Theodore J. Iwashyna, MD, PhD

Severe sepsis, defined as an infection leading to systemic inflammatory response and acute organ dysfunction, is a significant cause of morbidity and mortality.[1, 2, 3] Although it has been a condition classically attributed to patients in the intensive care unit (ICU), accumulating data suggest that a substantial proportion of patients with severe sepsis are managed by hospitalists and floor teams in non‐ICU, general ward settings.[1, 4, 5] Although the incidence of severe sepsis continues to rise both in the United States and other developed nations,[2, 6, 7] advances in early recognition, management, and care of this condition have resulted in improved rates of survival.[8] The resultant increase in a severe sepsis survivor population[6] make the long‐term sequelae of this condition an important public health problem.[9]

In both the ICU and on general wards, severe sepsis survivors suffer from decreased functional status, worsened quality of life, increased cognitive dysfunction, and sarcopenia.[4, 6, 10, 11, 12, 13, 14] Not surprisingly, many such patients are discharged to long‐term care facilities for physical rehabilitation,[15] with escalating utilization of resources[16] and cost.[17, 18] Inexpensive interventions that improve outcomes following sepsis would thus be welcomed.

It is well known that physical therapy (PT) and early mobilization are beneficial in mitigating functional decline in a number of conditions.[19, 20, 21, 22] PT can improve outcomes in several ways: prevention of bed rest deconditioning, mitigation of mechanisms that lead to sarcopenia, increased pulmonary and tissue aerobic capacity, and improved sense of well‐being. Indeed, among the population cared for in ICU settings, early mobility and PT lead to more ventilator‐free days, better functional status at discharge, shorter duration of delirium, and even a potentially reduced risk of central line‐associated bloodstream infection (CLABSI).[23, 24] However, whether initiating early PT can improve outcomes in patients with severe sepsis treated by either intensivists or hospitalists/floor teams outside the ICU is unknown.

Therefore, to better understand this phenomenon, we systematically reviewed and integrated the literature regarding early mobilization and PT for severe sepsis outside the ICU. To be more inclusive, a secondary review including populations with any infectious etiology and severe sepsis treated within the ICU was also conducted. Our review begins by providing an overview of the pathophysiology behind functional decline in severe sepsis, along with existing evidence on early mobilization efficacy in other patient populations. We then proceed with a review of the extant literature on the aforementioned topic. We conclude with an evaluation of the current evidence on the subject, along with assertions regarding future research in the area.

PATHOPHYSIOLOGY OF DISABILITY FOLLOWING HOSPITALIZATION FOR SEVERE SEPSIS

The pathophysiology behind functional decline in patients hospitalized with severe sepsis is multifactorial (Figure 1). During hospitalization, it is well known that patients suffer from restricted mobility,[25] and that this impediment is linked to poor functional outcomes.[26] Described as far back as Hippocrates,[27] more recent studies have elucidated how prolonged bed rest leads to a multitude of physiological changes that promote deconditioning.[28] Specifically, skeletal muscle atrophy and decreased protein synthesis, independent of ongoing disease processes and acute illness, have been demonstrated in both animal and human models of prolonged inactivity.[29, 30] Additionally, bed rest leading to insensible fluid losses, a decline in stroke volume and effective cardiac output, bone loss, and decreased insulin sensitivity has been reported.[28, 31] There is little doubt that the aforementioned issues pertain to severe sepsis patients outside the ICU. In fact, nearly all of the acute mechanisms driving Creditor's hazards of hospitalization are noted among patients with severe sepsis.[32]

Figure 1

Furthermore, several factors preceding hospitalization may increase risk of disability. For example, Covinsky et al. described a number of risk factors, such as comorbid conditions, cognitive impairment, and various psychosocial aspects such as depression and limited social support, as being associated with increased risk of functional decline.[33] Thus, both in‐hospital and prehospital factors likely combine within an individual patient's context to determine risk of physical decline.

