Abstract
Purpose
Sepsis survivors have a higher risk of rehospitalisation and of long-term mortality. We assessed the rate, diagnosis, and independent predictors for rehospitalisation in adult sepsis survivors.
Methods
We searched for non-randomized studies and randomized clinical trials in MEDLINE, Cochrane Library, Web of Science, and EMBASE (OVID interface, 1992–October 2019). The search strategy used controlled vocabulary terms and text words for sepsis and hospital readmission, limited to humans, and English language. Two authors independently selected studies and extracted data using predefined criteria and data extraction forms.
Results
The literature search identified 12,544 records. Among 56 studies (36 full and 20 conference abstracts) that met our inclusion criteria, all were non-randomised studies. Studies most often report 30-day rehospitalisation rate (mean 21.4%, 95% confidence interval [CI] 17.6–25.4%; N = 36 studies reporting 6,729,617 patients). The mean (95%CI) rehospitalisation rates increased from 9.3% (8.3–10.3%) by 7 days to 39.0% (22.0–59.4%) by 365 days. Infection was the most common rehospitalisation diagnosis. Risk factors that increased the rehospitalisation risk in sepsis survivors were generic characteristics such as older age, male, comorbidities, non-elective admissions, hospitalisation prior to index sepsis admission, and sepsis characteristics such as infection and illness severity, with hospital characteristics showing inconsistent associations. The overall certainty of evidence was moderate for rehospitalisation rates and low for risk factors.
Conclusions
Rehospitalisation events are common in sepsis survivors, with one in five rehospitalisation events occurring within 30 days of hospital discharge following an index sepsis admission. The generic and sepsis-specific characteristics at index sepsis admission are commonly reported risk factors for rehospitalisation.
Registration
PROSPERO CRD 42016039257, registered on 14-06-2016.
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Nearly 50% of sepsis survivors have at least one unplanned rehospitalisation by 1 year following hospital discharge from their index sepsis admission. Many of the risk factors for this rehospitalisation are acute illness characteristics at index sepsis admission such as age, comorbidities, site of infection, and illness severity. |
Introduction
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1] and is a global health priority [2]. In cohort studies, mainly from critically ill adults from high-income countries, sepsis diagnosis is increasing, and short-term mortality is improving [3,4,5]. This epidemiology pattern results in increasing numbers of sepsis survivors, defined as patients who survive a sepsis-related hospitalisation. Among the numerous long-term ill health consequences observed in sepsis survivors, increased risk of rehospitalisation and long-term mortality [6], when compared with non-sepsis hospitalisations and age-sex matched general population, are major challenges [7, 8]. Importantly, a proportion of this increased risk of rehospitalisation in sepsis survivors may be modifiable [9].
Similar to the challenge of determining causation with the reported associations between sepsis and long-term mortality [10], the risk of rehospitalisation in sepsis survivors may be sepsis-related or may reflect an event that is common to anyone who survives a hospitalisation episode [11]. Thus, we hypothesised that this rehospitalisation risk in sepsis survivors may vary with both patient characteristics and health care system characteristics [12, 13]. Therefore, understanding the independent and potentially modifiable risk factors that contribute towards this additional rehospitalisation risk seen in sepsis survivors would inform future interventional trials aimed at reducing this risk.
In this context, the first aim of our systematic review was to assess the rehospitalisation rate, the associated major rehospitalisation diagnoses, and the excess risk of all-cause rehospitalisation due to sepsis in sepsis survivors using studies reporting comparator populations. The second aim was to assess the independent risk factors for rehospitalisation using studies that report design features or analytic approach to control confounding [14, 15], such as use of comparator populations, matching, restriction, stratification, and regression. The third aim was to assess how studies handled the competing risk of mortality in sepsis survivors, when rehospitalisation events are studied as the outcome of interest [10, 16, 17]. This competing risk problem may be more common in health care settings where community-level end-of-life or hospice care is more prevalent [18, 19].
Methods
Our study conforms to the MOOSE checklist for systematic reviews of observational studies [20].
Information sources
Using the OVID interface, we searched for non-randomized studies and randomized clinical trials (RCTs) published since 1992 in the following databases: MEDLINE (including in-process and non-indexed citations), Cochrane Library and its associated databases (including Database of Abstracts of Reviews of Effects (DARE), Web of Science, and EMBASE. The search strategy used controlled vocabulary terms and text words for sepsis and hospital readmission, and the search set was limited to humans and English language. Subject headings were exploded and mapped to the appropriate controlled vocabulary terms. The year 1992 was chosen to coincide with the year of publication of the first consensus sepsis definitions [21]. The full electronic search strategy for MEDLINE is presented in electronic supplementary material (eTable-1) and modified for other databases and registered with the International prospective register of systematic reviews (PROSPERO CRD 42016039257). The initial literature search was on 31st March 2017 and was updated on 5th October 2019.
Study selection
Two reviewers (RS, MSH) independently screened citations for those reporting all-cause rehospitalisation for sepsis survivor populations in the title or abstract; the full text of any citation considered potentially relevant by either reviewer was retrieved. Eligible studies had a cohort, case–control, or Randomised-Controlled Trial (RCT) design; enrolled hospital survivors of an admission for sepsis; and reported all-cause readmission. An eligible RCT would have enrolled sepsis survivors and examined any intervention. The PICO framework for study selection is reported in Fig. 1.
