Temporal Trends in Rural vs Urban Sepsis-Related Mortality in the United States, 2010-2019

Abstract

Recent improvements in processes of care were associated with decreased case fatality in patients with sepsis,1Seymour C.W. Gesten F. Prescott H.C. et al.Time to treatment and mortality during mandated emergency care for sepsis.N Engl J Med. 2017; 376: 2235-2244Crossref PubMed Scopus (947) Google Scholar but outcome disparities persist across patient demographic traits. However, studies on the prognostic implications of demographic characteristics on sepsis-related mortality focused largely on those related to age, sex, and race and ethnicity,2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google Scholar with comparatively sparse data on the prognostic impact of patients’ area of residence.3Goodwin A.J. Nadig N.R. McElligott J.T. Simpson K.N. Ford D.W. Where you live matters: the impact of place of residence on severe sepsis incidence and mortality.Chest. 2016; 150: 829-836Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Nearly 20% of the US population resides in rural areas,4United States Census BureauWhat is rural America? United States Census Bureau website.https://www.census.gov/library/stories/2017/08/rural-america.htmlDate accessed: July 8, 2021Google Scholar and rural populations have higher burden of chronic illness; face considerable social, economic, and geographic barriers to health care; and have reduced life expectancy compared with those residing in urban areas.5Singh G.K. Siahpush M. Widening rural-urban disparities in all-cause mortality and mortality from major causes of death in the USA, 1969-2009.J Urban Health. 2014; 91: 272-292Crossref PubMed Scopus (189) Google Scholar Although all-cause mortality has been decreasing in both rural and urban populations in the United States,6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar the corresponding trajectories of sepsis-related mortality are unknown. Herein, we examine the sepsis-related mortality trends of rural vs urban populations in the United States over the past decade.MethodsWe queried the Centers for Disease Control and Prevention Wide Ranging Online Data for Epidemiological Research Multiple Cause of Death dataset for sepsis-related deaths in the United States from 2010 through 2019 using a previously described taxonomy.2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google ScholarThe National Center for Health Statistics Urban-Rural Classification Scheme was dichotomized into two population categories according to the 2013 US Census classification: urban (large metropolitan area [≥ 1 million] and small or medium metropolitan areas [50,000-999,999]) and rural (< 50,000).7Ingram D.D. Franco S.J. 2013 NCHS urban-rural classification scheme for counties.Vital Health Stat 2. 2014; 166: 1-73PubMed Google Scholar We calculated age-adjusted mortality rates (AAMRs) per 100,000 population using the direct standardization method based on the age group weights from the 2000 standard US population. Results were then stratified by age, sex, and race and ethnicity.We estimated the annual percent change (APC) in AAMR (and unadjusted mortality rates for age strata) using negative binomial regression with log-link and robust SEs. An interaction term was included to test for differences in temporal trends. All analyses were performed using R version 4.0.2 software (R Foundation for Statistical Computing). A two-sided P value of < .05 was considered statistically significant. The study was not subject to institutional review because of the use of publicly available data.ResultsFrom 2010 through 2019, sepsis-related AAMRs increased overall in rural areas, from 48.9 per 100,000 to 57.9 per 100,000, while remaining unchanged in urban areas at 48.3 per 100,000 (Fig 1, Table 1). The absolute difference between rural and urban areas’ AAMRs increased from 0.6 per 100,000 (95% CI, –0.1 to 1.3) to 9.6 per 100,000 (95% CI, 8.9-10.3), corresponding to an increase of 1,600%. Notably, in 2010, mortality rates were