Sepsis and Septic Shock Readmission Risk

Despite its decreasing mortality, sepsis remains a leading reason for intensive care unit (ICU) admission and is associated with crude mortality in excess of 25%.[1, 2] In the United States there are between 660,000 and 750,000 sepsis hospitalizations annually, with the direct costs surpassing $24 billion.[3, 4, 5] As mortality rates have begun to fall, attention has shifted to issues of morbidity and recovery, the intermediate and longer‐term consequences associated with survivorship, and how interventions made while the patient is acutely ill in the ICU alter later health outcomes.[3, 5, 6, 7, 8]

One area of particular interest is the need for healthcare utilization following an acute admission for sepsis, and specifically rehospitalization within 30 days of discharge. This outcome is important not just from the perspective of the patient's well‐being, but also from the point of view of healthcare financing. Through the establishment of Hospital Readmission Reduction Program, the Centers for Medicare and Medicaid Services have sharply reduced reimbursement to hospitals for excessive rates of 30‐day readmissions.[9]

For sepsis, little is known about such readmissions, and even less about how to prevent them. A handful of studies suggest that this rate is between 5% and 26%.[10, 11, 12, 13] Whereas some of these studies looked at some of the factors that impact readmissions,[11, 12] none examined the potential contribution of microbiology of sepsis to this outcome.

To explore these questions, we conducted a single‐center retrospective cohort study among critically ill patients admitted to the ICU with severe culture‐positive sepsis and/or septic shock and determined the rate of early posthospital discharge readmission. In addition, we sought to elucidate predictors of subsequent readmission.

METHODS

RESULTS

Among the 1697 patients with severe sepsis or septic shock who were discharged alive from the hospital, 543 (32.0%) required a rehospitalization within 30 days. There were no differences in age or gender distribution between the groups (Table 1). All comorbidities examined were more prevalent among those with a 30‐day readmission than among those without, with the median Charlson comorbidity score reflecting this imbalance (5 vs 4, P<0.001). Similarly, most of the HCA risk factors were more prevalent among the readmitted group than the comparator group, with HCA sepsis among 94.2% of the former and 90.7% of the latter (P = 0.014).

During the index hospitalization, 589 patients (34.7%) suffered from septic shock requiring vasopressors; this did not impact the 30‐day readmission risk (Table 1). Commensurately, markers of severity of acute illness (APACHE II score, mechanical ventilation, peak white blood cell count) did not differ between the groups. With respect to the primary source of sepsis, urine was less, whereas central nervous system was more likely among those readmitted within 30 days. Similarly, there was a significant imbalance between the groups in the prevalence of AKI (Table 1). Specifically, those who did require a readmission were slightly less likely to have sustained no AKI (RIFLE: None; 14.9% vs 18.5%, P = 0.073). Those requiring readmission were also less likely to be in the category RIFLE: Risk (20.6% vs 26.5%, P = 0.009). The direction of this disparity was reversed for the Injury and Failure categories. No differences between groups were seen among those with categories Loss and end‐stage kidney disease (ESKD) (Table 1).

The microbiology of sepsis did not differ in most respects between the 30‐day readmission groups, save for several organisms (Table 2). Most strikingly, those who required a readmission were more likely than those who did not to be infected with Bacteroides spp, Candida spp, an MDR or an ESBL organism (Table 2). As for the outcomes of the index hospitalization, those with a repeat admission had a longer overall and postonset of sepsis initial hospital length of stay, and were less likely to be discharged either home without home health care or transferred to another hospital at the end of their index hospitalization (Table 3).

In a logistic regression model, 5 factors emerged as predictors of 30‐day readmission (Table 4). Having RIFLE: Injury or RIFLE: Failure carried an approximately 2‐fold increase in the odds of 30‐day rehospitalization (odds ratio: 1.95, 95% confidence interval: 1.302.93, P = 0.001) relative to having a RIFLE: None or RIFLE: Risk. Although having strong association with this outcome, harboring an ESBL organism or Bacteroides spp were both relatively infrequent events (3.3% ESBL and 3.2% Bacteroides spp). Infection with Escherichia coli and urine as the source of sepsis both appeared to be significantly protective against a readmission (Table 4). The model's discrimination was moderate (AUROC = 0.653) and its calibration adequate (Hosmer‐Lemeshow P = 0.907). (See Supporting Information, Appendix 1, in the online version of this article for the steps in the development of the final model.)

