2008 (P=0.049); the combined use of both ventilation modalities remained stable (4%). Inpatient mortality decreased from 10% in 2006 to 7% in 2008 (P<0.001).

Figure 1

Figure 2 shows that the frequency of NIV use (including combined use of NIV and IMV) varied widely between hospitals, ranging from 0% to 100% with a median of 11%. In the unweighted cohort of AECOPD with acute respiratory failure, 43% received some forms of ventilatory support. Table 1 shows the patient and hospital characteristics of the patients receiving ventilatory support: 36% received NIV, 56% received IMV, and 8% received combined use. In general, patients receiving combined use of NIV and IMV tended to have more comorbidities (eg, congestive heart failure and pneumonia) compared with the NIV‐alone or IMV‐alone groups. With respect to hospital characteristics, NIV was used more often in hospitals with higher volumes of COPD exacerbation and respiratory failure, in nonmetropolitan hospitals, and in hospitals in the Northeast.

Figure 2

Table 1.Patient and Hospital Characteristics According to Ventilatory Mode

	NIV Alone (A) (n=10,032)	IMV Alone (B) (n=15,427)	Combined Use (C) (n=2311)	P Value, A vs B	P Value, B vs C
NOTE: Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; ED, emergency department; IMV, invasive mechanical ventilation; IQR, interquartile range; NIV, noninvasive ventilation.
Patient characteristics
Age, y,				<0.001	0.64
4049	5	5	5
5059	17	18	19
6069	31	33	33
7079	30	29	29
80	17	15	13
Female sex, %	57	53	54	<0.001	0.87
Quartile for median household income of patient ZIP code, $, %				<0.001	<0.001
138,999	30	34	29
39,00047,999	28	28	28
48,00062,999	24	22	24
63,000	18	15	19
Weekend admission, %	27	28	28	0.07	0.80
Insurance status, %				<0.001	0.91
Medicare	74	70	70
Medicaid	9	12	12
Private	12	13	13
Self‐pay	2	3	2
Other	2	2	2
Season, %				<0.001	0.16
Winter (January 1March 31)	29	32	31
Spring (April 1June 30)	24	25	26
Summer (July 1September 30)	22	20	19
Fall (October 1December 31)	25	22	24
No. of comorbidities, median (IQR)	4 (35)	4 (35)	4 (36)	<0.001	<0.001
Selected comorbidities, %
Hypertension	56	55	55	0.01	0.65
CHF	38	40	44	0.001	<0.001
Fluid and electrolyte disorders	37	44	49	<0.001	<0.001
Diabetes, uncomplicated	27	26	29	0.04	0.002
Pneumonia	19	34	39	<0.001	<0.001
Deficiency anemia	16	19	19	<0.001	0.39
Obesity	18	12	17	<0.001	<0.001
Depression	15	11	11	<0.001	0.54
Pulmonary circulatory diseases	15	11	14	<0.001	<0.001
Hospital characteristics
Annual ED visit volume, median (IQR)	42,704 (29,50562,470)	44,119 (29,89564,097)	46,695 (31,29866,235)	0.02	0.0003
Annual ED volume of COPD exacerbation with respiratory failure, median (IQR)	45 (2672)	42 (2368)	38 (2364)	<0.001	<0.001
Urban/rural and teaching status, %				<0.001	<0.001
Metropolitan nonteaching	53	52	47
Metropolitan teaching	31	35	39
Nonmetropolitan	16	13	13
US region, %				<0.001	<0.001
Northeast	28	16	36
Midwest	17	22	15
South	41	45	32
West	14	17	17

The unadjusted differences in outcomes are shown in Table 2. The combined‐use group had the highest inpatient mortality, longest LOS, and highest charges, followed by the IMV and NIV groups. In general, complications were few across all 3 groups, but the rate of iatrogenic pneumothorax was notably lower in the NIV group. Table 3 details the statistically significant predictors of NIV use in the propensity score model. Similar to the unadjusted analysis, older age, high‐income neighborhoods, Medicare insurance, and some comorbidities were positively associated with NIV use (eg, pulmonary circulatory disorders and liver disease), whereas a few comorbidities were negatively associated with NIV use (eg, pneumonia, and alcohol and drug abuse). With respect to hospital characteristics, higher case volumes of COPD exacerbation/respiratory failure, Northeastern and nonmetropolitan hospitals, and more recent years were associated with NIV use.