similar in rural and urban areas among those ≥ 65 years of age and non-Hispanic White individuals and were lower among men residing in rural areas.Table 1Sepsis-Related Age-Adjusted Mortality Rates per 100,000 Population per Year in the United States, 2010-2019VariableUrban Area (n = 1,514,511 [81.8%])Rural Area (n = 338,099 [18.2%])AAMR/100,000 (95% CI)APC, % (95% CI)AAMR/100,000 (95% CI)APC, % (95% CI)201020192010-2019201020192010-2019Overall48.3 (48.0-48.5)48.3 (48.1-48.6)0.6 (0.0-1.1)aP < .05.48.9 (48.4-49.5)57.9 (57.3-58.5)2.4 (1.8-3.0)bP < .001.Age group, y < 251.7 (1.7-1.8)1.4 (1.4-1.5)–1.4 (–2.5 to –0.3)aP < .05.2.0 (1.8-2.2)1.5 (1.3-1.7)–1.9 (–3.9 to 0.1)cNot statistically significant. 25-6420.9 (20.7-21.1)23.3 (23.1-23.5)1.6 (1.2-2.1)bP < .001.23.0 (22.5-23.6)32.5 (31.8-33.2)4.1 (3.3-4.9)bP < .001. ≥ 65291.0 (289.2-292.9)282.5 (280.9-284.1)0.3 (–0.3 to 0.9)cNot statistically significant.286.8 (282.9-290.7)320.2 (316.5-324.0)1.9 (1.2-2.5)bP < .001.Sex Male55.4 (55.0-55.9)55.9 (55.5-56.3)0.7 (0.2-1.2)aP < .05.53.7 (52.7-54.6)64.7 (63.8-65.6)2.7 (2-3.3)bP < .001. Female43.1 (42.8-43.5)42.6 (42.3-42.9)0.4 (-0.2 to 1.0)cNot statistically significant.45.4 (44.6-46.1)52.6 (51.8-53.3)2.1 (1.5-2.7)bP < .001.Race and ethnicitydReported by the funeral director as provided by an informant (typically the next of kin) or on the basis of observation in absence of an informant. Non-Hispanic White44.7 (44.4-45.0)46.5 (46.3-46.8)1.0 (0.5-1.6)bP < .001.45.6 (45.1-46.2)55.7 (55.1-56.3)2.8 (2.1-3.4)bP < .001. Non-Hispanic Black80.4 (79.2-81.5)71.3 (70.4-72.2)–0.8 (–1.2 to –0.3)aP < .05.90.2 (87.0-93.5)88.6 (85.6-91.5)0.3 (–0.3 to 0.9)cNot statistically significant. Non-Hispanic Asian or Pacific Islander34.7 (33.6-35.9)31.0 (30.2-31.8)–0.7 (–1.2 to –0.3)aP < .05.26.8 (21.7-32.8)26.9 (22.8-31.0)1.4 (–0.8 to 3.8)cNot statistically significant. Non-Hispanic American Indian or Alaska Native58.7 (53.7-63.8)53.8 (50.0-57.5)0.0 (–1.0 to 0.9)cNot statistically significant.77.1 (70.4-83.8)83.7 (77.9-89.501.2 (0.1-2.4)aP < .05. Hispanic48.5 (47.6-49.5)44.7 (44.0-45.5)–0.2 (–0.7 to 0.2)cNot statistically significant.55.0 (51.3-58.7)51.7 (48.9-54.5)0.1 (–0.4 to 0.6)cNot statistically significant.AAMR = age-adjusted mortality rate; APC = annual percentage change.a P < .05.b P < .001.c Not statistically significant.d Reported by the funeral director as provided by an informant (typically the next of kin) or on the basis of observation in absence of an informant. Open table in a new tab The trends of sepsis-related mortality rates in rural and urban areas varied across age groups. Among those younger than 25 years, mortality rates decreased only in urban areas, while increasing among those 25 to 64 years of age across areas. Among those ≥ 65 years of age, mortality rates rose in rural areas from 286.8 per 100,000 in 2010 to 320.2 per 100,000 in 2019, but were unchanged in urban areas.Across areas, men showed higher AAMRs than women (P < .001). The AAMRs increased in both rural (APC, 2.7%; 95% CI, 2.0%-3.3%) and urban (APC, 0.7%; 95% CI, 0.2%-1.2%) areas among men. Among women, the AAMRs increased in rural areas (APC, 2.1%; 95% CI, 1.5%-2.7%), but remained unchanged in urban areas.The highest AAMRs across racial and ethnic groups and across areas occurred among non-Hispanic Black people (P < .001). Among non-Hispanic Black people, the AAMRs remained unchanged in rural areas (APC, 0.3%; 95% CI, –0.3% to 0.9%), but decreased in urban areas (APC, –0.8%; 95% CI, –1.2% to –0.3%). Among rural residents, the AAMRs rose among non-Hispanic White and non-Hispanic American Indian or Alaska Native people and remained unchanged among non-Hispanic Asian and Hispanic people.DiscussionThe key finding of our study is that sepsis-related mortality has increased substantially over the past decade among rural residents in the United States, while rising modestly in urban populations, with the rural-urban outcome disparity rising 16-fold from 2010 through 2019. This finding contrasts the decreasing rural and urban all-cause mortality.6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar Because many of the disadvantages faced by rural populations are long-standing,5Singh G.K. Siahpush M. Widening rural-urban disparities in all-cause mortality and mortality from major causes of death in the USA, 1969-2009.J Urban Health. 