DISCUSSION

In this single‐center retrospective cohort study, nearly one‐third of survivors of culture‐positive severe sepsis or septic shock required a rehospitalization within 30 days of discharge from their index admission. Factors that contributed to a higher odds of rehospitalization were having mild‐to‐moderate AKI (RIFLE: Injury or RIFLE: Failure) and infection with ESBL organisms or Bacteroides spp, whereas urine as the source of sepsis and E coli as the pathogen appeared to be protective.

A recent study by Hua and colleagues examining the New York Statewide Planning and Research Cooperative System for the years 2008 to 2010 noted a 16.2% overall rate of 30‐day rehospitalization among survivors of initial critical illness.[11] Just as we observed, Hua et al. concluded that development of AKI correlated with readmission. Because they relied on administrative data for their analysis, AKI was diagnosed when hemodialysis was utilized. Examining AKI using SCr changes, our findings add a layer of granularity to the relationship between AKI stages and early readmission. Specifically, we failed to detect any rise in the odds of rehospitalization when either very mild (RIFLE: Risk) or severe (RIFLE: Loss or RIFLE: ESKD) AKI was present. Only when either RIFLE: Injury or RIFLE: Failure developed did the odds of readmission rise. In addition to diverging definitions between our studies, differences in populations also likely yielded different results.[11] Although Hua et al. examined all admissions to the ICU regardless of the diagnosis or illness severity, our cohort consisted of only those ICU patients who survived culture‐positive severe sepsis/septic shock. Because AKI is a known risk factor for mortality in sepsis,[19] the potential for immortal time bias leaves a smaller pool of surviving patients with ESKD at risk for readmission. Regardless of the explanation, it may be prudent to focus on preventing AKI not only to improve survival, but also from the standpoint of diminishing the risk of an early readmission.

Four additional studies have examined the frequency of early readmissions among survivors of critical illness. Liu et al. noted 17.9% 30‐day rehospitalization rate among sepsis survivors.[12] Factors associated with the risk of early readmission included acute and chronic diseases burdens, index hospital LOS, and the need for the ICU in the index sepsis admission. In contrast to our cohort, all of whom were in the ICU during their index episode, less than two‐thirds of the entire population studied by Liu had required an ICU admission. Additionally, Liu's study did not specifically examine the potential impact of AKI or of microbiology on this outcome.

Prescott and coworkers examined healthcare utilization following an episode of severe sepsis.[13] Among other findings, they reported a 30‐day readmission rate of 26.5% among survivors. Although closer to our estimate, this study included all patients surviving a severe sepsis hospitalization, and not only those with a positive culture. These investigators did not examine predictors of readmission.[13]

Horkan et al. examined specifically whether there was an association between AKI and postdischarge outcomes, including 30‐day readmission risk, in a large cohort of patients who survived their critical illness.[20] In it they found that readmission risk ranged from 19% to 21%, depending on the extent of the AKI. Moreover, similar to our findings, they reported that in an adjusted analysis RIFLE: Injury and RIFLE: Failure were associated with a rise in the odds of a 30‐day rehospitalizaiton. In contrast to our study, Horkan et al. did detect an increase in the odds of this outcome associated with RIFLE: Risk. There are likely at least 3 reasons for this difference. First, we focused only on patients with severe sepsis or septic shock, whereas Horkan and colleagues included all critical illness survivors. Second, we were able to explore the impact of microbiology on this outcome. Third, Horkan's study included an order of magnitude more patients than did ours, thus making it more likely either to have the power to detect a true association that we may have lacked or to be more susceptible to type I error.

Finally, Goodwin and colleagues utilized 3 states' databases included in the Health Care and Utilization Project (HCUP) from the Agency for Healthcare Research and Quality to study frequency and risk factors for 30‐day readmission among survivors of severe sepsis.[21] Patients were identified based on the use of the severe sepsis (995.92) and septic shock (785.52). These authors found a 30‐day readmission rate of 26%. Although chronic renal disease, among several other factors, was associated with an increase in this risk, the data source did not permit these investigators to examine the impact of AKI on the outcomes. Similarly, HCUP data do not contain microbiology, a distinct difference from our analysis.

If clinicians are to pursue strategies to reduce the risk of an all‐cause 30‐day readmission, the key goal is not simply to identify all variables associated with readmission, but to focus on factors that are potentially modifiable. Although neither Hua nor Liu and their teams identified any additional factors that are potentially modifiable,[11, 12] in the present study, among the 5 factors we identified, the development of mild to moderate AKI during the index hospitalization may deserve stronger consideration for efforts at prevention. Although one cannot conclude automatically that preventing AKI in this population could mitigate some of the early rehospitalization risk, critically ill patients are frequently exposed to a multitude of nephrotoxic agents. Those caring for subjects with sepsis should reevaluate the risk‐benefit equation of these factors more cautiously and apply guideline‐recommended AKI prevention strategies more aggressively, particularly because a relatively minor change in SCr resulted in an excess risk of readmission.[22]

In addition to AKI, which is potentially modifiable, we identified several other clinical factors predictive of 30‐day readmission, which are admittedly not preventable. Thus, microbiology was predictive of this outcome, with E coli engendering fewer and Bacteroides spp and ESBL organisms more early rehospitalizations. Similarly, urine as the source of sepsis was associated with a lower risk for this endpoint.