On this backdrop and the inherent immobilization associated with hospitalization, sepsis and inflammation catalyze physiologic changes that further propagate deconditioning.[7] Implicated pathways and proteins for this process include the mammalian target of rapamycin, human growth hormone, insulin‐like growth factors, interleukin‐1, and tumor necrosis factor‐. Through several metabolic alterations, sepsis independently promotes skeletal muscle breakdown and impairs skeletal muscle synthesis.[34, 35, 36] Inflammation associated with sepsis also increases oxidant burden, further leading to muscle dysfunction and dysregulation.[7, 31, 37, 38]

EFFECTS OF PHYSICAL THERAPY AND MOBILIZATION ON CLINICAL OUTCOMES

In patients with nonsepsis conditions who are at risk for functional decline, the effectiveness of physical therapy has been studied in multiple settings with positive outcomes. For example, in hospitalized elderly patients with general deconditioning, PT‐based interventions have demonstrated reductions in length of hospital stay.[39] Additionally, exercise in healthy subjects who have been subjected to bed rest has been shown to attenuate physiological changes, and maintain plasma and red cell volume and work capacity.[40] Adequate safety and improved outcomes have also been demonstrated in the general population of critically ill patients who receive early PT and mobilization. Improved functional capacity at discharge, decreases in duration of delirium, increased ventilator‐free days, decreased risk for CLABSI, and a better general sense of well‐being following these interventions have been widely reported in the literature.[14, 19, 23, 24, 41, 42, 43, 44, 45] Interestingly, critically ill patients may have a dose‐ and time‐dependent response to PT; that is, high intensity and early onset mobility‐based interventions are often associated with more ventilator‐free time and improved functional outcomes, resulting in shorter ICU and hospital length of stay.[42, 46, 47, 48]

Moderate intensity exercise has also been shown to improve 6‐minute walking distance in patients convalescing from coronary artery bypass grafting surgery.[49] Furthermore, in the postoperative setting, patients suffering traumatic hip fractures are known to benefit from physical and occupational therapies with shorter time to ambulation and improved locomotion in the recovery period.[21, 50, 51] Among patients with stroke, PT and gait training has led to improvements in speed, gait, independence during walking, activities of daily living, and extended activities of daily living.[52, 53, 54] A recent meta‐analysis also suggested that extra PT compared to regular treatment in patients with acute and subacute conditions such as stroke and postoperative states improved mobility and quality of life, while reducing length of hospital stay.[22]

Although this evidence suggests potential benefits for PT and mobilization, it is important to note that the effect of these treatments in dissimilar populations is unknown and may not necessarily be positive. For example, a recent study examining PT and its impact on patients with hip osteoarthritis showed no clinical benefit.[55] Mobilizing patients in severe illness may be associated with important risks, including falls, worsening of their clinical status, or moral discouragement in the setting of limited capacity. Therefore, understanding which elements of mobilization efforts create the greatest impact in the context of delivery of the intervention is critical to assessing the risk, benefit, and efficacy of PT‐based interventions.

EARLY PHYSICAL THERAPY FOR SEVERE SEPSIS OUTSIDE THE ICU: LITERATURE REVIEW

Given the functional decline associated with severe sepsis and the evidence of PT efficacy in other populations, we reviewed the current literature for studies evaluating physical therapy in severe sepsis patients outside the ICU. With the assistance of medical reference librarians, we searched MEDLINE via PubMed (1950present), EMBASE (1946present), Cochrane CENTRAL Register of Controlled Trials, and the Cochrane Database of Reviews of Effectiveness (1960present via Ovid). The search was last updated in June 2014.

We searched for studies that (1) involved human patients 18 years of age, (2) included patients with a primary diagnosis of sepsis or severe sepsis being treated outside the ICU, (3) featured a primary intervention that included PT or an early mobilization‐based initiative, and (4) reported a primary clinical or functional outcome of interest. Early was defined based on the included studies' definition. To be fully inclusive, we also conducted a secondary review with inclusion criteria expanded to studies of either any infectious pathology or severe sepsis patient in the ICU that employed PT interventions.