For inclusion into the systematic review, sepsis was defined as infection-related organ dysfunction [1] managed in hospital setting and includes studies that used the equivalent terminology of sepsis, severe sepsis, and septic shock [1, 22]. We excluded studies restricted to children and to special populations such as those with retroviral disease, cancer, and other immune-compromised states, although studies that enrolled these special populations as part of a more general cohort were eligible for inclusion. We also excluded studies enrolling survivors of uncomplicated infections, such as pneumonia, without referring to organ dysfunction or to International Classification of Diseases (ICD) codes for sepsis, severe sepsis, or septic shock in their index sepsis case definitions. Prior to finalising the literature strategy in October 2016, infection-related rehospitalisation was revised to a secondary outcome; the primary outcome was considered as all-cause rehospitalisation. However, this point was only updated in the PROSPERO record prior to submission for peer review. At the screening stage, we considered any study design and included review articles and editorials accompanying original relevant studies. We also screened reference lists of included studies, related review articles, and editorials.
Data collection and validity assessment
When two or more studies were identified that reported data from the same patient cohort, the most relevant article was chosen by consensus (JW, RS, MSH). The most relevant article was defined as the most recent full manuscript, if the data from the same patient cohort were reported as abstract or as an earlier full manuscript. Three authors (JW, RS, MSH) extracted data from the included studies and issues of uncertainty were resolved by consensus. We included full manuscripts and conference abstracts for estimating the timing and rate of rehospitalisation and only the full manuscripts for assessing rehospitalisation diagnoses, independent risk factors, and the competing risk problem. From each of the included studies, we extracted data on study design, number of patients, duration of follow-up, handling of loss during follow-up, description of index sepsis admission, rehospitalisation events, rehospitalisation diagnoses, independent risk factors for rehospitalisation, and approach to competing risk of long-term mortality [8]. We classified risk factors as generic, sepsis-related, or hospital-related according to a previously used framework [6, 8].
Assessment of methodological quality
For studies reported as full-text manuscripts, study quality was assessed using domains from the modified Newcastle Ottawa Score (NOS) checklist [23]. These included domains of patient selection (cohort data source for representativeness of exposed cohort, selection of non-exposed cohort, exposure ascertainment using sepsis definitions or International Classification of Diseases codes), minimum duration of follow-up for outcome to occur was defined as 30 days, assessment of confounding (use of comparator populations, matching, restriction, stratification, and regression), and comparability using non-sepsis controls and outcome (outcome assessment, length, and adequacy of follow-up). The independent risk factors for rehospitalisation were identified from studies that used regression models to account for confounders. We assessed the overall certainty of evidence using the GRADE framework [24], considering the risk of bias of included studies (as described above), inconsistency, imprecision, indirectness, and publication bias.
Statistics
Our conceptual approach is summarised in Fig. 1. The primary outcome of interest was all-cause rehospitalisation events in sepsis survivors following an index episode of sepsis, at follow-up time points as reported in studies. We recategorized the rehospitalisation-associated risk factors into generic, sepsis-specific, and hospital-level factors. We included age, sex, ethnicity, rural or urban residence, socioeconomic status, educational attainment, and comorbidity as generic risk factors. We included infection, septic shock status, acute illness severity including physiological disturbance, organ support, and organ dysfunction as sepsis-specific risk factors. We included hospital location (urban versus rural), university status (university-affiliated vs not), and other reported descriptions as hospital-level risk factors. We provide a descriptive comparison of risk factors included in analysis between studies and those risk factors identified as increasing the risk of rehospitalisation in sepsis survivors between studies. We performed random effect metanalysis of proportions (using metaprop package) [25] of cumulative rehospitalizations at 7, 30, 90, 180, and 365 days; between-study heterogeneity was assessed using I2, which is the percentage of between-study variation due to heterogeneity rather than chance, with values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively [26]. We assessed small-study effects using Egger’s test for 7-, 30-, 90-, 180-, and 365-day proportions, when there were at least ten studies at a given time point. All analyses were done using Stata/MP 14.2 StataCorp College Station, Texas 77845, USA.
Results
Study selection
The bibliographic database search identified 12,544 records. After exclusion of duplicates, we identified 7,872 records for screening. Following screening, 111 records were considered eligible for full-text evaluation. Based on full-text evaluation, we excluded 56 records (reasons for exclusion reported in Fig. 2 and the excluded papers are referenced in eMethods-1). We included one study from the reference scan of included full manuscripts, resulting in 56 unique studies that met our inclusion criteria for the systematic review (36 full manuscripts [9, 12, 13, 27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59] and 20 conference abstracts [60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79], (Fig. 2). All studies were observational; we did not identify any RCTs enrolling sepsis survivors.