Our study has a number of limitations. As a retrospective cohort, it is subject to bias, most notably a selection bias. Specifically, because the flagship hospital of the BJC HealthCare system is a referral center, it is possible that we did not capture all readmissions. However, generally, if a patient who receives healthcare within 1 of the BJC hospitals presents to a nonsystem hospital, that patient is nearly always transferred back into the integrated system because of issues of insurance coverage. Analysis of certain diagnosis‐related groups has indicated that 73% of all patients overall discharged from 4 of the large BJC system institutions who require a readmission within 30 days of discharge return to a BJC hospital (personal communication, Financial Analysis and Decision Support Department at BJC to Dr. Kollef May 12, 2015). Therefore, we may have misclassified the outcome in as many as 180 patients. The fact that our readmission rate was fully double that seen in Hua et al.'s and Liu et al.'s studies, and somewhat higher than that reported by Prescott et al., attests not only to the population differences, but also to the fact that we are unlikely to have missed a substantial percentage of readmissions.[11, 12, 13] Furthermore, to mitigate biases, we enrolled all consecutive patients meeting the predetermined criteria. Missing from our analysis are events that occurred between the index discharge and the readmission. Likewise, we were unable to obtain such potentially important variables as code status or outpatient mortality following discharge. These intervening factors, if included in subsequent studies, may increase the predictive power of the model. Because we relied on administrative coding to identify cases of severe sepsis and septic shock, it is possible that there is misclassification within our cohort. Recent studies indicate, however, that the Angus definition, used in our study, has high negative and positive predictive values for severe sepsis identification.[23] It is still possible that our cohort is skewed toward a more severely ill population, making our results less generalizable to the less severely ill septic patients.[24] The study was performed at a single healthcare system and included only cases of severe sepsis or septic shock that had a positive blood culture, and thus the findings may not be broadly generalizable either to patients without a positive blood culture or to institutions that do not resemble it.

In summary, we have demonstrated that survivors of culture‐positive severe sepsis or septic shock have a high rate of 30‐day rehospitalization. Because the US federal government's initiatives deem 30‐day readmissions to be a quality metric and penalize institutions with higher‐than average readmission rates, a high volume of critically ill patients with culture‐positive severe sepsis and septic shock may disproportionately put an institution at risk for such penalties. Unfortunately, not many of the determinants of readmission are amenable to prevention. As sepsis survival continues to improve, hospitals will need to concentrate their resources on coordinating care of these complex patients so as to improve both individual quality of life and the quality of care that they provide.

Despite its decreasing mortality, sepsis remains a leading reason for intensive care unit (ICU) admission and is associated with crude mortality in excess of 25%.[1, 2] In the United States there are between 660,000 and 750,000 sepsis hospitalizations annually, with the direct costs surpassing $24 billion.[3, 4, 5] As mortality rates have begun to fall, attention has shifted to issues of morbidity and recovery, the intermediate and longer‐term consequences associated with survivorship, and how interventions made while the patient is acutely ill in the ICU alter later health outcomes.[3, 5, 6, 7, 8]

One area of particular interest is the need for healthcare utilization following an acute admission for sepsis, and specifically rehospitalization within 30 days of discharge. This outcome is important not just from the perspective of the patient's well‐being, but also from the point of view of healthcare financing. Through the establishment of Hospital Readmission Reduction Program, the Centers for Medicare and Medicaid Services have sharply reduced reimbursement to hospitals for excessive rates of 30‐day readmissions.[9]

For sepsis, little is known about such readmissions, and even less about how to prevent them. A handful of studies suggest that this rate is between 5% and 26%.[10, 11, 12, 13] Whereas some of these studies looked at some of the factors that impact readmissions,[11, 12] none examined the potential contribution of microbiology of sepsis to this outcome.

To explore these questions, we conducted a single‐center retrospective cohort study among critically ill patients admitted to the ICU with severe culture‐positive sepsis and/or septic shock and determined the rate of early posthospital discharge readmission. In addition, we sought to elucidate predictors of subsequent readmission.

