key: cord-0809676-wdc7p4dn
authors: Parcha, Vibhu; Kalra, Rajat; Bhatt, Surya P.; Berra, Lorenzo; Arora, Garima; Arora, Pankaj
title: Trends and Geographic Variation in Acute Respiratory Failure and Acute Respiratory Distress Syndrome Mortality in the United States
date: 2020-10-22
journal: Chest
DOI: 10.1016/j.chest.2020.10.042
sha: 2f3c2f9ae896effaec76b5f3eb46e0af1c3af904
doc_id: 809676
cord_uid: wdc7p4dn

Background Despite numerous advances in the understanding of the pathophysiology, progression, and management of acute respiratory failure (ARF) and acute respiratory distress syndrome (ARDS), there is limited contemporary data on the mortality burden of ARF and ARDS in the United States (US). Research Question What are the contemporary trends and geographic variation in ARF and ARDS-related mortality in the US? Study Design and Methods A retrospective analysis of the National Center for Health ”Statistics’ nationwide mortality data was conducted to assess the ARF and ARDS-related mortality trends from 2014-2018 and the geographic distribution of ARF and ARDS-related deaths in 2018 for all American residents. Piecewise linear regression was used to evaluate the trends in age-adjusted mortality rates (AAMR) in the overall population and various demographic subgroups of age, sex, race, urbanization, and region. Results Among 1,434,349 ARF-related deaths and 52,958 ARDS-related deaths during the study period, the AAMR was highest in older individuals (≥65 years), non-Hispanic Blacks, those living in the non-metropolitan region. The AAMR for ARF-related deaths (per 100,000 persons) increased from 74.9 (95%CI:74.6-75.2) in 2014 to 85.6 (95%CI:85.3-85.9) in 2018 (Annual Percentage Change [APC]: 3.4 [95%CI:2.2-4.6];Ptrend=0.003). The AAMR (per 100,000) for ARDS-related deaths was 3.2 (95%CI:3.2-3.3) in 2014 and 3.0 (95%CI:3.0-3.1) (APC: -0.9 [95%CI:-5.4-3.8]; Ptrend=0.56). The observed increase in rates for ARF mortality was consistent across the subgroups of age, sex, race/ethnicity, urbanization status, and geographical region (Ptrend<0.05 for all). The AAMR (per 100,000 persons) for ARF (91.3 [95%CI: 90.8-91.8]) and ARDS-related mortality (3.3 [95%CI:32.34]) in 2018 were highest in the South. Interpretation The ARF-related mortality increased at ∼3.4% annually, and ARDS-related mortality showed a lack of decline in the last five years. These data contextualize important health information to guide priorities for research, clinical care, and policy, especially during the coronavirus disease-19 pandemic in the US.

Acute respiratory failure (ARF) is a life-threatening medical condition characterized by increased preponderance for admission to intensive care units and is frequently associated with the need for mechanical ventilation. [1] [2] [3] Acute respiratory distress syndrome (ARDS) is a potentially fatal condition characterized by acute-onset, diffuse, inflammatory lung injury that leads to hypoxemic respiratory insufficiency and failure due to an increase in pulmonary vascular permeability and loss of ventilated lung parenchyma. [4] [5] [6] [7] [8] ARDS is one of the leading causes of ARF. Nearly 3 million patients annually develop ARDS, which contributes to approximately 10% of intensive care unit admissions and ~24% of patients receiving mechanical ventilation. [3] [4] [5] This potentially fatal respiratory syndrome may be triggered by pulmonary (such as aspiration, coronavirus disease-2019 , pneumonia, inhalational injury) or nonpulmonary causes (such as trauma, pancreatitis, sepsis, drug toxicity), and is associated with high mortality of 35-46% based on disease severity at the onset. 3, 5, 7 Despite numerous advances in the understanding of the pathophysiology, progression, and management of ARF and ARDS, there are limited contemporary data on the mortality burden of ARF and ARDS in the United States. [3] [4] [5] 8 Importantly, there are limited data on the mortality trends in the United States after the adoption of the Berlin definition of ARDS, which was endorsed by the American Thoracic Society (ATS) and the Society of Critical Care Medicine (SCCM), and adopted into routine clinical care. 5, 8 There are well-recognized geographic differences in disease management and critical care practices, which may impact patient outcomes. The contemporary geographic differences in ARF and ARDS mortality in the J o u r n a l P r e -p r o o f 6 United States is not known. These geographic differences may be heightened in view of the significant infrastructure strain imposed by the COVID-19 pandemic.

We sought to evaluate the contemporary trends and geographic differences in ARF and ARDS mortality in the United States. We also sought to examine these trends in the demographic subgroups of age, sex, race/ethnicity, and level of urbanization. The population estimates incorporated in the CDC WONDER are derived from the United Census Bureau's intercensal population estimates. 10 The CDC WONDER database has been previously validated and utilized in numerous epidemiological investigations. [11] [12] [13] [14] [15] [16] The study was deemed as non-human subjects research and exempt from a full review of the Institutional Review Board.