Methodological quality of included studies
Our study selection criteria ensured that all 36 studies had the exposure of interest, sepsis, thereby avoiding differential exposure measurement that contributes towards risk of bias [9, 12, 13, 27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59]. All 36 studies met the minimum follow-up duration of 30 days [9, 12, 13, 27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59], that we considered as adequate for outcome of interest to occur. Ten studies report a sepsis cohort starting from their index admission [27, 35, 37, 41, 44, 46, 50, 51, 53, 55], twelve studies report a sepsis survivor cohort [9, 12, 30,31,32, 36, 45, 47, 52, 56, 58, 59], and four report a rehospitalisation cohort [28, 34, 40, 42]. Ten were single-centre studies [28, 37, 40, 44, 47, 50, 51, 55, 56, 59] with greater risk of bias compared to 21 studies [9, 12, 13, 27, 29,30,31, 33, 35, 36, 38, 39, 41, 42, 45, 48, 49, 53, 54, 57] that used large multi-centre databases with greater generalizability. Five studies that use notes review for outcome assessment [28, 37, 40, 51, 55] have a greater risk of ascertainment bias, compared to studies that use record linkage outcome assessment. The primary outcome was all-cause rehospitalisation in 21 studies [9, 12, 13, 28,29,30, 35, 36, 38, 39, 41, 42, 45, 47, 48, 50,51,52, 56, 57, 59]. Confounders for rehospitalisation risk factors were addressed with regression models in seventeen [12, 29, 33, 35, 36, 38,39,40,41, 45, 47, 50,51,52, 55, 56, 59] including competing risk models in two [38, 41], matching in two [9, 49], stratification in one [50], and restriction in one [33]. Twenty-one studies were of low risk of bias and 15 studies were at moderate risk of bias for the primary outcome of rehospitalisation risk, as per modified Newcastle–Ottawa criteria (Table 1).
Primary outcome (rate of all-cause rehospitalisation)
Studies most often reported the 30-day rehospitalisation events in a sepsis survivor population. The mean rehospitalisation proportion (95% CI) at 30 days was 21.4% (17.6%, 25.4%; N = 36 studies reporting 6,729,617 patients; Fig. 3), at 7 days was 9.3% (8.3%, 10.3%; N = 5 studies reporting 475,312 patients), at 90 days was 38.1% (34.3%, 42.0%; N = 14 studies, 388,044 patients), at 180 days was 36.2% (30.7%, 41.8%; N = 7 studies, 107,293 patients), and at 365 days was 39.0% (22.0%; 57.4%; N = 5 studies, 10,286 patients). All estimates had high heterogeneity. We did not observe any small-study effects (eTable-1). Two studies that use competing risk models [38, 41] also had similar 30-day rehospitalisation rates (eFigure-1; test for heterogeneity between groups p = 0.08). There were no differences in 30-day rehospitalisation rates by risk of bias (eFigure-2; test for heterogeneity between groups p = 0.33). In studies with non-sepsis comparator populations, the 30-day rehospitalisation proportions in sepsis survivors were reported as either comparable to congestive heart failure and acute myocardial infarction [9, 29, 54], or much higher than these and other similar acute medical conditions [33, 34, 39, 42, 55, 57]. The median (IQR) acute mortality among sepsis survivors who were re-hospitalised was 6.6% (4.6%, 8.7%; N = 8 studies) [12, 13, 29, 34, 36, 38, 39, 57].
Diagnosis at rehospitalisation
Studies that report rehospitalisation diagnoses in sepsis survivors grouped these diagnoses using clinical classification software (CCS) codes [29, 35, 38, 41], ambulatory care sensitive conditions codes (ACSCs) [9], or other customised categories [13, 47, 52] (Table 2). The relationship between infection at index sepsis admission and the infection diagnosis at rehospitalisation was reported in one study as recurrent or unresolved in nearly 50% of cases [52], often secondary to opportunistic pathogens like Pseudomonas aeruginosa and Candida species in another study [55], and same site as index sepsis admission in 68% of rehospitalisation events in another study [32]. Infection-related rehospitalisation was the most common rehospitalisation event in sepsis survivors. The median (IQR) 30-day event rate was 49.3% (38.0%, 61.2%) of the all rehospitalisation events in ten studies [12, 29, 34,35,36, 38, 47, 51, 52, 56], with similar proportions reported at 90 days [37, 40] and 365 days [41]. Between one-third and two-thirds of rehospitalisation episodes in sepsis survivors were coded as sepsis [29, 32, 52] (Table 2).
Independent risk factors for all-cause rehospitalisation
Among the 15 studies that identify independent risk factors for rehospitalisation events in sepsis survivors [12, 29, 30, 35, 36, 38,39,40,41, 45, 51, 52, 55, 56, 59], most analysed all-cause 30-day rehospitalisation as the outcome and two studies report independent risk factors for infection-related rehospitalisation [40, 55] (Table 3). Generic characteristics consistently highlighted as predictors for increased risk of rehospitalisation were increasing age, male sex, presence of one or comorbidities determined using either Charlson or Elixhauser comorbidity indices, non-white race, non-elective admissions, pre-index admission hospitalisation, and increased length of hospitalisation during index sepsis admission. Risk of rehospitalisation in sepsis survivors was increased when the discharge location was not to home following the index sepsis admission [13, 30, 34,35,36, 38, 51].
Among the sepsis-specific characteristics at index admission, infection features, organ dysfunction, and illness severity were identified as risk factors for rehospitalisation, especially when assessed with competing risk regression models [38, 41]. The type of infecting pathogen at index admission did not significantly alter the risk of rehospitalisation, with the exception of extended spectrum beta-lactamase (ESBL) producing bacteria [59]. When risk factors for the same pathogen as index sepsis admission for rehospitalisation were evaluated, same pathogen was identified only in 25% of rehospitalisation and the major risk factors for same pathogen rehospitalisation were Gram-negative bacteria, urosepsis, and same site of infection [40]. Similar to all-cause rehospitalisation, the risk factors for infection-related rehospitalisation were older age, prolonged hospitalisation, and nursing home residence [55]. In three studies, infection-related rehospitalisation episodes were associated with greater risk of death [32, 52, 55] when compared to non-infection-related hospitalisations.