METHODS

RESULTS

Among the 1697 patients with severe sepsis or septic shock who were discharged alive from the hospital, 543 (32.0%) required a rehospitalization within 30 days. There were no differences in age or gender distribution between the groups (Table 1). All comorbidities examined were more prevalent among those with a 30‐day readmission than among those without, with the median Charlson comorbidity score reflecting this imbalance (5 vs 4, P<0.001). Similarly, most of the HCA risk factors were more prevalent among the readmitted group than the comparator group, with HCA sepsis among 94.2% of the former and 90.7% of the latter (P = 0.014).

During the index hospitalization, 589 patients (34.7%) suffered from septic shock requiring vasopressors; this did not impact the 30‐day readmission risk (Table 1). Commensurately, markers of severity of acute illness (APACHE II score, mechanical ventilation, peak white blood cell count) did not differ between the groups. With respect to the primary source of sepsis, urine was less, whereas central nervous system was more likely among those readmitted within 30 days. Similarly, there was a significant imbalance between the groups in the prevalence of AKI (Table 1). Specifically, those who did require a readmission were slightly less likely to have sustained no AKI (RIFLE: None; 14.9% vs 18.5%, P = 0.073). Those requiring readmission were also less likely to be in the category RIFLE: Risk (20.6% vs 26.5%, P = 0.009). The direction of this disparity was reversed for the Injury and Failure categories. No differences between groups were seen among those with categories Loss and end‐stage kidney disease (ESKD) (Table 1).

The microbiology of sepsis did not differ in most respects between the 30‐day readmission groups, save for several organisms (Table 2). Most strikingly, those who required a readmission were more likely than those who did not to be infected with Bacteroides spp, Candida spp, an MDR or an ESBL organism (Table 2). As for the outcomes of the index hospitalization, those with a repeat admission had a longer overall and postonset of sepsis initial hospital length of stay, and were less likely to be discharged either home without home health care or transferred to another hospital at the end of their index hospitalization (Table 3).

In a logistic regression model, 5 factors emerged as predictors of 30‐day readmission (Table 4). Having RIFLE: Injury or RIFLE: Failure carried an approximately 2‐fold increase in the odds of 30‐day rehospitalization (odds ratio: 1.95, 95% confidence interval: 1.302.93, P = 0.001) relative to having a RIFLE: None or RIFLE: Risk. Although having strong association with this outcome, harboring an ESBL organism or Bacteroides spp were both relatively infrequent events (3.3% ESBL and 3.2% Bacteroides spp). Infection with Escherichia coli and urine as the source of sepsis both appeared to be significantly protective against a readmission (Table 4). The model's discrimination was moderate (AUROC = 0.653) and its calibration adequate (Hosmer‐Lemeshow P = 0.907). (See Supporting Information, Appendix 1, in the online version of this article for the steps in the development of the final model.)

DISCUSSION

In this single‐center retrospective cohort study, nearly one‐third of survivors of culture‐positive severe sepsis or septic shock required a rehospitalization within 30 days of discharge from their index admission. Factors that contributed to a higher odds of rehospitalization were having mild‐to‐moderate AKI (RIFLE: Injury or RIFLE: Failure) and infection with ESBL organisms or Bacteroides spp, whereas urine as the source of sepsis and E coli as the pathogen appeared to be protective.

A recent study by Hua and colleagues examining the New York Statewide Planning and Research Cooperative System for the years 2008 to 2010 noted a 16.2% overall rate of 30‐day rehospitalization among survivors of initial critical illness.[11] Just as we observed, Hua et al. concluded that development of AKI correlated with readmission. Because they relied on administrative data for their analysis, AKI was diagnosed when hemodialysis was utilized. Examining AKI using SCr changes, our findings add a layer of granularity to the relationship between AKI stages and early readmission. Specifically, we failed to detect any rise in the odds of rehospitalization when either very mild (RIFLE: Risk) or severe (RIFLE: Loss or RIFLE: ESKD) AKI was present. Only when either RIFLE: Injury or RIFLE: Failure developed did the odds of readmission rise. In addition to diverging definitions between our studies, differences in populations also likely yielded different results.[11] Although Hua et al. examined all admissions to the ICU regardless of the diagnosis or illness severity, our cohort consisted of only those ICU patients who survived culture‐positive severe sepsis/septic shock. Because AKI is a known risk factor for mortality in sepsis,[19] the potential for immortal time bias leaves a smaller pool of surviving patients with ESKD at risk for readmission. Regardless of the explanation, it may be prudent to focus on preventing AKI not only to improve survival, but also from the standpoint of diminishing the risk of an early readmission.