Our electronic search retrieved 815 records (Figure 2). Despite this approach, no publications met our primary inclusion criteria as we found no study that implemented a mobility intervention directed toward patients with sepsis treated outside the ICU. Our expanded secondary review included patients with any infectious pathology or those with severe sepsis in the ICU treated with PT; in this review, 2 studies met eligibility criteria.[56] In a 2003 cluster‐randomized trial, Mundy and colleagues randomized patients admitted with pneumonia to receive early PT or usual care. The outcomes of interest were hospital length of stay, mortality, number of chest radiographs, emergency department visits, and readmissions at 30 and 90 days after hospital admission. Although the study has important limitations (including patient‐level difference between trial arms, subjective definition of early mobilization), the authors found a significant decrease in length of stay among patients with pneumonia who received early PT compared to controls (5.8 vs 6.9 days, absolute difference 1.1 days, 95% confidence interval: 02.2 days). The study also reported a substantial decrease in adjusted mean hospital charges for the early mobilization group versus the usual care group ($10,159 per patient vs. $12,868 per patient, P=0.05). In the second study, Sossdorf et al. retrospectively evaluated a cohort of 999 patients with severe sepsis and septic shock and assessed whether onset and frequency of PT‐based interventions was associated with clinical benefit. After multivariate analysis, the authors reported a small mortality benefit associated with the relative number of PT interventions (hazard ratio: 0.982, P<0.001).[45]

Figure 2

EXPLAINING THE VOID

Our integrative review of the current literature reveals a gap in our understanding of the role of early mobilization in severe sepsis both within and beyond the ICU. Given the promise of PT‐based interventions and the toll of severe sepsis, one must ask: why may this be so?

First, the understanding that severe sepsis leads to significant, long‐term consequences for survivors has only been identified recently. Thus, it is possible that the burden and consequences related to this condition have not been fully recognized in clinical settings, leading to a paucity of research and interventions. Although the association between sepsis and mortality has been known since the 1990s,[57] long‐term complications and enduring morbidity of this disease continue to be realized. Indeed, many studies delineating the longer‐term effects of sepsis have been only recently published.[6, 10, 11, 12, 13]

Second, it is likely that many clinicians ascribe to the viewpoint that severe sepsis is an ICU‐only condition, a myth that has been discounted by multiple studies.[1, 4, 5] Although our study shows a paucity of evidence in both ICU and nonICU‐based severe sepsis, almost half of severe sepsis occurs outside the ICU, carrying with it many of the same clinical implications. Additionally, increased morbidity, mortality, and resource utilization are known to be true in all patients with severe sepsis, irrespective of where they receive treatment in the hospital.[4, 5, 6] Recent evidence has also shown that severe sepsis treated on the floor may be clinically, epidemiologically, and even prognostically unique from its ICU counterpart.[5, 58, 59] Therefore, it appears that research domains with tailored interventions to both ICU and non‐ICU severe sepsis patients are important areas of inquiry for clinicians. Such research may serve the purpose of assessing impact of early mobilization and unmasking any treatment heterogeneity that may exist when dealing with severe sepsis. Though trials of PT in ICU‐based severe sepsis are underway,[60] it is prudent that these also extend beyond the ICU‐setting.

Third, variability in early mobility practices and billing documentation for severe sepsis patients may exist, adding barriers to performing high‐quality research on this topic. In fact, administrative billing records for PT may offer insufficient granularity about services provided or therapies administered, particularly in the ICU where variability in early mobilization practices have been shown despite common employment of physiotherapists.[61]

Finally, many hospitalists may believe that patients with severe sepsis are simply too sick for early mobilization or PT, possibly limiting their participation in clinical or research‐based interventions. This perception has been well described in ICU populations, where it has been well studied and shown to be false.[41, 42, 43] Nevertheless, if severe sepsis patients are viewed as relatively sick hospitalized patients, it is plausible that resistance against early mobilization interventions may exist.[62] Understanding these biases and being mindful of such barriers when conducting studies in this area would be important.