Among hospital-level characteristics, risk of rehospitalisation in sepsis survivors varied significantly among hospitals in two studies [12, 29] and did not in one study [13]. The risk of rehospitalisation in sepsis survivors was higher in hospitals serving a higher proportion of minority population, in for profit hospitals compared with public/non-profit hospitals, in university or teaching hospitals vs. not, in hospitals that had higher sepsis case volume especially when associated with lower critical care usage, and in hospitals that had higher in-hospital mortality for sepsis index sepsis admissions [12, 29, 36, 45].
In studies with non-sepsis comparator populations, there were similarities in generic and hospital-level characteristics as risk factors for rehospitalisation in sepsis survivors and rehospitalisation seen with medical conditions such as congestive heart failure and acute myocardial infarction [29, 54]. Eight other studies report regression models that were not aimed at identifying rehospitalisation risk factors, but were designed to examine health care utilization [33], long-term organ dysfunction [37], effect of statins [44], subsequent severe sepsis following index all-cause hospitalization [48], variation in patterns of rehospitalization in sepsis survivors [13], additional risk of socioeconomic status in sepsis [50], and risk of sepsis compared to non-sepsis hospitalizations [55, 57].
Overall certainty of evidence
For the primary outcome of all-cause rehospitalisation, the certainty of evidence is moderate, based on low risk of bias in the majority of studies reporting 30-day rehospitalisation. We did not rate down further for imprecision or inconsistency, because confidence intervals around risks of rehospitalisation were reasonably narrow and compatible with clinically important risks. Studies generally had broad inclusion criteria representative of the exposure of interest, sepsis, and, therefore, provided direct evidence. There was no evidence of publication bias. For rehospitalisation risk factors, the certainty of evidence is low due to inconsistency in risk factor definitions, imprecision in strengths of association, and risk of bias in many studies due to lack of competing risk models.
Discussion
One in five sepsis survivors are re-hospitalised within 30 days of discharge from hospital. The cumulative proportion of sepsis survivors re-hospitalised plateaus at 40% between 90 and 365 days, which may be related to competing risk of long-term deaths in sepsis survivors. Only two studies considered competing risk of long-term mortality when studying risk factors for rehospitalisation in sepsis survivors. The most common rehospitalisation diagnosis in sepsis survivors was infection. Uncertainties remain as to whether this represents a new infection or recurring infection from the index sepsis admission. Independent risk factors of rehospitalisation were most often time-invariant predictors like older age, male sex, higher comorbidity burden, and hospitalisation immediately preceding the index sepsis admission, and discharge to non-home location. Among the sepsis-specific risk factors, gastrointestinal site of infection, infection with ESBL bacteria, increasing illness severity, and longer hospital length of stay during index admission increased the risk of rehospitalisation. Other characteristics that increased rehospitalisation risk were lower socioeconomic strata, lower discharge haemoglobin, use of total parenteral nutrition, and tracheostomy at index sepsis admission. Hospital-level characteristics such as for profit and university status and sepsis volumes also influenced the risk of rehospitalisation in sepsis survivors, albeit inconsistently.
Ours is first systematic review of the epidemiology of rehospitalisation events in the at-risk population of adult sepsis survivors, in the year following sepsis-related hospitalisation. We used a customized checklist to assess potential for bias in ascertainment of exposure, the outcome, and management of confounding. We limited the study population to adult sepsis survivors and the outcome to all-cause rehospitalisation. We report the rehospitalisation rates at different timepoints over the first year following sepsis survival. Our systematic review describes the excess risk of sepsis-related rehospitalisation up to 1 year, which will inform sample size estimations of trials focussing on sepsis survivors and when assessed within health care systems could inform follow-up care planning.
There are limitations to this systematic review. The rehospitalisation events and diagnoses were identified in most studies using data linkage. Although we excluded non-English language studies, this is unlikely to bias our results [80, 81]. We did not extract length of hospital stay data. The lack of any RCTs included in our systematic review may be related to the search strategy and screening criteria that focused on rehospitalisation events in sepsis survivors; we did not systematically examine all trials of septic patients to determine whether they reported rehospitalisation data. As the diagnostic codes are linked to hospital activity and remuneration, potential risk of bias from different coding practices cannot be ruled out. As our goal was to assess sepsis survivors’ risk of rehospitalisation, we excluded related conditions such as pneumonia [82] which could potentially have provided additional information on rehospitalisation risk factors. In a systematic review of that specifically addressed rehospitalisation after pneumonia, the 30-day all-cause rehospitalisation rates in 12 studies were 11.6%, which is lower than sepsis survivor rates which we observed [83]. Interestingly, the 1-year rehospitalisation rates following pneumonia was 46%, which is compared to the sepsis survivor rates which we observed [83]. Higher rehospitalisation rates following pneumonia were noted in US-based cohorts and the common reasons for rehospitalisation following pneumonia in the study were pneumonia (5.6%) and worsening of cardiac and pulmonary comorbidities [83]. We planned our study before guidelines for systematic reviews assessing prognostic factors were published [84]. Most studies have assessed rehospitalisation risk using previous definitions of sepsis or using ICD codes to identify sepsis. Thus, our study highlights that rehospitalisation epidemiology with a more recent sepsis survivor cohort, based on the updated sepsis definitions, would be a valuable addition to the literature [1, 85].