2014; 91: 272-292Crossref PubMed Scopus (189) Google Scholar the finding of comparable overall rural vs urban sepsis-related mortality in 2010 was unexpected, and its underlying factors are unclear. Disparities in sepsis-related mortality have evolved within each of the examined demographic categories. Notably, the recently reported improvements in sepsis-related mortality among non-Hispanic Black people2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google Scholar in the United States were confined to urban populations.The causes of the observed diverging trends of sepsis-related mortality are unclear and may represent differential changes in the risk of sepsis, sepsis-related case fatality, or their combination among rural vs urban populations. Residents of rural areas are increasingly older on average and have higher comorbidity burden compared with urban populations,8Villapiano N. Iwashyna T.J. Davis M.M. Worsening rural-urban gap in hospital mortality.J Am Board Fam Med. 2017; 30: 816-823Crossref PubMed Scopus (21) Google Scholar with both traits associated with increased risk of sepsis. The risk of sepsis in rural populations may have increased further because of a widening gap in access to primary care,9Zhang D. Son H. Shen Y. et al.Assessment of changes in rural and urban primary care workforce in the United States from 2009 to 2017.JAMA Netw Open. 2020; 3e2022914Crossref Scopus (11) Google Scholar with the latter barrier to health care possibly leading to an inadequate control of comorbid conditions, which in turn may increase susceptibility to sepsis and may worsen outcomes of sepsis events. Moreover, reduced access to primary care clinicians may lead to critical delays in the initial recognition and management of infections in the ambulatory setting. Such delays could result in progression to sepsis in some infections that could otherwise have been treated effectively. The gaps in rural vs urban sepsis-related mortality may have been exacerbated further by rural hospital closures.10Frakt A.B. The rural hospital problem.JAMA. 2019; 321: 2271-2272Crossref PubMed Scopus (24) Google Scholar However, reports on sepsis-related case fatality have been mixed, showing both higher3Goodwin A.J. Nadig N.R. McElligott J.T. Simpson K.N. Ford D.W. Where you live matters: the impact of place of residence on severe sepsis incidence and mortality.Chest. 2016; 150: 829-836Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar and lower8Villapiano N. Iwashyna T.J. Davis M.M. Worsening rural-urban gap in hospital mortality.J Am Board Fam Med. 2017; 30: 816-823Crossref PubMed Scopus (21) Google Scholar mortality in rural populations compared with urban populations. Critically, rather than increasing in rural areas from 2016 onward, sepsis-related mortality rates have instead plateaued (with similar plateauing in urban areas). These mortality trends dating from after 2015 in rural areas do not support increased documentation of sepsis as key driver of the overall faster uptrends in sepsis-related mortality in rural vs urban areas.Study limitations include inaccuracies of death certificates for cause of death and designation of race and ethnicity, and the structure of the dataset precludes adjustment for possible patient-level and health care system-level confounders.6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar In addition, this study cannot establish a causal relationship between mortality rates and rurality, but rather a statistical association. However, the use of a national longitudinal design allows us to infer the associations more accurately than a cross-sectional approach. Determination of the factors driving the growing rural-urban sepsis-related outcome disparities