Four additional studies have examined the frequency of early readmissions among survivors of critical illness. Liu et al. noted 17.9% 30‐day rehospitalization rate among sepsis survivors.[12] Factors associated with the risk of early readmission included acute and chronic diseases burdens, index hospital LOS, and the need for the ICU in the index sepsis admission. In contrast to our cohort, all of whom were in the ICU during their index episode, less than two‐thirds of the entire population studied by Liu had required an ICU admission. Additionally, Liu's study did not specifically examine the potential impact of AKI or of microbiology on this outcome.

Prescott and coworkers examined healthcare utilization following an episode of severe sepsis.[13] Among other findings, they reported a 30‐day readmission rate of 26.5% among survivors. Although closer to our estimate, this study included all patients surviving a severe sepsis hospitalization, and not only those with a positive culture. These investigators did not examine predictors of readmission.[13]

Horkan et al. examined specifically whether there was an association between AKI and postdischarge outcomes, including 30‐day readmission risk, in a large cohort of patients who survived their critical illness.[20] In it they found that readmission risk ranged from 19% to 21%, depending on the extent of the AKI. Moreover, similar to our findings, they reported that in an adjusted analysis RIFLE: Injury and RIFLE: Failure were associated with a rise in the odds of a 30‐day rehospitalizaiton. In contrast to our study, Horkan et al. did detect an increase in the odds of this outcome associated with RIFLE: Risk. There are likely at least 3 reasons for this difference. First, we focused only on patients with severe sepsis or septic shock, whereas Horkan and colleagues included all critical illness survivors. Second, we were able to explore the impact of microbiology on this outcome. Third, Horkan's study included an order of magnitude more patients than did ours, thus making it more likely either to have the power to detect a true association that we may have lacked or to be more susceptible to type I error.

Finally, Goodwin and colleagues utilized 3 states' databases included in the Health Care and Utilization Project (HCUP) from the Agency for Healthcare Research and Quality to study frequency and risk factors for 30‐day readmission among survivors of severe sepsis.[21] Patients were identified based on the use of the severe sepsis (995.92) and septic shock (785.52). These authors found a 30‐day readmission rate of 26%. Although chronic renal disease, among several other factors, was associated with an increase in this risk, the data source did not permit these investigators to examine the impact of AKI on the outcomes. Similarly, HCUP data do not contain microbiology, a distinct difference from our analysis.

If clinicians are to pursue strategies to reduce the risk of an all‐cause 30‐day readmission, the key goal is not simply to identify all variables associated with readmission, but to focus on factors that are potentially modifiable. Although neither Hua nor Liu and their teams identified any additional factors that are potentially modifiable,[11, 12] in the present study, among the 5 factors we identified, the development of mild to moderate AKI during the index hospitalization may deserve stronger consideration for efforts at prevention. Although one cannot conclude automatically that preventing AKI in this population could mitigate some of the early rehospitalization risk, critically ill patients are frequently exposed to a multitude of nephrotoxic agents. Those caring for subjects with sepsis should reevaluate the risk‐benefit equation of these factors more cautiously and apply guideline‐recommended AKI prevention strategies more aggressively, particularly because a relatively minor change in SCr resulted in an excess risk of readmission.[22]

In addition to AKI, which is potentially modifiable, we identified several other clinical factors predictive of 30‐day readmission, which are admittedly not preventable. Thus, microbiology was predictive of this outcome, with E coli engendering fewer and Bacteroides spp and ESBL organisms more early rehospitalizations. Similarly, urine as the source of sepsis was associated with a lower risk for this endpoint.

Our study has a number of limitations. As a retrospective cohort, it is subject to bias, most notably a selection bias. Specifically, because the flagship hospital of the BJC HealthCare system is a referral center, it is possible that we did not capture all readmissions. However, generally, if a patient who receives healthcare within 1 of the BJC hospitals presents to a nonsystem hospital, that patient is nearly always transferred back into the integrated system because of issues of insurance coverage. Analysis of certain diagnosis‐related groups has indicated that 73% of all patients overall discharged from 4 of the large BJC system institutions who require a readmission within 30 days of discharge return to a BJC hospital (personal communication, Financial Analysis and Decision Support Department at BJC to Dr. Kollef May 12, 2015). Therefore, we may have misclassified the outcome in as many as 180 patients. The fact that our readmission rate was fully double that seen in Hua et al.'s and Liu et al.'s studies, and somewhat higher than that reported by Prescott et al., attests not only to the population differences, but also to the fact that we are unlikely to have missed a substantial percentage of readmissions.[11, 12, 13] Furthermore, to mitigate biases, we enrolled all consecutive patients meeting the predetermined criteria. Missing from our analysis are events that occurred between the index discharge and the readmission. Likewise, we were unable to obtain such potentially important variables as code status or outpatient mortality following discharge. These intervening factors, if included in subsequent studies, may increase the predictive power of the model. Because we relied on administrative coding to identify cases of severe sepsis and septic shock, it is possible that there is misclassification within our cohort. Recent studies indicate, however, that the Angus definition, used in our study, has high negative and positive predictive values for severe sepsis identification.[23] It is still possible that our cohort is skewed toward a more severely ill population, making our results less generalizable to the less severely ill septic patients.[24] The study was performed at a single healthcare system and included only cases of severe sepsis or septic shock that had a positive blood culture, and thus the findings may not be broadly generalizable either to patients without a positive blood culture or to institutions that do not resemble it.