We categorised the rehospitalisation risk factors or predictors into generic, sepsis-specific, and hospital-level risk factors. We show that many of the risk factors for rehospitalisation are time-invariant predictors such as age, comorbidity, prior hospitalisation, site of infection at admission, and socioeconomic or deprivation status [29, 44, 50] such as insurance, lower income, urban residence, race, and education. These predictors have also been identified as risk factors for long-term mortality [6, 10] and are commonly available when sepsis survivors leave hospital. Therefore, a parsimonious prognostic risk score could be derived to stratify sepsis survivors based on their rehospitalisation risk, using their index sepsis admission variables. Our review also highlights the value of explicitly considering competing risk models in the analysis when assessing risk factors, as the cumulative rehospitalisation proportion plateaus after 90 days, potentially due to long-term mortality acting as competing event for rehospitalisation, especially in health care settings where community-level end-of-life or hospice care are more prevalent [18, 19].
Sepsis-specific characteristics such as features of infection and sepsis severity requiring critical care admission influenced this rehospitalisation risk [12, 34, 41, 59]. Furthermore, in our study, the most common rehospitalisation diagnosis in sepsis survivors was infection, which has been linked to microbiome alterations [48] and to immunological sequelae seen in sepsis survivors [58, 86]. Thus, understanding the microbiome and immunological status at critical care discharge will enable design of potential interventional trials in this population [8].
Hospital-level characteristics also influenced the risk of rehospitalisation in sepsis survivors, albeit inconsistently. Hospital sepsis case volume and critical care usage of sepsis patients influences subsequent rehospitalisation risk [36]. Furthermore, characteristics such as hospital size, university status, and serving a minority population appear to influence the risk of rehospitalisation. Thus, there is a need to assess the relative contributions of hospital- and patient-level predictors for this rehospitalisation risk, as reported for cardiovascular diseases [11]. These may provide opportunities for addressing this rehospitalisation problem with hospital-level quality-of-care interventions. For example, understanding how best to manage medical comorbidities in sepsis survivors [9] could alter the long-term risk of rehospitalisation and death.
Conclusions
One in five sepsis survivors are re-hospitalised within 30 days of discharge from hospital and this rehospitalisation risk is comparable with non-sepsis acute medical conditions. Generic patient characteristics (such as increasing age, comorbidity burden, and haemoglobin at discharge from hospital), sepsis-specific characteristics (such as type of infection), and hospital-level characteristics at their index sepsis admission influence this rehospitalisation risk. Our findings may inform the development of prognostic scores and the design of future interventional studies in this at-risk population of sepsis survivors.
References
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third International consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810
Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S (2017) Recognizing sepsis as a global health priority—a WHO resolution. N Engl J Med 377:414–417
Shankar-Hari M, Harrison DA, Rubenfeld GD, Rowan K (2017) Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database. Br J Anaesth 119:626–636
Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R (2014) Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311:1308–1316
Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K, International Forum of Acute Care T (2016) Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 193:259–272
Shankar-Hari M, Harrison DA, Ferrando-Vivas P, Rubenfeld GD, Rowan K (2019) Risk factors at index hospitalization associated with longer-term mortality in adult sepsis survivors. JAMA Netw Open 2:e194900
Prescott HC, Angus DC (2018) Enhancing recovery from sepsis: a review. JAMA 319:62–75
Shankar-Hari M, Rubenfeld GD (2016) Understanding long-term outcomes following sepsis: implications and challenges. Curr Infect Dis Rep 18:37
Prescott HC, Langa KM, Iwashyna TJ (2015) Readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions. JAMA 313:1055–1057
Shankar-Hari M, Ambler M, Mahalingasivam V, Jones A, Rowan K, Rubenfeld GD (2016) Evidence for a causal link between sepsis and long-term mortality: a systematic review of epidemiologic studies. Crit Care 20:101
Krumholz HM, Wang K, Lin Z, Dharmarajan K, Horwitz LI, Ross JS, Drye EE, Bernheim SM, Normand ST (2017) Hospital-readmission risk—isolating hospital effects from patient effects. N Engl J Med 377:1055–1064
Donnelly JP, Hohmann SF, Wang HE (2015) Unplanned readmissions after hospitalization for severe sepsis at academic medical center-affiliated hospitals. Crit Care Med 43:1916–1927