is needed to guide policy- and practice-level interventions. Recent improvements in processes of care were associated with decreased case fatality in patients with sepsis,1Seymour C.W. Gesten F. Prescott H.C. et al.Time to treatment and mortality during mandated emergency care for sepsis.N Engl J Med. 2017; 376: 2235-2244Crossref PubMed Scopus (947) Google Scholar but outcome disparities persist across patient demographic traits. However, studies on the prognostic implications of demographic characteristics on sepsis-related mortality focused largely on those related to age, sex, and race and ethnicity,2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google Scholar with comparatively sparse data on the prognostic impact of patients’ area of residence.3Goodwin A.J. Nadig N.R. McElligott J.T. Simpson K.N. Ford D.W. Where you live matters: the impact of place of residence on severe sepsis incidence and mortality.Chest. 2016; 150: 829-836Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Nearly 20% of the US population resides in rural areas,4United States Census BureauWhat is rural America? United States Census Bureau website.https://www.census.gov/library/stories/2017/08/rural-america.htmlDate accessed: July 8, 2021Google Scholar and rural populations have higher burden of chronic illness; face considerable social, economic, and geographic barriers to health care; and have reduced life expectancy compared with those residing in urban areas.5Singh G.K. Siahpush M. Widening rural-urban disparities in all-cause mortality and mortality from major causes of death in the USA, 1969-2009.J Urban Health. 2014; 91: 272-292Crossref PubMed Scopus (189) Google Scholar Although all-cause mortality has been decreasing in both rural and urban populations in the United States,6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar the corresponding trajectories of sepsis-related mortality are unknown. Herein, we examine the sepsis-related mortality trends of rural vs urban populations in the United States over the past decade. MethodsWe queried the Centers for Disease Control and Prevention Wide Ranging Online Data for Epidemiological Research Multiple Cause of Death dataset for sepsis-related deaths in the United States from 2010 through 2019 using a previously described taxonomy.2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google ScholarThe National Center for Health Statistics Urban-Rural Classification Scheme was dichotomized into two population categories according to the 2013 US Census classification: urban (large metropolitan area [≥ 1 million] and small or medium metropolitan areas [50,000-999,999]) and rural (< 50,000).7Ingram D.D. Franco S.J. 2013 NCHS urban-rural classification scheme for counties.Vital Health Stat 2. 2014; 166: 1-73PubMed Google Scholar We calculated age-adjusted mortality rates (AAMRs) per 100,000 population using the direct standardization method based on the age group weights from the 2000 standard US population. Results were then stratified by age, sex, and race and ethnicity.We estimated the annual percent change (APC) in AAMR (and unadjusted mortality rates for age strata) using negative binomial regression with log-link and robust SEs. An interaction term was included to test for differences in temporal trends. All analyses were performed using R version 4.0.2 software (R Foundation for Statistical Computing). A two-sided P value of < .05 was considered statistically significant. The study was not subject to institutional review because of the use of publicly available data. We queried the Centers for Disease Control and Prevention Wide Ranging Online Data for Epidemiological Research Multiple Cause of Death dataset for sepsis-related deaths in the United States from 2010 through 2019 using a previously described taxonomy.2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google Scholar The National Center for Health Statistics Urban-Rural Classification Scheme was dichotomized into two population categories according to the 2013 US Census classification: urban (large metropolitan area [≥ 1 million] and small or medium metropolitan areas [50,000-999,999]) and rural (< 50,000).7Ingram D.D. Franco S.J. 2013 NCHS urban-rural classification scheme for counties.Vital Health Stat 2. 