The crude and age-adjusted mortality rates (AAMR) for ARF-related deaths and ARDSrelated deaths were derived by analyzing the mortality data from January 1, 2014, to December 31, 2018. ARF-related mortality was defined as deaths with relevant ICD-10 codes (J80, J96.0, and J96.9) enlisted as the contributing cause of death. ARDS-related mortality was defined using the ICD-10 code J80 (acute respiratory distress) enlisted as the contributing cause of death. 8 In the sensitivity analysis for ARF-related mortality, we included the combination of J80 and J96.0. The AAMR were age-standardized to the 2010 United States census population proportions. 17 The AAMR estimates were computed and reported as age-adjusted deaths per 100,000 individuals. The mortality estimates were evaluated by stratifying the population on the J o u r n a l P r e -p r o o f basis of sex, race/ethnicity (non-Hispanic Whites, non-Hispanic Blacks, non-Hispanic Asians or Pacific Islanders, non-Hispanic American Indians or Alaska Natives, Hispanics), level of urbanization (as per the 2013 Urban-Rural Scheme for Counties), geographic region of residence (defined as per the United States Census Bureau), and state of residence at the time of death. We also evaluated the causes of death associated with ARF-related mortality by identifying common diagnoses enlisted as a contributing cause of death. The previously used ICD-10 codes were utilized for identifying the causes of ARF-related deaths such as influenza and pneumonia, 8 septicemia, 8,18 trauma and burns, 8 pneumonitis caused by food and vomit, 8 and acute pancreatitis (eTable 1). We also explored the seasonal periodicity in the ARF-related and ARDS-related deaths during the study period.

The mortality trends were analyzed using the National Cancer ' 'Institute's Joinpoint Regression Program 4.7.0.0 to assess the ARF-related and ARDS-related mortality during the study period. 19 Using a piecewise linear regression approach, the ideal fit for the AAMR trends during the study period was ascertained. The Joinpoint algorithm estimates the best approach to describe the mortality trend over time, either by a straight line or ≥1 linear segments, to create a parsimonious model that provides a good weighted-least-squared fit to the data. 19,20 The annual percentage change (APC) was estimated along with the 95% confidence intervals (CIs) using previously validated methods. 21,22 APCs were obtained using Monte-Carlo permutation analysis to overcome the uncertainty of the mortality estimates (CIs) by fitting a line through 4,500 different samples of the annual AAMR. 16 The AAPC was calculated for the ARF-related and ARDS-related mortality in the overall population and each pre-defined sub-groups of age, sex, Table 1) .

Similarly, ARDS-related mortality was highest in males, non-Hispanic Blacks, individuals ≥65 years of age, living in the non-metropolitan areas, and in the South ( Table 1) .

The nationwide crude mortality for ARF-related deaths increased from 79.6 (95% CI: and middle-aged (age 45-64 years) adults (p<0.05 for both)( Table 2 ). The ARF-related mortality increased in all racial/ethnic subgroups (p<0.05 for all) except non-Hispanic American Indians/Alaska Natives (p=0.12) (Figure 2 , Table 2 ). This increasing trend was consistent across Table 2 ).

The sensitivity analysis of the ARF-related mortality trends using the ICD-10 codes J80

and J96.0 also demonstrated an increasing mortality trend (eFigure 1). This was consistent across the subgroups of sex, race/ethnicity, census regions, and urbanization status (eFigures 2-

The crude mortality (per 100,000) for ARDS-related deaths was 3.4 (95% CI Table 2 ).

All the geographical regions showed an increase in ARF-related mortality rates (p<0.05 for all) (Figure 3) . The ARDS-related mortality remained stable across all census regions 

The contribution of associated causes of ARF-related mortality are depicted in eTable 2-3. Influenza and pneumonia, and septicemia contributed nearly 41.3% and 37.8% of ARFrelated deaths with etiology evaluated, respectively, through the study period. In the study period, 16.3%, 3.7%, and 0.9% ARF-related deaths with etiology evaluated were accounted for by food and vomit associated pneumonitis, trauma and burns, and acute pancreatitis, respectively. The AAMR of the various associated causes of ARF-related deaths is depicted in Prior nationwide studies in the American population suggested an increasing incidence of ARDS 23 but with declining national mortality between 1999-2013 with a plateau from 2010-2013. 8 We note that the ARDS-related mortality has continued to show a lack of decline after 2013 with an increase in ARF-related deaths after 2013. The observed lack of decline in the ARDS-related mortality and increase in the ARF-related deaths in the United States in our study may be consequent of numerous factors. Under-recognition and under-treatment have been stipulated to contribute to the high in-hospital mortality rate of ~40% associated with the development of ARDS. 3, 24 Due to under-recognition, up to one-in-five cases of severe ARDS may be overlooked, which may result in under-treatment, leading to a greater adverse outcome burden. 24 Resultantly, the more sensitive definition of ARDS was introduced in 2012. 5, 6 There may also be an unaccounted lag between the introduction of the Berlin definition and its dissemination and adoption into routine clinical care. This may have also contributed to the observed lack of decline in AAMR for ARDS-related deaths. The rising ARF mortality and nondeclining ARDS mortality in recent years may be partially attributed to the aging population.

