The Association Between Days Alive and Out of Hospital and Health-Related Quality of Life in Patients With Sepsis

Abstract

BackgroundThe number of days alive and out of hospital (DAOH) is being used as a primary outcome in clinical trials. Limited data support the contention that it is a patient-important outcome.Research QuestionThe primary objective was to assess the association between DAOH and health-related quality of life (HRQoL) at 6 months, as well as to assess the construct validity of DAOH as an outcome measure.Study Design and MethodsUsing data from the Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock, Australasian Resuscitation in Sepsis Evaluation, and Crystalloid vs Hydroxyethyl Starch trials, we calculated the number of DOAH at day 90 (DAOH-90). HRQoL was estimated with the EQ-5D utility index score (range, –0.59 to 1) and the EQ-5D visual analog scale (range, 0-100) at 6 months. The association between DAOH and HRQoL was assessed using linear models, nonlinear models, and nonparametric measures of association.ResultsSix thousand two hundred thirteen trial participants included. The median index hospital length of stay was 16 days (interquartile range [IQR], 8-30), and mortality for the index hospitalization was 1,402 of 6,213 (22.6%). The median number of DAOH-90 was 60 days (IQR, 0-77 days). Each additional DAOH-90 was associated with an estimated increase in the 6-month EQ-5D utility index (range, 0-1) of 0.01 (95% CI, 0.01-0.011; P < .001). Adjusted analysis showed that each additional DAOH-90 was associated with an increase of 1.01 (95% CI, 0.99-1.04; P < .001) in the EQ-5D visual analog scale (range, 0-100). Trial participants at higher risk of adverse outcomes showed fewer DAOH-90.InterpretationWe found a small positive incremental association between the number of DAOH-90 and HRQoL at 6 months and a negative association between the number of DAOH-90 and risk factors for adverse outcomes. These data provide some support for the use of DAOH-90 as an outcome measure in clinical trials of patients with sepsis.Trial RegistryClinicalTrials.gov; No.: NCT04567433; URL: www.clinicaltrials.gov The number of days alive and out of hospital (DAOH) is being used as a primary outcome in clinical trials. Limited data support the contention that it is a patient-important outcome. The primary objective was to assess the association between DAOH and health-related quality of life (HRQoL) at 6 months, as well as to assess the construct validity of DAOH as an outcome measure. Using data from the Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock, Australasian Resuscitation in Sepsis Evaluation, and Crystalloid vs Hydroxyethyl Starch trials, we calculated the number of DOAH at day 90 (DAOH-90). HRQoL was estimated with the EQ-5D utility index score (range, –0.59 to 1) and the EQ-5D visual analog scale (range, 0-100) at 6 months. The association between DAOH and HRQoL was assessed using linear models, nonlinear models, and nonparametric measures of association. Six thousand two hundred thirteen trial participants included. The median index hospital length of stay was 16 days (interquartile range [IQR], 8-30), and mortality for the index hospitalization was 1,402 of 6,213 (22.6%). The median number of DAOH-90 was 60 days (IQR, 0-77 days). Each additional DAOH-90 was associated with an estimated increase in the 6-month EQ-5D utility index (range, 0-1) of 0.01 (95% CI, 0.01-0.011; P < .001). Adjusted analysis showed that each additional DAOH-90 was associated with an increase of 1.01 (95% CI, 0.99-1.04; P < .001) in the EQ-5D visual analog scale (range, 0-100). Trial participants at higher risk of adverse outcomes showed fewer DAOH-90. We found a small positive incremental association between the number of DAOH-90 and HRQoL at 6 months and a negative association between the number of DAOH-90 and risk factors for adverse outcomes. These data provide some support for the use of DAOH-90 as an outcome measure in clinical trials of patients with sepsis. ClinicalTrials.gov; No.: NCT04567433; URL: www.clinicaltrials.gov Take-home PointsStudy Question: Does evidence exist to support the use of days alive and out of hospital (DAOH) as a patient-important outcome for clinical trials in patients with sepsis?Results: We found a small positive