2014; 166: 1-73PubMed Google Scholar We calculated age-adjusted mortality rates (AAMRs) per 100,000 population using the direct standardization method based on the age group weights from the 2000 standard US population. Results were then stratified by age, sex, and race and ethnicity. We estimated the annual percent change (APC) in AAMR (and unadjusted mortality rates for age strata) using negative binomial regression with log-link and robust SEs. An interaction term was included to test for differences in temporal trends. All analyses were performed using R version 4.0.2 software (R Foundation for Statistical Computing). A two-sided P value of < .05 was considered statistically significant. The study was not subject to institutional review because of the use of publicly available data. ResultsFrom 2010 through 2019, sepsis-related AAMRs increased overall in rural areas, from 48.9 per 100,000 to 57.9 per 100,000, while remaining unchanged in urban areas at 48.3 per 100,000 (Fig 1, Table 1). The absolute difference between rural and urban areas’ AAMRs increased from 0.6 per 100,000 (95% CI, –0.1 to 1.3) to 9.6 per 100,000 (95% CI, 8.9-10.3), corresponding to an increase of 1,600%. Notably, in 2010, mortality rates were similar in rural and urban areas among those ≥ 65 years of age and non-Hispanic White individuals and were lower among men residing in rural areas.Table 1Sepsis-Related Age-Adjusted Mortality Rates per 100,000 Population per Year in the United States, 2010-2019VariableUrban Area (n = 1,514,511 [81.8%])Rural Area (n = 338,099 [18.2%])AAMR/100,000 (95% CI)APC, % (95% CI)AAMR/100,000 (95% CI)APC, % (95% CI)201020192010-2019201020192010-2019Overall48.3 (48.0-48.5)48.3 (48.1-48.6)0.6 (0.0-1.1)aP < .05.48.9 (48.4-49.5)57.9 (57.3-58.5)2.4 (1.8-3.0)bP < .001.Age group, y < 251.7 (1.7-1.8)1.4 (1.4-1.5)–1.4 (–2.5 to –0.3)aP < .05.2.0 (1.8-2.2)1.5 (1.3-1.7)–1.9 (–3.9 to 0.1)cNot statistically significant. 25-6420.9 (20.7-21.1)23.3 (23.1-23.5)1.6 (1.2-2.1)bP < .001.23.0 (22.5-23.6)32.5 (31.8-33.2)4.1 (3.3-4.9)bP < .001. ≥ 65291.0 (289.2-292.9)282.5 (280.9-284.1)0.3 (–0.3 to 0.9)cNot statistically significant.286.8 (282.9-290.7)320.2 (316.5-324.0)1.9 (1.2-2.5)bP < .001.Sex Male55.4 (55.0-55.9)55.9 (55.5-56.3)0.7 (0.2-1.2)aP < .05.53.7 (52.7-54.6)64.7 (63.8-65.6)2.7 (2-3.3)bP < .001. Female43.1 (42.8-43.5)42.6 (42.3-42.9)0.4 (-0.2 to 1.0)cNot statistically significant.45.4 (44.6-46.1)52.6 (51.8-53.3)2.1 (1.5-2.7)bP < .001.Race and ethnicitydReported by the funeral director as provided by an informant (typically the next of kin) or on the basis of observation in absence of an informant. Non-Hispanic White44.7 (44.4-45.0)46.5 (46.3-46.8)1.0 (0.5-1.6)bP < .001.45.6 (45.1-46.2)55.7 (55.1-56.3)2.8 (2.1-3.4)bP < .001. Non-Hispanic Black80.4 (79.2-81.5)71.3 (70.4-72.2)–0.8 (–1.2 to –0.3)aP < .05.90.2 (87.0-93.5)88.6 (85.6-91.5)0.3 (–0.3 to 0.9)cNot statistically significant. Non-Hispanic Asian or Pacific Islander34.7 (33.6-35.9)31.0 (30.2-31.8)–0.7 (–1.2 to –0.3)aP < .05.26.8 (21.7-32.8)26.9 (22.8-31.0)1.4 (–0.8 to 3.8)cNot statistically significant. Non-Hispanic American Indian or Alaska Native58.7 (53.7-63.8)53.8 (50.0-57.5)0.0 (–1.0 to 0.9)cNot statistically significant.77.1 (70.4-83.8)83.7 (77.9-89.501.2 (0.1-2.4)aP < .05. Hispanic48.5 (47.6-49.5)44.7 (44.0-45.5)–0.2 (–0.7 to 0.2)cNot statistically significant.55.0 (51.3-58.7)51.7 (48.9-54.5)0.1 (–0.4 to 0.6)cNot statistically significant.AAMR = age-adjusted mortality rate; APC = annual percentage change.a P < .05.b P < .001.c Not statistically significant.d Reported by the funeral director as provided by an informant (typically the next of kin) or on the basis of observation in absence of an informant. Open table in a new tab The trends of sepsis-related mortality rates in rural and urban