Table 2.Clinical Outcomes Among COPD Patients With Acute Respiratory Failure According to Ventilatory Mode

Outcome	NIV Alone (A) (n=10,032)	IMV Alone (B) (n=15,427)	Combined Use (C) (n=2311)	P Value. A vs B	P Value, B vs C
NOTE: Abbreviations: COPD, chronic obstructive pulmonary disease; IMV, invasive mechanical ventilation; IQR, interquartile range; NIV, noninvasive ventilation. *For privacy protection, we are not able to report cells in the tables 10 individual records.
Inpatient mortality, n (%)	825 (8)	2,454 (16)	407 (18)	<0.001	0.04
Hospital length of stay, median (IQR), d	5 (48)	8 (513)	10 (716)	<0.001	<0.001
Hospital charge per visit, median (IQR), $	26,002 (15,74744,638)	53,432 (31,99892,664)	64,585 (39,024110,336)	<0.001	<0.001
Complications*
Ventilator‐associated pneumonia, n (%)	10 (0.1)	10 (0.1)	10 (0.5)	0.09	1.00
Facial injury, n (%)	10 (0.1)	10 (0.1)	10 (0.5)	0.26	1.00
Iatrogenic pneumothorax, n (%)	10 (0.1)	90 (0.6)	14 (0.6)	<0.001	0.90

Table 3.Statistically Significant Predictors of NIV Use Alone

Patient Characteristics	Adjusted OR (95% CI)*	P Value
NOTE: Abbreviations: AIDS, acquired immune deficiency syndrome; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ED, emergency department; NIV, noninvasive ventilation; OR, odds ratio; RA, rheumatoid arthritis. *Propensity score model included the following patient and hospital characteristics: age, sex, median household income, insurance status, weekend admission, season, comorbid conditions, US region, urban/rural and teaching status, annual ED volume, annual ED volume of COPD with respiratory failure, and calendar year. Nonsignificant predictors that are not reported in the table include sex, weekend admission, and the following comorbid conditions: peripheral vascular disorders, paralysis, uncomplicated diabetes, hypothyroidism, renal failure, peptic ulcer disease excluding bleeding, hypertension, lymphoma, AIDS, solid tumor without metastasis, and metastatic cancer.
Age, y
4049	1.00 (Reference)
5059	0.96 (0.84‐1.11)	0.61
6069	0.96 (0.84‐1.10)	0.56
7079	1.09 (0.94‐1.25)	0.25
80	1.30 (1.12‐1.52)	0.001
Quartile for median household income of patient ZIP code, $
138,999	1.00 (Reference)
39,00047,999	1.13 (1.05‐1.21)	0.001
48,00062,999	1.21 (1.12‐1.30)	<0.001
63,000	1.21 (1.11‐1.32)	<0.001
Insurance status
Medicare	1.00 (Reference)
Medicaid	0.79 (0.72‐0.88)	<0.001
Private	0.88 (0.81‐0.96)	0.004
Self‐pay	0.68 (0.56‐0.82)	<0.001
Other	0.88 (0.73‐1.07)	0.22
Season
Winter (January 1March 31)	1.00 (Reference)
Spring (April 1June 30)	1.06 (0.99‐1.14)	0.11
Summer (July 1September 30)	1.17 (1.08‐1.26)	<0.001
Fall (October 1December 31)	1.24 (1.15‐1.33)	<0.001
Comorbidity
CHF	0.90 (0.85‐0.95)	<0.001
Pulmonary circulatory disorders	1.40 (1.29‐1.52)	<0.001
Diabetes, complicated	1.25 (1.08‐1.44)	0.002
Liver disease	1.79 (1.40‐2.28)	<0.001
Coagulopathy	0.54 (0.46‐0.63)	<0.001
Obesity	1.52 (1.41‐1.65)	<0.001
Weight loss	0.50 (0.44‐0.57)	<0.001
Fluid and electrolyte disorders	0.84 (0.80‐0.89)	<0.001
Deficiency anemia	0.83 (0.78‐0.90)	<0.001
Alcohol abuse	0.66 (0.58‐0.76)	<0.001
Drug abuse	0.74 (0.62‐0.88)	0.001
Psychoses	1.22 (1.10‐1.37)	<0.001
Depression	1.45 (1.34‐1.57)	<0.001
Pneumonia	0.48 (0.45‐0.51)	<0.001
Valvular heart disease	0.87 (0.77‐0.97)	0.01
Neurological disorders	0.89 (0.80‐0.98)	0.02
RA/collagen vascular diseases	1.25 (1.02‐1.53)	0.04
Blood‐loss anemia	0.72 (0.53‐0.97)	0.03
Hospital characteristics
Annual ED visit volume, per 1000‐visit increase	0.997 (0.996‐0.998)	<0.001
Annual ED volume of COPD exacerbation with respiratory failure, per 10‐visit increase	1.03 (1.02‐1.03)	<0.001
Urban/rural and teaching status
Metropolitan nonteaching	1.00 (Reference)
Metropolitan teaching	0.91 (0.85‐0.97)	0.006
Nonmetropolitan	1.30 (1.20‐1.42)	<0.001
US region
Northeast	1.00 (Reference)
Midwest	0.44 (0.40‐0.48)	<0.001
South	0.54 (0.50‐0.58)	<0.001
West	0.51 (0.46‐0.56)	<0.001
Calendar year
2006	1.00 (Reference)
2007	1.30 (1.22‐1.39)	<0.001
2008	1.65 (1.54‐1.76)	<0.001