incremental association between the number of DAOH to day 90 (DOAH-90) and health-related quality of life at 6 months and a negative association between the number of DAOH-90 and risk factors for adverse outcomes.Interpretation: These data provide some support for the use of DAOH-90 as an outcome measure in clinical trials of patients with sepsis. Study Question: Does evidence exist to support the use of days alive and out of hospital (DAOH) as a patient-important outcome for clinical trials in patients with sepsis? Results: We found a small positive incremental association between the number of DAOH to day 90 (DOAH-90) and health-related quality of life at 6 months and a negative association between the number of DAOH-90 and risk factors for adverse outcomes. Interpretation: These data provide some support for the use of DAOH-90 as an outcome measure in clinical trials of patients with sepsis. Sepsis, life-threatening organ dysfunction associated with a dysregulated host response to infection,1Singer M. Deutschman C.S. Seymour C.W. et al.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (14528) Google Scholar is estimated to affect approximately 50 million people and to be responsible for 11 million deaths globally every year.2Rudd K.E. Johnson S.C. Agesa K.M. et al.Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.Lancet. 2020; 395: 200-211Abstract Full Text Full Text PDF PubMed Google Scholar International efforts to reduce the mortality of sepsis3Rhodes A. Evans L.E. Alhazzani W. et al.Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016.Intensive Care Med. 2017; 43: 304-377Crossref PubMed Scopus (4290) Google Scholar seem to be having some effect on the mortality rate,4Kaukonen K.M. Bailey M. Suzuki S. Pilcher D. Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012.JAMA. 2014; 311: 1308-1316Crossref PubMed Scopus (1242) Google Scholar despite patients with sepsis often having frailty5Darvall J.N. Bellomo R. Paul E. et al.Frailty in very old critically ill patients in Australia and New Zealand: a population-based cohort study.Med J Aust. 2019; 211: 318-323Crossref PubMed Scopus (58) Google Scholar with one or more life-limiting comorbidity.6Yende S. Austin S. Rhodes A. et al.Long-term quality of life among survivors of severe sepsis: analyses of two international trials.Crit Care Med. 2016; 44: 1461-1467Crossref PubMed Scopus (163) Google Scholar Survivors of sepsis show increased health care use,7Prescott H.C. Langa K.M. Liu V. Escobar G.J. Iwashyna T.J. Increased 1-year healthcare use in survivors of severe sepsis.Am J Respir Crit Care Med. 2014; 190: 62-69Crossref PubMed Scopus (202) Google Scholar increased rates of hospital readmission, and impaired health-related quality of life (HRQoL).6Yende S. Austin S. Rhodes A. et al.Long-term quality of life among survivors of severe sepsis: analyses of two international trials.Crit Care Med. 2016; 44: 1461-1467Crossref PubMed Scopus (163) Google Scholar Recognition that clinical trials in populations of patients with sepsis should incorporate measures of both short-term mortality and longer-term HRQoL is growing.6Yende S. Austin S. Rhodes A. et al.Long-term quality of life among survivors of severe sepsis: analyses of two international trials.Crit Care Med. 2016; 44: 1461-1467Crossref PubMed Scopus (163) Google Scholar One measure that has been suggested is days alive and out of hospital (DAOH).8Auriemma C.L. Taylor S.P. Harhay M.O. Courtright K.R. Halpern S.D. Hospital-free days: a pragmatic and patient-centered outcome for trials among critically and seriously ill patients.Am J Respir Crit Care Med. 2021; 204: 902-909Crossref PubMed Scopus (38) Google Scholar This composite variable aims to capture elements of both mortality and morbidity, the latter quantified via the duration of hospital admission in survivors,9Myles P.S. Shulman M.A. Heritier S. et al.Validation of days at home as an outcome measure after surgery: a prospective cohort study in Australia.BMJ Open. 2017; 7e015828Crossref Scopus (126) Google Scholar and recently was used as a primary outcome measure in trials in critically ill populations10Andersen-Ranberg N.C. Poulsen L.M. Perner A. et al.Haloperidol for the treatment of delirium in ICU patients.N Engl J Med. 2022; 387: 2425-2435Crossref PubMed Scopus (35) Google