areas varied across age groups. Among those younger than 25 years, mortality rates decreased only in urban areas, while increasing among those 25 to 64 years of age across areas. Among those ≥ 65 years of age, mortality rates rose in rural areas from 286.8 per 100,000 in 2010 to 320.2 per 100,000 in 2019, but were unchanged in urban areas.Across areas, men showed higher AAMRs than women (P < .001). The AAMRs increased in both rural (APC, 2.7%; 95% CI, 2.0%-3.3%) and urban (APC, 0.7%; 95% CI, 0.2%-1.2%) areas among men. Among women, the AAMRs increased in rural areas (APC, 2.1%; 95% CI, 1.5%-2.7%), but remained unchanged in urban areas.The highest AAMRs across racial and ethnic groups and across areas occurred among non-Hispanic Black people (P < .001). Among non-Hispanic Black people, the AAMRs remained unchanged in rural areas (APC, 0.3%; 95% CI, –0.3% to 0.9%), but decreased in urban areas (APC, –0.8%; 95% CI, –1.2% to –0.3%). Among rural residents, the AAMRs rose among non-Hispanic White and non-Hispanic American Indian or Alaska Native people and remained unchanged among non-Hispanic Asian and Hispanic people. From 2010 through 2019, sepsis-related AAMRs increased overall in rural areas, from 48.9 per 100,000 to 57.9 per 100,000, while remaining unchanged in urban areas at 48.3 per 100,000 (Fig 1, Table 1). The absolute difference between rural and urban areas’ AAMRs increased from 0.6 per 100,000 (95% CI, –0.1 to 1.3) to 9.6 per 100,000 (95% CI, 8.9-10.3), corresponding to an increase of 1,600%. Notably, in 2010, mortality rates were similar in rural and urban areas among those ≥ 65 years of age and non-Hispanic White individuals and were lower among men residing in rural areas. AAMR = age-adjusted mortality rate; APC = annual percentage change. The trends of sepsis-related mortality rates in rural and urban areas varied across age groups. Among those younger than 25 years, mortality rates decreased only in urban areas, while increasing among those 25 to 64 years of age across areas. Among those ≥ 65 years of age, mortality rates rose in rural areas from 286.8 per 100,000 in 2010 to 320.2 per 100,000 in 2019, but were unchanged in urban areas. Across areas, men showed higher AAMRs than women (P < .001). The AAMRs increased in both rural (APC, 2.7%; 95% CI, 2.0%-3.3%) and urban (APC, 0.7%; 95% CI, 0.2%-1.2%) areas among men. Among women, the AAMRs increased in rural areas (APC, 2.1%; 95% CI, 1.5%-2.7%), but remained unchanged in urban areas. The highest AAMRs across racial and ethnic groups and across areas occurred among non-Hispanic Black people (P < .001). Among non-Hispanic Black people, the AAMRs remained unchanged in rural areas (APC, 0.3%; 95% CI, –0.3% to 0.9%), but decreased in urban areas (APC, –0.8%; 95% CI, –1.2% to –0.3%). Among rural residents, the AAMRs rose among non-Hispanic White and non-Hispanic American Indian or Alaska Native people and remained unchanged among non-Hispanic Asian and Hispanic people. DiscussionThe key finding of our study is that sepsis-related mortality has increased substantially over the past decade among rural residents in the United States, while rising modestly in urban populations, with the rural-urban outcome disparity rising 16-fold from 2010 through 2019. This finding contrasts the decreasing rural and urban all-cause mortality.6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar Because many of the disadvantages faced by rural populations are long-standing,5Singh G.K. Siahpush M. Widening rural-urban disparities in all-cause mortality and mortality from major causes of death in the USA, 1969-2009.J Urban Health. 