In terms of propensity score distributions (see Supporting Information, Figure E1, in the online version of this article), there was sufficient overlap of the NIV and IMV groups. After matching on propensity score for the NIV and IMV groups, the differences in baseline characteristics were all balanced (see Supporting Information, Table E1, in the online version of this article), as indicated by <10% standardized differences in all covariates between the 2 groups. Finally, in the propensity scorematched cohort (see Supporting Information, Table E2, in the online version of this article), NIV use remained associated with significantly lower inpatient mortality (risk ratio: 0.54; 95% CI: 0.50‐0.59, P<0.001), a shorter hospital LOS (mean difference, 3.2 days; 95% CI: 3.4 to 2.9 days, P<0.001), and lower hospital charges (mean difference, P<$35,012; 95% CI: $36,848 to $33,176, P<0.001), compared with IMV use. Use of NIV also was associated with a lower rate of iatrogenic pneumothorax than IMV use (0.05% vs 0.5%, P<0.001).

Using hospital preference for NIV vs IMV as an instrument, the instrumental analysis confirmed the benefits of NIV use, with a 5% reduction in inpatient mortality in the NIV‐preferring hospitals (risk difference, P<5%; 95% CI: P<1.8% to P<8.3%).

In the sensitivity analysis to assess the impact of an unmeasured confounder, the confounder would have had to have a very strong impact on outcome (risk ratio: 5) and a severe exposure‐confounder imbalance (odds ratio of exposure on confounder: 5) to reduce the observed association to 1.0. In other words, an individual unmeasured confounder is unlikely to explain the observed association.

DISCUSSION

In this nationally representative sample of 67,651 ED visits for AECOPD with acute respiratory failure, we found that NIV use was increasing from 2006 to 2008. However, the utilization of NIV remained low (16% in 2008) and varied widely by patient and hospital characteristic. As with all observational studies, causality cannot be inferred definitely; however, our study suggests that, NIV usecompared with IMV usewas associated with potentially important benefits: a reduction of inpatient mortality by 46%, shortened hospital LOS by 3 days, reduced hospital charges by approximately $35,000 per visit, and modestly reduced risk of iatrogenic pneumothorax.

A recent analysis using the US Nationwide Inpatient Sample has shown increasing use of NIV and concomitant decreasing mortality in AECOPD over time.[28] Our analysis confirmed these favorable trends in the United States using a much larger NEDS sample (28 million visits in the NEDS vs 8 million visits in the Nationwide Inpatient Sample per year). Despite these favorable trends, NIV was still underutilized for AECOPD with respiratory failure in the United States (16% in 2008) compared with major European countries (40%).[29] Although our study lacked clinical details to arrive at the optimal rate of NIV use, the low rate of NIV use is concerning and suggests room for improvement in NIV use in appropriate patients as outlined by the current COPD guidelines.[18, 30] Why is NIV not widely adopted, given its demonstrated efficacy? Previous surveys have identified several perceived reasons for low NIV use, including lack of physician knowledge, insufficient respiratory therapist training, inadequate equipment, and time required for setting up NIV.[29, 31, 32] Our study adds to the literature by showing the actual predictors of NIV use in the real world. Our data showed that the early adopters were hospitals with higher case volumes, and hospitals in the Northeast and in nonmetropolitan areas. A higher case volume has been linked with lower mortality in AECOPD (ie, practice makes perfect),[33] and frequent NIV use could explain the lower AECOPD mortality in highcase volume centers. Alternatively, smaller hospitals tend to have moonlighters working in EDs who may not be board certified in emergency medicine. Perhaps the logical next step is to conduct a qualitative study to understand the specifics of best practices and provider characteristics in these Northeastern, highercase volume centers. Another incentive to promote NIV use in clinical practice is the cost‐effectiveness associated with this intervention, as previous studies have shown that, compared with usual care, receiving NIV was associated with a reduction in costs, mainly through reduced use of the ICU.[34, 35]

Some patient factors associated with NIV use may be well justified. For example, older AECOPD patients may have an advance directive describing their treatment wishes (eg, do‐not‐intubate order),[36] and therefore NIV was preferred to IMV. Also, our data suggested AECOPD patients with a suspected pneumonia component were less likely to be placed on NIV, which is consistent with COPD guideline recommendations.[18, 30] As outlined in the current guidelines, the major contraindications to NIV include impending respiratory arrest, excessive respiratory secretions, massive gastrointestinal bleeding, recent facial trauma, or altered mental status.[18, 30] By contrast, some factors associated with NIV use may be targeted for intervention, such as lower rates of NIV use in the uninsured, patients who live in low‐income neighborhoods, and hospitals in US regions other than the Northeast.