In summary, we have demonstrated that survivors of culture‐positive severe sepsis or septic shock have a high rate of 30‐day rehospitalization. Because the US federal government's initiatives deem 30‐day readmissions to be a quality metric and penalize institutions with higher‐than average readmission rates, a high volume of critically ill patients with culture‐positive severe sepsis and septic shock may disproportionately put an institution at risk for such penalties. Unfortunately, not many of the determinants of readmission are amenable to prevention. As sepsis survival continues to improve, hospitals will need to concentrate their resources on coordinating care of these complex patients so as to improve both individual quality of life and the quality of care that they provide.

Despite its decreasing mortality, sepsis remains a leading reason for intensive care unit (ICU) admission and is associated with crude mortality in excess of 25%.[1, 2] In the United States there are between 660,000 and 750,000 sepsis hospitalizations annually, with the direct costs surpassing $24 billion.[3, 4, 5] As mortality rates have begun to fall, attention has shifted to issues of morbidity and recovery, the intermediate and longer‐term consequences associated with survivorship, and how interventions made while the patient is acutely ill in the ICU alter later health outcomes.[3, 5, 6, 7, 8]

One area of particular interest is the need for healthcare utilization following an acute admission for sepsis, and specifically rehospitalization within 30 days of discharge. This outcome is important not just from the perspective of the patient's well‐being, but also from the point of view of healthcare financing. Through the establishment of Hospital Readmission Reduction Program, the Centers for Medicare and Medicaid Services have sharply reduced reimbursement to hospitals for excessive rates of 30‐day readmissions.[9]

For sepsis, little is known about such readmissions, and even less about how to prevent them. A handful of studies suggest that this rate is between 5% and 26%.[10, 11, 12, 13] Whereas some of these studies looked at some of the factors that impact readmissions,[11, 12] none examined the potential contribution of microbiology of sepsis to this outcome.

To explore these questions, we conducted a single‐center retrospective cohort study among critically ill patients admitted to the ICU with severe culture‐positive sepsis and/or septic shock and determined the rate of early posthospital discharge readmission. In addition, we sought to elucidate predictors of subsequent readmission.

METHODS

RESULTS

Among the 1697 patients with severe sepsis or septic shock who were discharged alive from the hospital, 543 (32.0%) required a rehospitalization within 30 days. There were no differences in age or gender distribution between the groups (Table 1). All comorbidities examined were more prevalent among those with a 30‐day readmission than among those without, with the median Charlson comorbidity score reflecting this imbalance (5 vs 4, P<0.001). Similarly, most of the HCA risk factors were more prevalent among the readmitted group than the comparator group, with HCA sepsis among 94.2% of the former and 90.7% of the latter (P = 0.014).

During the index hospitalization, 589 patients (34.7%) suffered from septic shock requiring vasopressors; this did not impact the 30‐day readmission risk (Table 1). Commensurately, markers of severity of acute illness (APACHE II score, mechanical ventilation, peak white blood cell count) did not differ between the groups. With respect to the primary source of sepsis, urine was less, whereas central nervous system was more likely among those readmitted within 30 days. Similarly, there was a significant imbalance between the groups in the prevalence of AKI (Table 1). Specifically, those who did require a readmission were slightly less likely to have sustained no AKI (RIFLE: None; 14.9% vs 18.5%, P = 0.073). Those requiring readmission were also less likely to be in the category RIFLE: Risk (20.6% vs 26.5%, P = 0.009). The direction of this disparity was reversed for the Injury and Failure categories. No differences between groups were seen among those with categories Loss and end‐stage kidney disease (ESKD) (Table 1).