Prescott HC (2016) Variation in post-sepsis readmission patterns: a cohort study of veterans affairs beneficiaries. Ann Am Thoracic Soc 14:230–237
Grimes DA, Schulz KF (2002) Bias and causal associations in observational research. Lancet 359:248–252
Rothman KJ, Greenland S (2005) Causation and causal inference in epidemiology. Am J Public Health 95(Suppl 1):S144–150
Lau B, Cole SR, Gange SJ (2009) Competing risk regression models for epidemiologic data. Am J Epidemiol 170:244–256
Andersen PK, Geskus RB, de Witte T, Putter H (2012) Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol 41:861–870
Pivodic L, Pardon K, Morin L, Addington-Hall J, Miccinesi G, Cardenas-Turanzas M, Onwuteaka-Philipsen B, Naylor W, Ruiz Ramos M, Van den Block L, Wilson DM, Loucka M, Csikos A, Rhee YJ, Teno J, Deliens L, Houttekier D, Cohen J (2016) Place of death in the population dying from diseases indicative of palliative care need: a cross-national population-level study in 14 countries. J Epidemiol Commun Health 70:17–24
Bekelman JE, Halpern SD, Blankart CR, Bynum JP, Cohen J, Fowler R, Kaasa S, Kwietniewski L, Melberg HO, Onwuteaka-Philipsen B, Oosterveld-Vlug M, Pring A, Schreyogg J, Ulrich CM, Verne J, Wunsch H, Emanuel EJ (2016) Comparison of site of death, health care utilization, and hospital expenditures for patients dying with cancer in 7 developed countries. JAMA 315:272–283
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283:2008–2012
Bone RC, Sprung CL, Sibbald WJ (1992) Definitions for sepsis and organ failure. Crit Care Med 20:724–726
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, Sccm/Esicm/Accp/Ats/Sis (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256
Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605
Iorio A, Spencer FA, Falavigna M, Alba C, Lang E, Burnand B, McGinn T, Hayden J, Williams K, Shea B, Wolff R, Kujpers T, Perel P, Vandvik PO, Glasziou P, Schunemann H, Guyatt G (2015) Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients. BMJ 350:h870
Nyaga VN, Arbyn M, Aerts M (2014) Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health 72:39
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
Braun L, Riedel AA, Cooper LM (2004) Severe sepsis in managed care: analysis of incidence, 1-year mortality, and associated costs of care. J Manag Care Pharm 10:521–530
Cakir B, Gammon G (2010) Evaluating readmission rates: how can we improve? South Med J 103:1079–1083
Chang DW, Tseng CH, Shapiro MF (2015) Rehospitalizations following sepsis: common and costly. Crit Care Med 43:2085–2093
Deb P, Murtaugh CM, Bowles KH, Mikkelsen ME, Khajavi HN, Moore S, Barron Y, Feldman PH (2019) Does early follow-up improve the outcomes of sepsis survivors discharged to home health care? Med Care 57:633–640
DeMerle KM, Vincent BM, Iwashyna TJ, Prescott HC (2017) Increased healthcare facility use in veterans surviving sepsis hospitalization. J Crit Care 42:59–64
DeMerle KM, Royer SC, Mikkelsen ME, Prescott HC (2017) Readmissions for recurrent sepsis: new or relapsed infection? Crit Care Med 45:1702–1708
Dick A, Liu H, Zwanziger J, Perencevich E, Furuya EY, Larson E, Pogorzelska-Maziarz M, Stone PW (2012) Long-term survival and healthcare utilization outcomes attributable to sepsis and pneumonia. BMC Health Serv Res 12:432
Dietz BW, Jones TK, Small DS, Gaieski DF, Mikkelsen ME (2016) The relationship between index hospitalizations, sepsis, and death or transition to hospice care during 30-day hospital readmissions. Med care 55:362–370
Gadre SK, Shah M, Mireles-Cabodevila E, Patel B, Duggal A (2019) Epidemiology and predictors of 30-day readmission in patients with sepsis. Chest 155:483–490
Goodwin AJ, Rice DA, Simpson KN, Ford DW (2015) Frequency, cost, and risk factors of readmissions among severe sepsis survivors. Crit Care Med 43:738–746
Guirgis FW, Brakenridge S, Sutchu S, Khadpe JD, Robinson T, Westenbarger R, Topp ST, Kalynych CJ, Reynolds J, Dodani S, Moore FA, Jones AE (2016) The long-term burden of severe sepsis and septic shock: sepsis recidivism and organ dysfunction. J Trauma Acute Care Surg 81:525–532
Hua M, Gong MN, Brady J, Wunsch H (2015) Early and late unplanned rehospitalizations for survivors of critical illness. Crit Care Med 43:430–438
Jones TK, Fuchs BD, Small DS, Halpern SD, Hanish A, Umscheid CA, Baillie CA, Kerlin MP, Gaieski DF, Mikkelsen ME (2015) Post-acute care use and hospital readmission after sepsis. Ann Am Thoracic Soc 12:904–913
Kim JS, Kim YJ, Ryoo SM, Sohn CH, Ahn S, Seo DW, Lim KS, Kim WY (2019) Risk factors for same pathogen sepsis readmission following hospitalization for septic shock. J Clin Med 8:181
Liu V, Lei X, Prescott HC, Kipnis P, Iwashyna TJ, Escobar GJ (2014) Hospital readmission and healthcare utilization following sepsis in community settings. J Hosp Med 9:502–507
Mayr FB, Talisa VB, Balakumar V, Chang CH, Fine M, Yende S (2017) Proportion and cost of unplanned 30-day readmissions after sepsis compared with other medical conditions. JAMA 317:530–531