Current guidelines recommend using NIV in AECOPD patients with early signs of respiratory failure, such as arterial pH of 7.257.35 or pCO₂ 45 mm Hg.[18, 30] When NIV is considered as the modality of ventilatory support, it should probably be used as early as possible,[37] because evidence suggests that delayed use of NIV may lead to severe respiratory acidosis and increased mortality.[38] Other than in ICUs, NIV can be used on general wards and in EDs that have adequate staff training and experience, because the success rates of NIV in these settings are similar to those reported in ICU studies.[8, 36, 39] In addition, NIV is more cost‐effective when performed outside the ICU.[35] In fact, studies have found a substantial portion of patients had NIV started in the ED (one‐fourth) and on the general ward (one‐fourth).[31, 40] Given the shortage of intensivists in the United States, hospitalists begin to play an important role in provision of critical care outside the ICU.[41] Once NIV is used, it is important to ensure that it is delivered effectively and monitored closely because NIV failure has been shown to be associated with high mortality.[28, 42]

This study has some potential limitations. First, we used administrative claims that lack clinical details such as data on arterial blood gases and severity scores, and thus potential residual confounding may exist. In our study, the IMV group may be sicker than the NIV group, which could partially explain the increased mortality with IMV. However, the propensity scores overlap to a great extent between the 2 study groups, suggesting that a strong confounding bias is less likely, given the observed covariates. Furthermore, the instrumental variable and sensitivity analyses taking into account unmeasured confounders still suggested the benefits of NIV. Second, the NEDS does not contain data on the location where NIV was initiated (eg, ED, ward, or ICU) or the timing of initiating NIV or IMV. As a result, for the combined‐use group, we could not further distinguish the group switching from NIV to IMV (ie, NIV failure)[42] or from IMV to NIV (ie, NIV as a weaning strategy).[43] Accordingly, we chose to focus on the comparativeness effectiveness of NIV vs IMV. Third, although the NEDS data have undergone quality‐control procedures,[44] some misclassification may exist in identifying patient population and interventions. Finally, the analysis may not reflect the most recent trend in NIV use, as the 2010 NEDS data have just been released. In addition, although the study is the largest to date on this topic, our findings may not be generalizable to EDs that were not part of the NEDS.

In summary, in this nationally representative ED and inpatient database, NIV use is increasing for AECOPD with acute respiratory failure; however, its adoption remains low and varies widely between US hospitals. Our observational study suggests that NIV appears to be more effective and safer than IMV in the real‐world setting. There is an opportunity to increase the use of NIV as recommended in guidelines and to promote the use NIV in replacement of IMV in patients with severe AECOPD. Given the increasing mortality burden of COPD, such a strategy may help reduce COPD mortality at the population level, thereby fulfilling the objectives of Healthy People 2020.

Disclosure

Partial results from this study were presented at the 2012 Society for Academic Emergency Medicine Annual Meeting, Chicago, Illinois, May 912, 2012. This project was supported by grant number R03HS020722 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The authors have no conflicts of interest to disclose.

Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States,[1] and its rising mortality trend is unique among the top 5 causes of death.[2] Acute exacerbations of COPD (AECOPD) are important events in the natural history of COPD, accounting for 1.5 million emergency department (ED) visits and 726,000 hospitalizations each year in the United States.[3, 4] Given the significant morbidity and mortality from AECOPD, Healthy People 2020 lists reducing deaths, hospitalizations, and ED visits as the key objectives for COPD.[5]

Over the past 2 decades, noninvasive ventilation (NIV) has emerged as a potentially useful treatment modality in AECOPD patients with acute respiratory failure. Noninvasive ventilation commonly refers to positive‐pressure ventilatory support delivered through a nasal or full‐face mask, such as bilevel positive airway pressure.[6] A number of randomized controlled trials[7, 8, 9] and meta‐analyses[10] have suggested a mortality‐reduction benefit with NIV use compared with standard medical care in AECOPD. To our knowledge, however, very few small randomized controlled trials compared NIV vs invasive mechanical ventilation (IMV) head‐to‐head,[11, 12, 13] and a recent evidence review found only 5 studies (405 subjects) on this topic.[14] Collectively, the limited evidence from randomized trials showed that NIV use resulted in similar intensive care unit (ICU) and in‐hospital mortality, fewer complications (eg, ventilator‐associated pneumonia and sepsis), and shorter hospital length of stays (LOS). Given that these trials have a smaller sample size and tend to exclude older patient (age >75 years) or patients with multiple comorbidities, there is a need to better understand the adoption and effectiveness of NIV treatment for AECOPD in a much larger patient population in the real‐world setting using observational data.