Scholar,11Hodgson C.L. Bailey M. Bellomo R. et al.Early active mobilization during mechanical ventilation in the ICU.N Engl J Med. 2022; 387: 1747-1758Crossref PubMed Scopus (55) Google Scholar as well as trials in cardiology12Ariti C.A. Cleland J.G. Pocock S.J. et al.Days alive and out of hospital and the patient journey in patients with heart failure: insights from the Candesartan in of in Mortality and PubMed Scopus Google D. et al.Days alive and out of a pragmatic outcome in a clinical trial of patients with Scopus Google Scholar and M.A. D. D. for to of PubMed Scopus Google Scholar of DAOH is that it be via it for for rates of an additional on trial to the more use of measure is that been that DAOH be a patient-important outcome C.L. Taylor S.P. Harhay M.O. Courtright K.R. Halpern S.D. Hospital-free days: a pragmatic and patient-centered outcome for trials among critically and seriously ill patients.Am J Respir Crit Care Med. 2021; 204: 902-909Crossref PubMed Scopus (38) Google Scholar data to support the validity of that contention The of a positive association between DAOH and HRQoL provide some evidence in support of the contention that DAOH is a patient-important outcome. we a cohort study to assess the association between DAOH and as well as to assess the construct in and PubMed Scopus Google Scholar of DAOH as a measure of outcome of critically ill patients with sepsis. We a cohort study using data from clinical the Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock S. et in patients with septic Engl J Med. PubMed Scopus Google Scholar the Australasian Resuscitation in Sepsis A. Bailey M. et for patients with septic Engl J Med. 2014; PubMed Scopus Google Scholar and the Crystalloid vs Hydroxyethyl Starch S. Bellomo R. et or for in Engl J Med. PubMed Scopus Google Scholar These data for the analysis and an of and the to the The study was at for study was from the We trial participants from the S. et in patients with septic Engl J Med. PubMed Scopus Google Scholar A. Bailey M. et for patients with septic Engl J Med. 2014; PubMed Scopus Google Scholar and Crystalloid vs Hydroxyethyl S. Bellomo R. et or for in Engl J Med. PubMed Scopus Google Scholar trials sepsis. Full of the for each trial in the trial S. et in patients with septic Engl J Med. PubMed Scopus Google A. Bailey M. et for patients with septic Engl J Med. 2014; PubMed Scopus Google S. Bellomo R. et or for in Engl J Med. PubMed Scopus Google Scholar the trial patients mechanical ventilation to two or more of the for response et for sepsis and organ and guidelines for the use of in sepsis. The Consensus of of Care Full Text Full Text PDF PubMed Google Scholar and or for a of S. et in patients with septic Engl J Med. PubMed Scopus Google Scholar The trial patients in the a or two or more of the response and showed evidence of or A. Bailey M. et for patients with septic Engl J Med. 2014; PubMed Scopus Google Scholar trial participants from the and trials in The Crystalloid vs Hydroxyethyl Starch trial patients to the ICU to the Crystalloid vs Hydroxyethyl Starch we participants at as having with the of two or more response Taylor S. et outcomes of critically ill patients with and Care Med. 44: PubMed Scopus Google Scholar Sepsis was the primary for hospital admission for trial participants in the participants in the and Crystalloid vs Hydroxyethyl Starch sepsis was the primary for hospital admission or sepsis as a during the we data from trial participants with and for outcome data each data we of using the and a of Care Med. PubMed Google Scholar organ using the R. et al.The score to organ of the on of the of Care Care Med. PubMed Google Scholar and of to the S. et in patients with septic Engl J Med. PubMed Scopus Google Scholar and the A. Bailey M. et for patients with septic Engl J Med. 2014; PubMed Scopus Google of in and Full Text PDF PubMed Scopus Google Scholar We shock at as a of < or of a M. Deutschman C.S. Seymour C.W. et al.