The microbiology of sepsis did not differ in most respects between the 30‐day readmission groups, save for several organisms (Table 2). Most strikingly, those who required a readmission were more likely than those who did not to be infected with Bacteroides spp, Candida spp, an MDR or an ESBL organism (Table 2). As for the outcomes of the index hospitalization, those with a repeat admission had a longer overall and postonset of sepsis initial hospital length of stay, and were less likely to be discharged either home without home health care or transferred to another hospital at the end of their index hospitalization (Table 3).

In a logistic regression model, 5 factors emerged as predictors of 30‐day readmission (Table 4). Having RIFLE: Injury or RIFLE: Failure carried an approximately 2‐fold increase in the odds of 30‐day rehospitalization (odds ratio: 1.95, 95% confidence interval: 1.302.93, P = 0.001) relative to having a RIFLE: None or RIFLE: Risk. Although having strong association with this outcome, harboring an ESBL organism or Bacteroides spp were both relatively infrequent events (3.3% ESBL and 3.2% Bacteroides spp). Infection with Escherichia coli and urine as the source of sepsis both appeared to be significantly protective against a readmission (Table 4). The model's discrimination was moderate (AUROC = 0.653) and its calibration adequate (Hosmer‐Lemeshow P = 0.907). (See Supporting Information, Appendix 1, in the online version of this article for the steps in the development of the final model.)

DISCUSSION

In this single‐center retrospective cohort study, nearly one‐third of survivors of culture‐positive severe sepsis or septic shock required a rehospitalization within 30 days of discharge from their index admission. Factors that contributed to a higher odds of rehospitalization were having mild‐to‐moderate AKI (RIFLE: Injury or RIFLE: Failure) and infection with ESBL organisms or Bacteroides spp, whereas urine as the source of sepsis and E coli as the pathogen appeared to be protective.

A recent study by Hua and colleagues examining the New York Statewide Planning and Research Cooperative System for the years 2008 to 2010 noted a 16.2% overall rate of 30‐day rehospitalization among survivors of initial critical illness.[11] Just as we observed, Hua et al. concluded that development of AKI correlated with readmission. Because they relied on administrative data for their analysis, AKI was diagnosed when hemodialysis was utilized. Examining AKI using SCr changes, our findings add a layer of granularity to the relationship between AKI stages and early readmission. Specifically, we failed to detect any rise in the odds of rehospitalization when either very mild (RIFLE: Risk) or severe (RIFLE: Loss or RIFLE: ESKD) AKI was present. Only when either RIFLE: Injury or RIFLE: Failure developed did the odds of readmission rise. In addition to diverging definitions between our studies, differences in populations also likely yielded different results.[11] Although Hua et al. examined all admissions to the ICU regardless of the diagnosis or illness severity, our cohort consisted of only those ICU patients who survived culture‐positive severe sepsis/septic shock. Because AKI is a known risk factor for mortality in sepsis,[19] the potential for immortal time bias leaves a smaller pool of surviving patients with ESKD at risk for readmission. Regardless of the explanation, it may be prudent to focus on preventing AKI not only to improve survival, but also from the standpoint of diminishing the risk of an early readmission.

Four additional studies have examined the frequency of early readmissions among survivors of critical illness. Liu et al. noted 17.9% 30‐day rehospitalization rate among sepsis survivors.[12] Factors associated with the risk of early readmission included acute and chronic diseases burdens, index hospital LOS, and the need for the ICU in the index sepsis admission. In contrast to our cohort, all of whom were in the ICU during their index episode, less than two‐thirds of the entire population studied by Liu had required an ICU admission. Additionally, Liu's study did not specifically examine the potential impact of AKI or of microbiology on this outcome.

Prescott and coworkers examined healthcare utilization following an episode of severe sepsis.[13] Among other findings, they reported a 30‐day readmission rate of 26.5% among survivors. Although closer to our estimate, this study included all patients surviving a severe sepsis hospitalization, and not only those with a positive culture. These investigators did not examine predictors of readmission.[13]

Horkan et al. examined specifically whether there was an association between AKI and postdischarge outcomes, including 30‐day readmission risk, in a large cohort of patients who survived their critical illness.[20] In it they found that readmission risk ranged from 19% to 21%, depending on the extent of the AKI. Moreover, similar to our findings, they reported that in an adjusted analysis RIFLE: Injury and RIFLE: Failure were associated with a rise in the odds of a 30‐day rehospitalizaiton. In contrast to our study, Horkan et al. did detect an increase in the odds of this outcome associated with RIFLE: Risk. There are likely at least 3 reasons for this difference. First, we focused only on patients with severe sepsis or septic shock, whereas Horkan and colleagues included all critical illness survivors. Second, we were able to explore the impact of microbiology on this outcome. Third, Horkan's study included an order of magnitude more patients than did ours, thus making it more likely either to have the power to detect a true association that we may have lacked or to be more susceptible to type I error.