To address these knowledge gaps in the literature, we analyzed data from a large, nationally representative ED and inpatient sample. The objective of the present analysis was 2‐fold: (1) to characterize the use of NIV and IMV in AECOPD patients with acute respiratory failure at a national level; and (2) to compare the effectiveness of NIV vs IMV in the real‐world setting.

METHODS

RESULTS

Patient and ED Characteristics

The 20062008 NEDS sample contained 67,651 ED visits for AECOPD with acute respiratory failure from 1594 US EDs. After the weighting procedure, there were an estimated 101,000 visits annually for AECOPD with acute respiratory failure from approximately 4700 US EDs. In the weighted analysis, the mean patient age of these visits was 68 years, and 56% were made by women. Ninety‐six percent were admitted to the hospital. Of these, the mortality rate was 9% and the mean hospital LOS was 7 days. Figure 1 shows the secular trends in NIV, IMV, and the combined use over the 3‐year study period. Use of IMV decreased from 28% in 2006 to 19% in 2008 (P<0.001), whereas NIV use increased slightly from 14% in 2006 to 16% in 2008 (P=0.049); the combined use of both ventilation modalities remained stable (4%). Inpatient mortality decreased from 10% in 2006 to 7% in 2008 (P<0.001).

Figure 1

Figure 2 shows that the frequency of NIV use (including combined use of NIV and IMV) varied widely between hospitals, ranging from 0% to 100% with a median of 11%. In the unweighted cohort of AECOPD with acute respiratory failure, 43% received some forms of ventilatory support. Table 1 shows the patient and hospital characteristics of the patients receiving ventilatory support: 36% received NIV, 56% received IMV, and 8% received combined use. In general, patients receiving combined use of NIV and IMV tended to have more comorbidities (eg, congestive heart failure and pneumonia) compared with the NIV‐alone or IMV‐alone groups. With respect to hospital characteristics, NIV was used more often in hospitals with higher volumes of COPD exacerbation and respiratory failure, in nonmetropolitan hospitals, and in hospitals in the Northeast.

Figure 2

Table 1.Patient and Hospital Characteristics According to Ventilatory Mode

	NIV Alone (A) (n=10,032)	IMV Alone (B) (n=15,427)	Combined Use (C) (n=2311)	P Value, A vs B	P Value, B vs C
NOTE: Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; ED, emergency department; IMV, invasive mechanical ventilation; IQR, interquartile range; NIV, noninvasive ventilation.
Patient characteristics
Age, y,				<0.001	0.64
4049	5	5	5
5059	17	18	19
6069	31	33	33
7079	30	29	29
80	17	15	13
Female sex, %	57	53	54	<0.001	0.87
Quartile for median household income of patient ZIP code, $, %				<0.001	<0.001
138,999	30	34	29
39,00047,999	28	28	28
48,00062,999	24	22	24
63,000	18	15	19
Weekend admission, %	27	28	28	0.07	0.80
Insurance status, %				<0.001	0.91
Medicare	74	70	70
Medicaid	9	12	12
Private	12	13	13
Self‐pay	2	3	2
Other	2	2	2
Season, %				<0.001	0.16
Winter (January 1March 31)	29	32	31
Spring (April 1June 30)	24	25	26
Summer (July 1September 30)	22	20	19
Fall (October 1December 31)	25	22	24
No. of comorbidities, median (IQR)	4 (35)	4 (35)	4 (36)	<0.001	<0.001
Selected comorbidities, %
Hypertension	56	55	55	0.01	0.65
CHF	38	40	44	0.001	<0.001
Fluid and electrolyte disorders	37	44	49	<0.001	<0.001
Diabetes, uncomplicated	27	26	29	0.04	0.002
Pneumonia	19	34	39	<0.001	<0.001
Deficiency anemia	16	19	19	<0.001	0.39
Obesity	18	12	17	<0.001	<0.001
Depression	15	11	11	<0.001	0.54
Pulmonary circulatory diseases	15	11	14	<0.001	<0.001
Hospital characteristics
Annual ED visit volume, median (IQR)	42,704 (29,50562,470)	44,119 (29,89564,097)	46,695 (31,29866,235)	0.02	0.0003
Annual ED volume of COPD exacerbation with respiratory failure, median (IQR)	45 (2672)	42 (2368)	38 (2364)	<0.001	<0.001
Urban/rural and teaching status, %				<0.001	<0.001
Metropolitan nonteaching	53	52	47
Metropolitan teaching	31	35	39
Nonmetropolitan	16	13	13
US region, %				<0.001	<0.001
Northeast	28	16	36
Midwest	17	22	15
South	41	45	32
West	14	17	17