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (14528) Google Scholar We data the and duration organ support and We measures of use ICU and hospital length of stay for the index hospital as well as data to an care hospital to 90 days after Taylor S. et outcomes of critically ill patients with and Care Med. 44: PubMed Scopus Google et quality of life in survivors of septic shock: 6-month from the Care Med. 2020; PubMed Scopus Google Bellomo R. et of life and 1-year in patients with septic shock: of the Australasian Resuscitation in Sepsis Care Med. 2019; PubMed Scopus Google S. et for of patients in outcomes and analysis of a cohort from Respir Med. 2016; Full Text Full Text PDF PubMed Google Scholar Mortality at index ICU and hospital and at 6 months We calculated the number of DAOH the number of care hospital days both the index admission and to care 90 days after from the primary participants day 90 DAOH of that days out of an care We a analysis of DAOH to day calculated as the of days alive and out of an care hospital of in HRQoL was using the EQ-5D for participants in the Bellomo R. et of life and 1-year in patients with septic shock: of the Australasian Resuscitation in Sepsis Care Med. 2019; PubMed Scopus Google Scholar and Crystalloid vs Hydroxyethyl Starch Taylor S. et outcomes of critically ill patients with and Care Med. 44: PubMed Scopus Google Scholar and the EQ-5D for participants in the et quality of life in survivors of septic shock: 6-month from the Care Med. 2020; PubMed Scopus Google Scholar The utility index calculated from patient using the for the EQ-5D A. M. and Google Scholar or the for EQ-5D et for the the to Full Text Full Text PDF PubMed Scopus Google Scholar HRQoL was assessed using both the utility index a range from to with a score of health and of as a being as as being and of < a being and the visual analog scale to with health and higher The EQ-5D score in each trial was at 6 months after at for the utility index score and With the of evidence that support the contention that DAOH is a patient-important the primary objective of the study was to assess the association between DAOH at day 90 and HRQoL at 6 months with the we to the that participants a higher number of DAOH-90 higher HRQoL at 6 months as the EQ-5D utility The objective was to assess the construct validity of the DAOH-90 as an outcome measure using to P.S. Shulman M.A. Heritier S. et al.Validation of days at home as an outcome measure after surgery: a prospective cohort study in Australia.BMJ Open. 2017; 7e015828Crossref Scopus (126) Google Scholar We that trial participants at higher risk of an adverse outcome fewer DAOH-90. we that participants with of with the and with more at as well as more organ fewer DAOH-90. We to assess a in the of DAOH-90 in and of as and for and median and range for the and of of we provide and as of the each the primary we assessed the association between DAOH-90 and EQ-5D utility using linear on of composite DAOH-90 was to a or C.L. Taylor S.P. Harhay M.O. Courtright K.R. Halpern S.D. Hospital-free days: a pragmatic and patient-centered outcome for trials among critically and seriously ill patients.Am J Respir Crit Care Med. 2021; 204: 902-909Crossref PubMed Scopus (38) Google Scholar linear analyses the of the outcome variable using that DAOH linear that the association of with a of a variable as the median the These for the or of the outcome of be more to outcome E. a on and Scopus Google Scholar The DAOH-90 data in the study using in a linear for the D. in linear a 2017; PubMed Scopus Google Scholar using the in for with study and Crystalloid vs Hydroxyethyl Starch as a shock of mechanical ventilation and as or as These using clinical Using effect for an of the range to the and of analysis was for the primary data and analyses with the range of We analysis to survivors at day 90 and day as well as the association between DAOH to day and HRQoL at 6 months. the for a nonlinear association between DAOH-90 and the was as a with at was to effect and for effect increased as on the cohort we assessed the nonparametric between the DAOH and both the EQ-5D utility index score and the EQ-5D as well as and for the cohort and each the was used to median in DAOH-90 with and analyses out using using the EQ-5D and each was and with P of < been for the of both and between from a of 6,213 trial the of the The of the participants from each trial and the cohort in of the trial participants in each trial and the as well as ICU and hospital length of stay and mortality, in with of the of data in mortality between the two in each of the trials of the Patients With Sepsis in the and