CONCLUSION AND FUTURE DIRECTIONS

The cost burdens of severe sepsis are substantial. Elixhauser et al. suggest that it is currently the single most expensive cause of acute hospitalization in the United States.[63] Importantly, a large proportion of patients with severe sepsis receive care from hospitalists and/or floor teams on the general wards. Our integrative review has demonstrated a knowledge gap when it comes to rigorous assessments of PT and mobilization treatments in patients with severe sepsis within and beyond the ICU. Existing evidence provides a strong rationale for why functional decline occurs in patients with severe sepsis. A reasonable argument for PT‐based interventions to mitigate functional decline in this subset exists, but rigorous evaluation of such interventions is necessary. Physical and mobilization‐based treatments are routinely available and efficacious in several other settings and populations. It could be rapidly deployed and potentially improve outcomes in those with severe sepsis. Research would be welcomed to establish optimal dosing, efficacy, and cost effectiveness of PT and early mobilization for severe sepsis, particularly in patients treated on the general wards by hospitalists and floor teams.

How may such a research agenda be launched? A balanced multipronged approach is necessary. First, large‐scale epidemiological data to understand variation in practice are needed. Focused studies carried out by community and academic hospitalists on septic patients treated outside the ICU are the call of the hour. These data, in turn, can help create registries that assess for risk factors, quality of treatment, and long‐term outcomes among survivors of this condition. Second, evaluation and improvement of the coding and precision of physical and occupational therapy billing records is necessary so that their added value can be assessed and tracked using administrative data. Third, targeted prospective studies and clinical trials to directly evaluate the effect of PT in well‐defined patient populations with sepsis outside the ICU are needed. In this arena, hospitalist expertise and trained physical therapists will be crucial. The focus of this work should be directed toward both short‐term and long‐term functional outcomes, as well as mortality and morbidity assessments. Fourth, these patient‐centered efforts should loop back and inform the foundational biology of severe sepsis, thus illuminating patient‐centered end points, from biomarker analysis to physiometric measurements in basic and translational research.

In conclusion, this review sheds light on the fact that interventions that may mitigate the functional and cognitive decline in survivors of severe sepsis appear underdeveloped. Although the precise benefit of such interventions remains unclear, the low‐cost, widespread availability and generalizability of PT‐based interventions make it a worthy candidate for future research. As the numbers of survivors of sepsis expand, an unmet public health need for interventions to improve the long‐term outcomes of this population exists. Hospitalists and intensivists caring for severe sepsis patients must rise to meet this need. Together, we can help improve the lives of patients afflicted with severe sepsis, wherever they may receive care in the hospital.

Severe sepsis, defined as an infection leading to systemic inflammatory response and acute organ dysfunction, is a significant cause of morbidity and mortality.[1, 2, 3] Although it has been a condition classically attributed to patients in the intensive care unit (ICU), accumulating data suggest that a substantial proportion of patients with severe sepsis are managed by hospitalists and floor teams in non‐ICU, general ward settings.[1, 4, 5] Although the incidence of severe sepsis continues to rise both in the United States and other developed nations,[2, 6, 7] advances in early recognition, management, and care of this condition have resulted in improved rates of survival.[8] The resultant increase in a severe sepsis survivor population[6] make the long‐term sequelae of this condition an important public health problem.[9]

In both the ICU and on general wards, severe sepsis survivors suffer from decreased functional status, worsened quality of life, increased cognitive dysfunction, and sarcopenia.[4, 6, 10, 11, 12, 13, 14] Not surprisingly, many such patients are discharged to long‐term care facilities for physical rehabilitation,[15] with escalating utilization of resources[16] and cost.[17, 18] Inexpensive interventions that improve outcomes following sepsis would thus be welcomed.

It is well known that physical therapy (PT) and early mobilization are beneficial in mitigating functional decline in a number of conditions.[19, 20, 21, 22] PT can improve outcomes in several ways: prevention of bed rest deconditioning, mitigation of mechanisms that lead to sarcopenia, increased pulmonary and tissue aerobic capacity, and improved sense of well‐being. Indeed, among the population cared for in ICU settings, early mobility and PT lead to more ventilator‐free days, better functional status at discharge, shorter duration of delirium, and even a potentially reduced risk of central line‐associated bloodstream infection (CLABSI).[23, 24] However, whether initiating early PT can improve outcomes in patients with severe sepsis treated by either intensivists or hospitalists/floor teams outside the ICU is unknown.