The unadjusted differences in outcomes are shown in Table 2. The combined‐use group had the highest inpatient mortality, longest LOS, and highest charges, followed by the IMV and NIV groups. In general, complications were few across all 3 groups, but the rate of iatrogenic pneumothorax was notably lower in the NIV group. Table 3 details the statistically significant predictors of NIV use in the propensity score model. Similar to the unadjusted analysis, older age, high‐income neighborhoods, Medicare insurance, and some comorbidities were positively associated with NIV use (eg, pulmonary circulatory disorders and liver disease), whereas a few comorbidities were negatively associated with NIV use (eg, pneumonia, and alcohol and drug abuse). With respect to hospital characteristics, higher case volumes of COPD exacerbation/respiratory failure, Northeastern and nonmetropolitan hospitals, and more recent years were associated with NIV use.

Table 2.Clinical Outcomes Among COPD Patients With Acute Respiratory Failure According to Ventilatory Mode

Outcome	NIV Alone (A) (n=10,032)	IMV Alone (B) (n=15,427)	Combined Use (C) (n=2311)	P Value. A vs B	P Value, B vs C
NOTE: Abbreviations: COPD, chronic obstructive pulmonary disease; IMV, invasive mechanical ventilation; IQR, interquartile range; NIV, noninvasive ventilation. *For privacy protection, we are not able to report cells in the tables 10 individual records.
Inpatient mortality, n (%)	825 (8)	2,454 (16)	407 (18)	<0.001	0.04
Hospital length of stay, median (IQR), d	5 (48)	8 (513)	10 (716)	<0.001	<0.001
Hospital charge per visit, median (IQR), $	26,002 (15,74744,638)	53,432 (31,99892,664)	64,585 (39,024110,336)	<0.001	<0.001
Complications*
Ventilator‐associated pneumonia, n (%)	10 (0.1)	10 (0.1)	10 (0.5)	0.09	1.00
Facial injury, n (%)	10 (0.1)	10 (0.1)	10 (0.5)	0.26	1.00
Iatrogenic pneumothorax, n (%)	10 (0.1)	90 (0.6)	14 (0.6)	<0.001	0.90

Table 3.Statistically Significant Predictors of NIV Use Alone

Patient Characteristics	Adjusted OR (95% CI)*	P Value
NOTE: Abbreviations: AIDS, acquired immune deficiency syndrome; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ED, emergency department; NIV, noninvasive ventilation; OR, odds ratio; RA, rheumatoid arthritis. *Propensity score model included the following patient and hospital characteristics: age, sex, median household income, insurance status, weekend admission, season, comorbid conditions, US region, urban/rural and teaching status, annual ED volume, annual ED volume of COPD with respiratory failure, and calendar year. Nonsignificant predictors that are not reported in the table include sex, weekend admission, and the following comorbid conditions: peripheral vascular disorders, paralysis, uncomplicated diabetes, hypothyroidism, renal failure, peptic ulcer disease excluding bleeding, hypertension, lymphoma, AIDS, solid tumor without metastasis, and metastatic cancer.
Age, y
4049	1.00 (Reference)
5059	0.96 (0.84‐1.11)	0.61
6069	0.96 (0.84‐1.10)	0.56
7079	1.09 (0.94‐1.25)	0.25
80	1.30 (1.12‐1.52)	0.001
Quartile for median household income of patient ZIP code, $
138,999	1.00 (Reference)
39,00047,999	1.13 (1.05‐1.21)	0.001
48,00062,999	1.21 (1.12‐1.30)	<0.001
63,000	1.21 (1.11‐1.32)	<0.001
Insurance status
Medicare	1.00 (Reference)
Medicaid	0.79 (0.72‐0.88)	<0.001
Private	0.88 (0.81‐0.96)	0.004
Self‐pay	0.68 (0.56‐0.82)	<0.001
Other	0.88 (0.73‐1.07)	0.22
Season
Winter (January 1March 31)	1.00 (Reference)
Spring (April 1June 30)	1.06 (0.99‐1.14)	0.11
Summer (July 1September 30)	1.17 (1.08‐1.26)	<0.001
Fall (October 1December 31)	1.24 (1.15‐1.33)	<0.001
Comorbidity
CHF	0.90 (0.85‐0.95)	<0.001
Pulmonary circulatory disorders	1.40 (1.29‐1.52)	<0.001
Diabetes, complicated	1.25 (1.08‐1.44)	0.002
Liver disease	1.79 (1.40‐2.28)	<0.001
Coagulopathy	0.54 (0.46‐0.63)	<0.001
Obesity	1.52 (1.41‐1.65)	<0.001
Weight loss	0.50 (0.44‐0.57)	<0.001
Fluid and electrolyte disorders	0.84 (0.80‐0.89)	<0.001
Deficiency anemia	0.83 (0.78‐0.90)	<0.001
Alcohol abuse	0.66 (0.58‐0.76)	<0.001
Drug abuse	0.74 (0.62‐0.88)	0.001
Psychoses	1.22 (1.10‐1.37)	<0.001
Depression	1.45 (1.34‐1.57)	<0.001
Pneumonia	0.48 (0.45‐0.51)	<0.001
Valvular heart disease	0.87 (0.77‐0.97)	0.01
Neurological disorders	0.89 (0.80‐0.98)	0.02
RA/collagen vascular diseases	1.25 (1.02‐1.53)	0.04
Blood‐loss anemia	0.72 (0.53‐0.97)	0.03
Hospital characteristics
Annual ED visit volume, per 1000‐visit increase	0.997 (0.996‐0.998)	<0.001
Annual ED volume of COPD exacerbation with respiratory failure, per 10‐visit increase	1.03 (1.02‐1.03)	<0.001
Urban/rural and teaching status
Metropolitan nonteaching	1.00 (Reference)
Metropolitan teaching	0.91 (0.85‐0.97)	0.006
Nonmetropolitan	1.30 (1.20‐1.42)	<0.001
US region
Northeast	1.00 (Reference)
Midwest	0.44 (0.40‐0.48)	<0.001
South	0.54 (0.50‐0.58)	<0.001
West	0.51 (0.46‐0.56)	<0.001
Calendar year
2006	1.00 (Reference)
2007	1.30 (1.22‐1.39)	<0.001
2008	1.65 (1.54‐1.76)	<0.001