Increasing age has been associated with increased mortality secondary to ARDS, 25 although the mechanisms remain somewhat unclear. 26 The striking racial differences in ARF and ARDS mortality observed in our study also warrant explanation. Variations in race-based susceptibility to ARDS has been documented previously. 27,28 Higher ARDS mortality in non-Hispanic Blacks observed in our study indicate that the racial disparities in ARDS mortality, first recognized over two decades ago, continue to persist. It has also been postulated that a greater burden of comorbidities among non-Hispanic Blacks and Hispanic-Americans at the time of admission to the intensive care unit may be associated with greater mortality due to ARDS. 29 The observed increase could also be consequent of the increasing incidence of the ARF/ARDS, limited availability of mechanical ventilation devices, and appropriately trained personnel contributing to the burdened of the critical care infrastructure. [3] [4] [5] [30] [31] [32] [33] The inclusion of the wider ICD-10 codes aided in increased recognition of deaths attributable to ARF. Though there was a nonsignificant change in ARDS-related mortality, the demographic patterns remained mostly consistent with ARF-related mortality. We found that influenza and pneumonia, and septicemia are the most common etiologies associated with ARF-related mortality. We also note a higher ARF-related and ARDS-related mortality during the winter season, which has a close temporal association with the annual increase in influenza cases in the United States. [38] [39] [40] , which is the most common cause of death in COVID-19 patients. 41 The pandemic may disproportionately burden healthcare systems in certain geographic regions and amplify the existing regional and state-level differences in ARDS-mortality.

Our data have significant public health implications, especially in the times of the COVID-19 pandemic. Firstly, our data regarding ARF and ARDS mortality trends may allow for advanced planning for healthcare staffing and scarce inpatient resources, such as ventilators and extracorporeal membrane oxygenation machines, in areas where mortality is traditionally high. Secondly, our data regarding ARDS mortality could further be used to organize local and/or regional centers of excellence for the management of severe ARDS associated COVID-19 J o u r n a l P r e -p r o o f in areas where there is a high prior burden of ARDS mortality. This may serve to centralize intensive care resources and expertise for the management of this devastating condition. Finally, our data should also be a call to action to align different health policies and social mechanisms during this pandemic. There are a vast number of local, regional, and federal government organizations and non-governmental organizations that are often working independently to provide funding, supplies, and urgent administrative support throughout the United States. By demonstrating that there is likely to be differential ARF and ARDS mortality on the basis of historical trends, we hope that all of these organizations may seek collaborative alignment to prioritize resources to areas with the highest proportions of high-risk candidates or higher historic ARDS mortality. In addition to broad national health objectives, addressing risk factors at the local level by the use of focused and tailored health goals and health interventions specific to the population will have positive implications in the improvement of health status nationally in the long term.

We acknowledge that our investigation has several important limitations. The study is limited by the absence of individual-level measures such as comorbidity burden, etiological agent, the severity of ARDS, global clinical condition, and provision of optimal medical therapy.

The subjective ascertainment of the cause of death and the use of administrative ICD codes may result in underreporting of ARDS as the cause of death. Additionally, it is difficult to differentiate if the observed increase is due to an increase in disease incidence or the case-fatality rate. We used a broader definition of ARF using the ICD-10 codes, which allow for increased sensitivity for capturing ARF-related mortality and was primarily guided by the previously 3) 0.58 ≥65 Years 11.5 (11.2-11.8) 11.3 (11.0-11.7) 11.7 (11.3-12.0) 11.5 (11.2-11.8) 11. 

Highlights in acute respiratory failure

Association of Noninvasive Oxygenation Strategies With All-Cause Mortality in Adults With Acute Hypoxemic Respiratory Failure: A Systematic Review and Meta-analysis

Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units

Fifty Years of Research in ARDS. The Epidemiology of Acute Respiratory Distress Syndrome. A 50th Birthday Review

Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment

Acute respiratory distress syndrome: the Berlin Definition

Pulmonary and extrapulmonary acute 10. U.S. Department of Health & Human Services. Multiple Cause of Death

Mortality Due to Aortic Stenosis in the United States

Patterns of Cardiovascular Mortality for HIV-Infected Adults in the United States: 1999 to 2013

Association Between Aging of the US Population and Heart Disease Mortality From

Trends in Cardiometabolic Mortality in the United States

Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data

Epidemiological trends in invasive mechanical ventilation in the United States: A population-based study

Risk of Death Influences Regional Variation in Intensive Care Unit Admission Rates among the Elderly in the United States

Clinical Characteristics of Coronavirus Disease 2019 in China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive care medicine

Abbreviations: ARF: Acute Respiratory Failure; ARDS: Acute Respiratory Distress Syndrome