Meyer N, Harhay MO, Small DS, Prescott HC, Bowles KH, Gaieski DF, Mikkelsen ME (2018) Temporal trends in incidence, sepsis-related mortality, and hospital-based acute care after sepsis. Crit Care Med 46:354–360
Nkemdirim Okere A, Renier CM (2015) Effects of statins on hospital length of stay and all-cause readmissions among hospitalized patients with a primary diagnosis of sepsis. Ann Pharmacother 49:1273–1283
Norman BC, Cooke CR, Ely EW, Graves JA (2017) Sepsis-associated 30-day risk-standardized readmissions: analysis of a nationwide medicare sample. Crit Care Med 45:1130–1137
Nsutebu EF, Ibarz-Pavon AB, Kanwar E, Prospero N, French N, McGrath C (2018) Advancing quality in sepsis management: a large-scale programme for improving sepsis recognition and management in the North West region of England. Postgrad Med J 94:463–468
Ortego A, Gaieski DF, Fuchs BD, Jones T, Halpern SD, Small DS, Sante SC, Drumheller B, Christie JD, Mikkelsen ME (2015) Hospital-based acute care use in survivors of septic shock. Crit Care Med 43:729–737
Prescott HC, Dickson RP, Rogers MA, Langa KM, Iwashyna TJ (2015) Hospitalization type and subsequent severe sepsis. Am J Respir Crit Care Med 192:581–588
Prescott HC, Langa KM, Liu V, Escobar GJ, Iwashyna TJ (2014) Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med 190:62–69
Schnegelsberg A, Mackenhauer J, Nibro HL, Dreyer P, Koch K, Kirkegaard H (2016) Impact of socioeconomic status on mortality and unplanned readmission in septic intensive care unit patients. Acta Anaesthesiol Scand 60:465–475
Singh A, Bhagat M, George SV, Gorthi R, Chaturvedula C (2019) Factors associated with 30-day unplanned readmissions of sepsis patients: a retrospective analysis of patients admitted with sepsis at a community hospital. Cureus 11:e5118
Sun A, Netzer G, Small DS, Hanish A, Fuchs BD, Gaieski DF, Mikkelsen ME (2016) Association between index hospitalization and hospital readmission in sepsis survivors. Crit Care Med 44:478–487
Sutton JP, Friedman B (2013) Trends in septicemia hospitalizations and readmissions in selected HCUP States, 2005 and 2010: statistical brief #161Healthcare Cost and utilization project (HCUP) statistical briefs. Agency for Healthcare Research and Quality (US), Rockville (MD)
Vashi AA, Fox JP, Carr BG, D'Onofrio G, Pines JM, Ross JS, Gross CP (2013) Use of hospital-based acute care among patients recently discharged from the hospital. JAMA 309:364–371
Wang T, Derhovanessian A, De Cruz S, Belperio JA, Deng JC, Hoo GS (2014) Subsequent infections in survivors of sepsis: epidemiology and outcomes. J Intensive Care Med 29:87–95
Weinreich MA, Styrvoky K, Chang S, Girod CE, Ruggiero R (2017) Sepsis at a safety net hospital: risk factors associated with 30-day readmission. J Intensive Care Med. https://doi.org/10.1177/0885066617726753
Wong EL, Cheung AW, Leung MC, Yam CH, Chan FW, Wong FY, Yeoh EK (2011) Unplanned readmission rates, length of hospital stay, mortality, and medical costs of ten common medical conditions: a retrospective analysis of Hong Kong hospital data. BMC Health Serv Res 11:149
Yende S, Kellum JA, Talisa VB, Peck Palmer OM, Chang CH, Filbin MR, Shapiro NI, Hou PC, Venkat A, LoVecchio F, Hawkins K, Crouser ED, Newman AB, Angus DC (2019) Long-term host immune response trajectories among hospitalized patients with sepsis. JAMA Netw Open 2:e198686
Zilberberg MD, Shorr AF, Micek ST, Kollef MH (2015) Risk factors for 30-day readmission among patients with culture-positive severe sepsis and septic shock: a retrospective cohort study. J Hosp Med 10:678–685
Ahmad S, Baig S, Taneja A, Nanchal R, Kumar G (2014) The outcomes of severe sepsis in homeless. Chest 146:230
Bath AS, Farishta M, Deepak V (2019) Trends and 30-day readmission rate for patients discharged with septicemia: analysis of 3,082,888 admissions. Am J Respir Crit Care Med 199:3457
Demiralp B, He F, Koenig L, Hengesbach D, Prister J (2017) A regional analysis of patient outcomes and medicare payments for sepsis patients treated in long-term care hospitals and skilled nursing facilities. Am J Respir Crit Care Med 195:5023
Galiatsatos P, Follin A, Uradu N, Alghanim F, Daniel Y, Saria S, Townsend J, Sylvester C, Chanmugam A, Chen ES (2019) The association between neighborhood socioeconomic disadvantage and readmissions for patients hospitalized with sepsis. Am J Respir Crit Care Med 199:5569
Jones TK, Fuchs BD, Small DS, Halpern SD, Hanish A, Baillie C, Umscheid CA, Kerlin MP, Gaieski DF, Mikkelsen ME (2014) Severe sepsis is associated with high rates of hospital readmission. Am J Respir Crit Care Med 189:79–83
Kaplan M, Chowdhury MAB, Hurwitz J, Metellus V, Martin E, Elie MC (2017) Sepsis recidivism: return visits and recurrence (S3R analysis). Ann Emerg Med 70:S60–S60
Kopterides P, Diane I, Lucko N, Shapiro N, Hou P, Filbin M, Kellum J, Yende S (2015) Rehospitalizations and fatal outcome are common among severe sepsis survivors. Crit Care Med 43:252