In terms of propensity score distributions (see Supporting Information, Figure E1, in the online version of this article), there was sufficient overlap of the NIV and IMV groups. After matching on propensity score for the NIV and IMV groups, the differences in baseline characteristics were all balanced (see Supporting Information, Table E1, in the online version of this article), as indicated by <10% standardized differences in all covariates between the 2 groups. Finally, in the propensity scorematched cohort (see Supporting Information, Table E2, in the online version of this article), NIV use remained associated with significantly lower inpatient mortality (risk ratio: 0.54; 95% CI: 0.50‐0.59, P<0.001), a shorter hospital LOS (mean difference, 3.2 days; 95% CI: 3.4 to 2.9 days, P<0.001), and lower hospital charges (mean difference, P<$35,012; 95% CI: $36,848 to $33,176, P<0.001), compared with IMV use. Use of NIV also was associated with a lower rate of iatrogenic pneumothorax than IMV use (0.05% vs 0.5%, P<0.001).

Using hospital preference for NIV vs IMV as an instrument, the instrumental analysis confirmed the benefits of NIV use, with a 5% reduction in inpatient mortality in the NIV‐preferring hospitals (risk difference, P<5%; 95% CI: P<1.8% to P<8.3%).

In the sensitivity analysis to assess the impact of an unmeasured confounder, the confounder would have had to have a very strong impact on outcome (risk ratio: 5) and a severe exposure‐confounder imbalance (odds ratio of exposure on confounder: 5) to reduce the observed association to 1.0. In other words, an individual unmeasured confounder is unlikely to explain the observed association.

DISCUSSION

In this nationally representative sample of 67,651 ED visits for AECOPD with acute respiratory failure, we found that NIV use was increasing from 2006 to 2008. However, the utilization of NIV remained low (16% in 2008) and varied widely by patient and hospital characteristic. As with all observational studies, causality cannot be inferred definitely; however, our study suggests that, NIV usecompared with IMV usewas associated with potentially important benefits: a reduction of inpatient mortality by 46%, shortened hospital LOS by 3 days, reduced hospital charges by approximately $35,000 per visit, and modestly reduced risk of iatrogenic pneumothorax.