Therefore, to better understand this phenomenon, we systematically reviewed and integrated the literature regarding early mobilization and PT for severe sepsis outside the ICU. To be more inclusive, a secondary review including populations with any infectious etiology and severe sepsis treated within the ICU was also conducted. Our review begins by providing an overview of the pathophysiology behind functional decline in severe sepsis, along with existing evidence on early mobilization efficacy in other patient populations. We then proceed with a review of the extant literature on the aforementioned topic. We conclude with an evaluation of the current evidence on the subject, along with assertions regarding future research in the area.

PATHOPHYSIOLOGY OF DISABILITY FOLLOWING HOSPITALIZATION FOR SEVERE SEPSIS

The pathophysiology behind functional decline in patients hospitalized with severe sepsis is multifactorial (Figure 1). During hospitalization, it is well known that patients suffer from restricted mobility,[25] and that this impediment is linked to poor functional outcomes.[26] Described as far back as Hippocrates,[27] more recent studies have elucidated how prolonged bed rest leads to a multitude of physiological changes that promote deconditioning.[28] Specifically, skeletal muscle atrophy and decreased protein synthesis, independent of ongoing disease processes and acute illness, have been demonstrated in both animal and human models of prolonged inactivity.[29, 30] Additionally, bed rest leading to insensible fluid losses, a decline in stroke volume and effective cardiac output, bone loss, and decreased insulin sensitivity has been reported.[28, 31] There is little doubt that the aforementioned issues pertain to severe sepsis patients outside the ICU. In fact, nearly all of the acute mechanisms driving Creditor's hazards of hospitalization are noted among patients with severe sepsis.[32]

Figure 1

Furthermore, several factors preceding hospitalization may increase risk of disability. For example, Covinsky et al. described a number of risk factors, such as comorbid conditions, cognitive impairment, and various psychosocial aspects such as depression and limited social support, as being associated with increased risk of functional decline.[33] Thus, both in‐hospital and prehospital factors likely combine within an individual patient's context to determine risk of physical decline.

On this backdrop and the inherent immobilization associated with hospitalization, sepsis and inflammation catalyze physiologic changes that further propagate deconditioning.[7] Implicated pathways and proteins for this process include the mammalian target of rapamycin, human growth hormone, insulin‐like growth factors, interleukin‐1, and tumor necrosis factor‐. Through several metabolic alterations, sepsis independently promotes skeletal muscle breakdown and impairs skeletal muscle synthesis.[34, 35, 36] Inflammation associated with sepsis also increases oxidant burden, further leading to muscle dysfunction and dysregulation.[7, 31, 37, 38]

EFFECTS OF PHYSICAL THERAPY AND MOBILIZATION ON CLINICAL OUTCOMES

In patients with nonsepsis conditions who are at risk for functional decline, the effectiveness of physical therapy has been studied in multiple settings with positive outcomes. For example, in hospitalized elderly patients with general deconditioning, PT‐based interventions have demonstrated reductions in length of hospital stay.[39] Additionally, exercise in healthy subjects who have been subjected to bed rest has been shown to attenuate physiological changes, and maintain plasma and red cell volume and work capacity.[40] Adequate safety and improved outcomes have also been demonstrated in the general population of critically ill patients who receive early PT and mobilization. Improved functional capacity at discharge, decreases in duration of delirium, increased ventilator‐free days, decreased risk for CLABSI, and a better general sense of well‐being following these interventions have been widely reported in the literature.[14, 19, 23, 24, 41, 42, 43, 44, 45] Interestingly, critically ill patients may have a dose‐ and time‐dependent response to PT; that is, high intensity and early onset mobility‐based interventions are often associated with more ventilator‐free time and improved functional outcomes, resulting in shorter ICU and hospital length of stay.[42, 46, 47, 48]

Moderate intensity exercise has also been shown to improve 6‐minute walking distance in patients convalescing from coronary artery bypass grafting surgery.[49] Furthermore, in the postoperative setting, patients suffering traumatic hip fractures are known to benefit from physical and occupational therapies with shorter time to ambulation and improved locomotion in the recovery period.[21, 50, 51] Among patients with stroke, PT and gait training has led to improvements in speed, gait, independence during walking, activities of daily living, and extended activities of daily living.[52, 53, 54] A recent meta‐analysis also suggested that extra PT compared to regular treatment in patients with acute and subacute conditions such as stroke and postoperative states improved mobility and quality of life, while reducing length of hospital stay.[22]