2014; 91: 272-292Crossref PubMed Scopus (189) Google Scholar the finding of comparable overall rural vs urban sepsis-related mortality in 2010 was unexpected, and its underlying factors are unclear. Disparities in sepsis-related mortality have evolved within each of the examined demographic categories. Notably, the recently reported improvements in sepsis-related mortality among non-Hispanic Black people2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google Scholar in the United States were confined to urban populations.The causes of the observed diverging trends of sepsis-related mortality are unclear and may represent differential changes in the risk of sepsis, sepsis-related case fatality, or their combination among rural vs urban populations. Residents of rural areas are increasingly older on average and have higher comorbidity burden compared with urban populations,8Villapiano N. Iwashyna T.J. Davis M.M. Worsening rural-urban gap in hospital mortality.J Am Board Fam Med. 2017; 30: 816-823Crossref PubMed Scopus (21) Google Scholar with both traits associated with increased risk of sepsis. The risk of sepsis in rural populations may have increased further because of a widening gap in access to primary care,9Zhang D. Son H. Shen Y. et al.Assessment of changes in rural and urban primary care workforce in the United States from 2009 to 2017.JAMA Netw Open. 2020; 3e2022914Crossref Scopus (11) Google Scholar with the latter barrier to health care possibly leading to an inadequate control of comorbid conditions, which in turn may increase susceptibility to sepsis and may worsen outcomes of sepsis events. Moreover, reduced access to primary care clinicians may lead to critical delays in the initial recognition and management of infections in the ambulatory setting. Such delays could result in progression to sepsis in some infections that could otherwise have been treated effectively. The gaps in rural vs urban sepsis-related mortality may have been exacerbated further by rural hospital closures.10Frakt A.B. The rural hospital problem.JAMA. 2019; 321: 2271-2272Crossref PubMed Scopus (24) Google Scholar However, reports on sepsis-related case fatality have been mixed, showing both higher3Goodwin A.J. Nadig N.R. McElligott J.T. Simpson K.N. Ford D.W. Where you live matters: the impact of place of residence on severe sepsis incidence and mortality.Chest. 2016; 150: 829-836Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar and lower8Villapiano N. Iwashyna T.J. Davis M.M. Worsening rural-urban gap in hospital mortality.J Am Board Fam Med. 2017; 30: 816-823Crossref PubMed Scopus (21) Google Scholar mortality in rural populations compared with urban populations. Critically, rather than increasing in rural areas from 2016 onward, sepsis-related mortality rates have instead plateaued (with similar plateauing in urban areas). These mortality trends dating from after 2015 in rural areas do not support increased documentation of sepsis as key driver of the overall faster uptrends in sepsis-related mortality in rural vs urban areas.Study limitations include inaccuracies of death certificates for cause of death and designation of race and ethnicity, and the structure of the dataset precludes adjustment for possible patient-level and health care system-level confounders.6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar In addition, this study cannot establish a causal relationship between mortality rates and rurality, but rather a statistical association. However, the use of a national longitudinal design allows us to infer the associations more accurately than a cross-sectional approach. Determination of the factors driving the growing rural-urban sepsis-related outcome disparities is needed to guide policy- and practice-level interventions. The key finding of our study is that sepsis-related mortality has increased substantially over the past decade among rural residents in the United States, while rising modestly in urban populations, with the rural-urban outcome disparity rising 16-fold from 2010 through 2019. This finding contrasts the decreasing rural and urban all-cause mortality.6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar Because many of the disadvantages faced by rural populations are long-standing,5Singh G.K. Siahpush M. Widening rural-urban disparities in all-cause mortality and mortality from major causes of death in the USA, 1969-2009.J Urban Health. 