A recent analysis using the US Nationwide Inpatient Sample has shown increasing use of NIV and concomitant decreasing mortality in AECOPD over time.[28] Our analysis confirmed these favorable trends in the United States using a much larger NEDS sample (28 million visits in the NEDS vs 8 million visits in the Nationwide Inpatient Sample per year). Despite these favorable trends, NIV was still underutilized for AECOPD with respiratory failure in the United States (16% in 2008) compared with major European countries (40%).[29] Although our study lacked clinical details to arrive at the optimal rate of NIV use, the low rate of NIV use is concerning and suggests room for improvement in NIV use in appropriate patients as outlined by the current COPD guidelines.[18, 30] Why is NIV not widely adopted, given its demonstrated efficacy? Previous surveys have identified several perceived reasons for low NIV use, including lack of physician knowledge, insufficient respiratory therapist training, inadequate equipment, and time required for setting up NIV.[29, 31, 32] Our study adds to the literature by showing the actual predictors of NIV use in the real world. Our data showed that the early adopters were hospitals with higher case volumes, and hospitals in the Northeast and in nonmetropolitan areas. A higher case volume has been linked with lower mortality in AECOPD (ie, practice makes perfect),[33] and frequent NIV use could explain the lower AECOPD mortality in highcase volume centers. Alternatively, smaller hospitals tend to have moonlighters working in EDs who may not be board certified in emergency medicine. Perhaps the logical next step is to conduct a qualitative study to understand the specifics of best practices and provider characteristics in these Northeastern, highercase volume centers. Another incentive to promote NIV use in clinical practice is the cost‐effectiveness associated with this intervention, as previous studies have shown that, compared with usual care, receiving NIV was associated with a reduction in costs, mainly through reduced use of the ICU.[34, 35]

Some patient factors associated with NIV use may be well justified. For example, older AECOPD patients may have an advance directive describing their treatment wishes (eg, do‐not‐intubate order),[36] and therefore NIV was preferred to IMV. Also, our data suggested AECOPD patients with a suspected pneumonia component were less likely to be placed on NIV, which is consistent with COPD guideline recommendations.[18, 30] As outlined in the current guidelines, the major contraindications to NIV include impending respiratory arrest, excessive respiratory secretions, massive gastrointestinal bleeding, recent facial trauma, or altered mental status.[18, 30] By contrast, some factors associated with NIV use may be targeted for intervention, such as lower rates of NIV use in the uninsured, patients who live in low‐income neighborhoods, and hospitals in US regions other than the Northeast.

Current guidelines recommend using NIV in AECOPD patients with early signs of respiratory failure, such as arterial pH of 7.257.35 or pCO₂ 45 mm Hg.[18, 30] When NIV is considered as the modality of ventilatory support, it should probably be used as early as possible,[37] because evidence suggests that delayed use of NIV may lead to severe respiratory acidosis and increased mortality.[38] Other than in ICUs, NIV can be used on general wards and in EDs that have adequate staff training and experience, because the success rates of NIV in these settings are similar to those reported in ICU studies.[8, 36, 39] In addition, NIV is more cost‐effective when performed outside the ICU.[35] In fact, studies have found a substantial portion of patients had NIV started in the ED (one‐fourth) and on the general ward (one‐fourth).[31, 40] Given the shortage of intensivists in the United States, hospitalists begin to play an important role in provision of critical care outside the ICU.[41] Once NIV is used, it is important to ensure that it is delivered effectively and monitored closely because NIV failure has been shown to be associated with high mortality.[28, 42]

This study has some potential limitations. First, we used administrative claims that lack clinical details such as data on arterial blood gases and severity scores, and thus potential residual confounding may exist. In our study, the IMV group may be sicker than the NIV group, which could partially explain the increased mortality with IMV. However, the propensity scores overlap to a great extent between the 2 study groups, suggesting that a strong confounding bias is less likely, given the observed covariates. Furthermore, the instrumental variable and sensitivity analyses taking into account unmeasured confounders still suggested the benefits of NIV. Second, the NEDS does not contain data on the location where NIV was initiated (eg, ED, ward, or ICU) or the timing of initiating NIV or IMV. As a result, for the combined‐use group, we could not further distinguish the group switching from NIV to IMV (ie, NIV failure)[42] or from IMV to NIV (ie, NIV as a weaning strategy).[43] Accordingly, we chose to focus on the comparativeness effectiveness of NIV vs IMV. Third, although the NEDS data have undergone quality‐control procedures,[44] some misclassification may exist in identifying patient population and interventions. Finally, the analysis may not reflect the most recent trend in NIV use, as the 2010 NEDS data have just been released. In addition, although the study is the largest to date on this topic, our findings may not be generalizable to EDs that were not part of the NEDS.

In summary, in this nationally representative ED and inpatient database, NIV use is increasing for AECOPD with acute respiratory failure; however, its adoption remains low and varies widely between US hospitals. Our observational study suggests that NIV appears to be more effective and safer than IMV in the real‐world setting. There is an opportunity to increase the use of NIV as recommended in guidelines and to promote the use NIV in replacement of IMV in patients with severe AECOPD. Given the increasing mortality burden of COPD, such a strategy may help reduce COPD mortality at the population level, thereby fulfilling the objectives of Healthy People 2020.

Disclosure

Partial results from this study were presented at the 2012 Society for Academic Emergency Medicine Annual Meeting, Chicago, Illinois, May 912, 2012. This project was supported by grant number R03HS020722 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The authors have no conflicts of interest to disclose.