Finally, Goodwin and colleagues utilized 3 states' databases included in the Health Care and Utilization Project (HCUP) from the Agency for Healthcare Research and Quality to study frequency and risk factors for 30‐day readmission among survivors of severe sepsis.[21] Patients were identified based on the use of the severe sepsis (995.92) and septic shock (785.52). These authors found a 30‐day readmission rate of 26%. Although chronic renal disease, among several other factors, was associated with an increase in this risk, the data source did not permit these investigators to examine the impact of AKI on the outcomes. Similarly, HCUP data do not contain microbiology, a distinct difference from our analysis.

If clinicians are to pursue strategies to reduce the risk of an all‐cause 30‐day readmission, the key goal is not simply to identify all variables associated with readmission, but to focus on factors that are potentially modifiable. Although neither Hua nor Liu and their teams identified any additional factors that are potentially modifiable,[11, 12] in the present study, among the 5 factors we identified, the development of mild to moderate AKI during the index hospitalization may deserve stronger consideration for efforts at prevention. Although one cannot conclude automatically that preventing AKI in this population could mitigate some of the early rehospitalization risk, critically ill patients are frequently exposed to a multitude of nephrotoxic agents. Those caring for subjects with sepsis should reevaluate the risk‐benefit equation of these factors more cautiously and apply guideline‐recommended AKI prevention strategies more aggressively, particularly because a relatively minor change in SCr resulted in an excess risk of readmission.[22]

In addition to AKI, which is potentially modifiable, we identified several other clinical factors predictive of 30‐day readmission, which are admittedly not preventable. Thus, microbiology was predictive of this outcome, with E coli engendering fewer and Bacteroides spp and ESBL organisms more early rehospitalizations. Similarly, urine as the source of sepsis was associated with a lower risk for this endpoint.

Our study has a number of limitations. As a retrospective cohort, it is subject to bias, most notably a selection bias. Specifically, because the flagship hospital of the BJC HealthCare system is a referral center, it is possible that we did not capture all readmissions. However, generally, if a patient who receives healthcare within 1 of the BJC hospitals presents to a nonsystem hospital, that patient is nearly always transferred back into the integrated system because of issues of insurance coverage. Analysis of certain diagnosis‐related groups has indicated that 73% of all patients overall discharged from 4 of the large BJC system institutions who require a readmission within 30 days of discharge return to a BJC hospital (personal communication, Financial Analysis and Decision Support Department at BJC to Dr. Kollef May 12, 2015). Therefore, we may have misclassified the outcome in as many as 180 patients. The fact that our readmission rate was fully double that seen in Hua et al.'s and Liu et al.'s studies, and somewhat higher than that reported by Prescott et al., attests not only to the population differences, but also to the fact that we are unlikely to have missed a substantial percentage of readmissions.[11, 12, 13] Furthermore, to mitigate biases, we enrolled all consecutive patients meeting the predetermined criteria. Missing from our analysis are events that occurred between the index discharge and the readmission. Likewise, we were unable to obtain such potentially important variables as code status or outpatient mortality following discharge. These intervening factors, if included in subsequent studies, may increase the predictive power of the model. Because we relied on administrative coding to identify cases of severe sepsis and septic shock, it is possible that there is misclassification within our cohort. Recent studies indicate, however, that the Angus definition, used in our study, has high negative and positive predictive values for severe sepsis identification.[23] It is still possible that our cohort is skewed toward a more severely ill population, making our results less generalizable to the less severely ill septic patients.[24] The study was performed at a single healthcare system and included only cases of severe sepsis or septic shock that had a positive blood culture, and thus the findings may not be broadly generalizable either to patients without a positive blood culture or to institutions that do not resemble it.

In summary, we have demonstrated that survivors of culture‐positive severe sepsis or septic shock have a high rate of 30‐day rehospitalization. Because the US federal government's initiatives deem 30‐day readmissions to be a quality metric and penalize institutions with higher‐than average readmission rates, a high volume of critically ill patients with culture‐positive severe sepsis and septic shock may disproportionately put an institution at risk for such penalties. Unfortunately, not many of the determinants of readmission are amenable to prevention. As sepsis survival continues to improve, hospitals will need to concentrate their resources on coordinating care of these complex patients so as to improve both individual quality of life and the quality of care that they provide.