Crystalloid vs Hydroxyethyl Starch of as median (interquartile or Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock and Australasian Resuscitation in Sepsis Crystalloid vs Hydroxyethyl Starch in a ICU and of and EQ-5D and in the and Crystalloid vs Hydroxyethyl Starch of score Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock Australasian Resuscitation in Sepsis Crystalloid vs Hydroxyethyl Starch DAOH-90 days alive and out of hospital at day length of visual analog scale (range, with and higher in a as median (interquartile or Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock and Australasian Resuscitation in Sepsis Crystalloid vs Hydroxyethyl Starch Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock Australasian Resuscitation in Sepsis Crystalloid vs Hydroxyethyl Starch DAOH-90 days alive and out of hospital at day length of visual analog scale (range, with and higher The median number of DAOH-90 in the cohort was 60 days (interquartile 0-77 with a as in The of EQ-5D utility and EQ-5D in and The median EQ-5D utility score at 6 months in the cohort was (interquartile with a median EQ-5D score of 60 (interquartile an increase of DAOH day was associated with an estimated increase in the median EQ-5D utility index of 0.01 (95% CI, 0.01-0.011; 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We found that DAOH-90 was associated with higher EQ-5D utility index and EQ-5D at 6 months. The positive association between EQ-5D and DAOH-90 was to the of the use of linear and nonlinear and nonparametric and was to a the analysis was to survivors at day We found an association between DAOH at day and we found that trial participants to be at risk of adverse outcomes after an of sepsis showed fewer DAOH-90 and in to outcomes showed more DAOH-90. These data provide some support for the use of DAOH-90 as an outcome measure in clinical trials of patients with sepsis. This study is in DAOH-90 as an outcome measure in The construct validity of has been assessed in a cohort of participants in trials in P.S. Shulman M.A. Heritier S. et al.Validation of days at home as an outcome measure after surgery: a prospective cohort study in Australia.BMJ Open. 2017; 7e015828Crossref Scopus (126) Google Scholar to study of a critically ill with sepsis and mortality 90 the of DAOH at days in the mortality show the at to the that the construct of DAOH at days was of use as a composite outcome variable for use in trials in two cohort of critically ill populations the association between DAOH and longer-term positive association between DAOH and HRQoL was recently in a cohort of study participants with mechanical ventilation for days or S. E. et of days alive and at home at day 90 after care admission with and among Open. PubMed Scopus Google Scholar in a of patients with severe association between DAOH and HRQoL was A. et between days alive life of hospital and health-related quality of PubMed Scopus Google Scholar The study has a number of was to a and used data from international clinical S. et in patients with septic Engl J Med. PubMed Scopus Google A. Bailey M. et for patients with septic Engl J Med. 2014; PubMed Scopus Google S. Bellomo R. et or for in Engl J Med. PubMed Scopus Google Scholar The participants a range of of to that the to a of patients with sepsis. The study has a number of for study from clinical trials in Australia and New Zealand, with participants from to 2017; the association be in health care in we to an association between DAOH-90 and a patient-important outcomes be used as 2020; PubMed Scopus Google Scholar data to assess DAOH-90 the effect of in clinical and Med. PubMed Google Scholar is to that the association for of that is to that a association between DAOH and HRQoL at 6 months be for and that the association for survivors was as We participants with sepsis as in the trials, and it is that the in populations of critically ill patients or more of sepsis used to the data and data to be at The and analysis has and analyses should be as very support for the primary we used the to with the of a composite with a been N.C. Poulsen L.M. Perner A. et al.Haloperidol for the treatment of delirium in ICU patients.N Engl J Med. 2022; 387: 2425-2435Crossref PubMed Scopus (35) Google M. M. 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