2014; 91: 272-292Crossref PubMed Scopus (189) Google Scholar the finding of comparable overall rural vs urban sepsis-related mortality in 2010 was unexpected, and its underlying factors are unclear. Disparities in sepsis-related mortality have evolved within each of the examined demographic categories. Notably, the recently reported improvements in sepsis-related mortality among non-Hispanic Black people2Prest J. Matheni S. Jeganathan N. Current trends in sepsis-related mortality in the United States.Crit Care Med. 2021; 49: 1276-1284PubMed Google Scholar in the United States were confined to urban populations. The causes of the observed diverging trends of sepsis-related mortality are unclear and may represent differential changes in the risk of sepsis, sepsis-related case fatality, or their combination among rural vs urban populations. Residents of rural areas are increasingly older on average and have higher comorbidity burden compared with urban populations,8Villapiano N. Iwashyna T.J. Davis M.M. Worsening rural-urban gap in hospital mortality.J Am Board Fam Med. 2017; 30: 816-823Crossref PubMed Scopus (21) Google Scholar with both traits associated with increased risk of sepsis. The risk of sepsis in rural populations may have increased further because of a widening gap in access to primary care,9Zhang D. Son H. Shen Y. et al.Assessment of changes in rural and urban primary care workforce in the United States from 2009 to 2017.JAMA Netw Open. 2020; 3e2022914Crossref Scopus (11) Google Scholar with the latter barrier to health care possibly leading to an inadequate control of comorbid conditions, which in turn may increase susceptibility to sepsis and may worsen outcomes of sepsis events. Moreover, reduced access to primary care clinicians may lead to critical delays in the initial recognition and management of infections in the ambulatory setting. Such delays could result in progression to sepsis in some infections that could otherwise have been treated effectively. The gaps in rural vs urban sepsis-related mortality may have been exacerbated further by rural hospital closures.10Frakt A.B. The rural hospital problem.JAMA. 2019; 321: 2271-2272Crossref PubMed Scopus (24) Google Scholar However, reports on sepsis-related case fatality have been mixed, showing both higher3Goodwin A.J. Nadig N.R. McElligott J.T. Simpson K.N. Ford D.W. Where you live matters: the impact of place of residence on severe sepsis incidence and mortality.Chest. 2016; 150: 829-836Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar and lower8Villapiano N. Iwashyna T.J. Davis M.M. Worsening rural-urban gap in hospital mortality.J Am Board Fam Med. 2017; 30: 816-823Crossref PubMed Scopus (21) Google Scholar mortality in rural populations compared with urban populations. Critically, rather than increasing in rural areas from 2016 onward, sepsis-related mortality rates have instead plateaued (with similar plateauing in urban areas). These mortality trends dating from after 2015 in rural areas do not support increased documentation of sepsis as key driver of the overall faster uptrends in sepsis-related mortality in rural vs urban areas. Study limitations include inaccuracies of death certificates for cause of death and designation of race and ethnicity, and the structure of the dataset precludes adjustment for possible patient-level and health care system-level confounders.6Cross S.H. Califf R.M. Warraich H.J. Rural-urban disparity in mortality in the US from 1999 to 2019.JAMA. 2021; 325: 2312-2314Crossref PubMed Scopus (19) Google Scholar In addition, this study cannot establish a causal relationship between mortality rates and rurality, but rather a statistical association. However, the use of a national longitudinal design allows us to infer the associations more accurately than a cross-sectional approach. Determination of the factors driving the growing rural-urban sepsis-related outcome disparities is needed to guide policy- and practice-level interventions. Financial/nonfinancial disclosures: None declared.