Leu M, Gonzalez C, Rico-Crescencio J, Kaur T, Kanna B, Loganathan R (2013) Survivors of severe sepsis/septic shock—a need to focus on healthcare utilization post-discharge among inner-city minority New-Yorkers. Am J Respir Crit Care Med 187:502–507
Leung S, Gong MN (2012) Healthcare utilization prior to and following patients admitted to the ICU with severe sepsis. Am J Respir Crit Care Med 185:513–516
Mayr F, Balakumar V, Talisa V, Fine M, Yende S (2016) Understanding the burden of unplanned sepsis readmissions. Crit Care Med 44:409
Perakis PG, Rubinfeld I, Narayana A, Cumba M, Takis L, Coba V, Blyden D, Horst M (2012) Hospital readmission incidence for septic patients from the surgical intensive care unit. Shock 37:76–76
Prescott HC, Langa KM, Iwashyna TJ (2015) Forty percent of hospitalizations after severe sepsis are potentially preventable. Am J Respir Crit Care Med 191:35
Rice D, Goodwin AJ, Simpson K, Ford DW (2014) Risk factors for 30-day hospital readmissions in sepsis. Am J Respir Crit Care Med 189:322–330
Rice D, Simpson K, Goodwin A, Ford D (2013) Patterns of hospital readmission following an index hospitalization for sepsis. Chest 144:400
Rico Crescencio JC, Leu M, Balaventakesh B, Loganathan R (2012) REadmissions among patients with severe sepsis/septic shock among inner-city minority new yorkers. Chest 142:286A–286A
Rudym D, Uppal A, Evans L (2015) Readmission rates in severe sepsis. Am J Respir Crit Care Med 191:2085–2093
Styrvoky K, Weinreich M, Girod C, Ruggiero R (2015) Beyond surviving sepsis: thirty-day readmission rates and patient characteristics at a safety net hospital. Chest 148:336
Styrvoky K, Weinreich M, Girod CE, Ruggiero RM (2016) Risk factors for thirty-day readmissions among sepsis survivors at a safety net hospital. Am J Respir Crit Care Med 193:3676
Tsen R, Seoane L, Li D, Pavlov A, Winterbottom F, Nash T (2015) Frequency and timing of readmissions among survivors of severe sepsis and septic shock. Am J Respir Crit Care Med 191:6240
Whiles B, Deis A, Miller P, Simpson S (2016) Comorbid conditions predict outcomes in patients with severe sepsis. Chest 149:A170
Nussbaumer-Streit B, Klerings I, Dobrescu AI, Persad E, Stevens A, Garritty C, Kamel C, Affengruber L, King VJ, Gartlehner G (2019) Excluding non-english publications from evidence-syntheses did not change conclusions: a meta-epidemiological study. J Clin Epidemiol 118:42–54
Morrison A, Polisena J, Husereau D, Moulton K, Clark M, Fiander M, Mierzwinski-Urban M, Clifford T, Hutton B, Rabb D (2012) The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies. Int J Technol Assess Health Care 28:138–144
Dharmarajan K, Wang Y, Lin Z, Normand ST, Ross JS, Horwitz LI, Desai NR, Suter LG, Drye EE, Bernheim SM, Krumholz HM (2017) Association of changing hospital readmission rates with mortality rates after hospital discharge. JAMA 318:270–278
Prescott HC, Sjoding MW, Iwashyna TJ (2014) Diagnoses of early and late readmissions after hospitalization for pneumonia. A systematic review. Ann Am Thorac Soc 11:1091–1100
Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, Hayden J, Collins GS, Debray TPA (2019) A guide to systematic review and meta-analysis of prognostic factor studies. BMJ 364:k4597
Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M, Sepsis Definitions Task F (2016) Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:775–787
Riche F, Chousterman BG, Valleur P, Mebazaa A, Launay JM, Gayat E (2018) Protracted immune disorders at one year after ICU discharge in patients with septic shock. Crit Care 22:42
Shankar-Hari M, Harrison DA, Rowan KM, Rubenfeld GD (2018) Estimating attributable fraction of mortality from sepsis to inform clinical trials. J Crit Care 45:33–39
Acknowledgements
Manu Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (NIHR-CS-2016-16-011). Hallie Prescott was supported by US National Institutes of Health (K08 GM115859). This material is the result of work supported with resources and the use of facilities at the Ann ArborVA medical facility. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health, and social care. The views expressed in this publication are those of the author(s) and not necessarily those of the US Department of Veterans Affairs.
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MSH conceived the study. MSH developed the search strategy and performed the literature search. MSH/RS/JW/NA did the study selection and data extraction for the systematic review. MSH/NA wrote the first draft of the manuscript. All authors contributed to the interpretation of data and critical revision of the manuscript, and approved the final manuscript. All authors confirm to the accuracy or integrity of the work.
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Shankar-Hari, M., Saha, R., Wilson, J. et al. Rate and risk factors for rehospitalisation in sepsis survivors: systematic review and meta-analysis. Intensive Care Med 46, 619–636 (2020). https://doi.org/10.1007/s00134-019-05908-3
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DOI: https://doi.org/10.1007/s00134-019-05908-3