Although this evidence suggests potential benefits for PT and mobilization, it is important to note that the effect of these treatments in dissimilar populations is unknown and may not necessarily be positive. For example, a recent study examining PT and its impact on patients with hip osteoarthritis showed no clinical benefit.[55] Mobilizing patients in severe illness may be associated with important risks, including falls, worsening of their clinical status, or moral discouragement in the setting of limited capacity. Therefore, understanding which elements of mobilization efforts create the greatest impact in the context of delivery of the intervention is critical to assessing the risk, benefit, and efficacy of PT‐based interventions.

EARLY PHYSICAL THERAPY FOR SEVERE SEPSIS OUTSIDE THE ICU: LITERATURE REVIEW

Given the functional decline associated with severe sepsis and the evidence of PT efficacy in other populations, we reviewed the current literature for studies evaluating physical therapy in severe sepsis patients outside the ICU. With the assistance of medical reference librarians, we searched MEDLINE via PubMed (1950present), EMBASE (1946present), Cochrane CENTRAL Register of Controlled Trials, and the Cochrane Database of Reviews of Effectiveness (1960present via Ovid). The search was last updated in June 2014.

We searched for studies that (1) involved human patients 18 years of age, (2) included patients with a primary diagnosis of sepsis or severe sepsis being treated outside the ICU, (3) featured a primary intervention that included PT or an early mobilization‐based initiative, and (4) reported a primary clinical or functional outcome of interest. Early was defined based on the included studies' definition. To be fully inclusive, we also conducted a secondary review with inclusion criteria expanded to studies of either any infectious pathology or severe sepsis patient in the ICU that employed PT interventions.

Our electronic search retrieved 815 records (Figure 2). Despite this approach, no publications met our primary inclusion criteria as we found no study that implemented a mobility intervention directed toward patients with sepsis treated outside the ICU. Our expanded secondary review included patients with any infectious pathology or those with severe sepsis in the ICU treated with PT; in this review, 2 studies met eligibility criteria.[56] In a 2003 cluster‐randomized trial, Mundy and colleagues randomized patients admitted with pneumonia to receive early PT or usual care. The outcomes of interest were hospital length of stay, mortality, number of chest radiographs, emergency department visits, and readmissions at 30 and 90 days after hospital admission. Although the study has important limitations (including patient‐level difference between trial arms, subjective definition of early mobilization), the authors found a significant decrease in length of stay among patients with pneumonia who received early PT compared to controls (5.8 vs 6.9 days, absolute difference 1.1 days, 95% confidence interval: 02.2 days). The study also reported a substantial decrease in adjusted mean hospital charges for the early mobilization group versus the usual care group ($10,159 per patient vs. $12,868 per patient, P=0.05). In the second study, Sossdorf et al. retrospectively evaluated a cohort of 999 patients with severe sepsis and septic shock and assessed whether onset and frequency of PT‐based interventions was associated with clinical benefit. After multivariate analysis, the authors reported a small mortality benefit associated with the relative number of PT interventions (hazard ratio: 0.982, P<0.001).[45]

Figure 2

EXPLAINING THE VOID

Our integrative review of the current literature reveals a gap in our understanding of the role of early mobilization in severe sepsis both within and beyond the ICU. Given the promise of PT‐based interventions and the toll of severe sepsis, one must ask: why may this be so?

First, the understanding that severe sepsis leads to significant, long‐term consequences for survivors has only been identified recently. Thus, it is possible that the burden and consequences related to this condition have not been fully recognized in clinical settings, leading to a paucity of research and interventions. Although the association between sepsis and mortality has been known since the 1990s,[57] long‐term complications and enduring morbidity of this disease continue to be realized. Indeed, many studies delineating the longer‐term effects of sepsis have been only recently published.[6, 10, 11, 12, 13]

Second, it is likely that many clinicians ascribe to the viewpoint that severe sepsis is an ICU‐only condition, a myth that has been discounted by multiple studies.[1, 4, 5] Although our study shows a paucity of evidence in both ICU and nonICU‐based severe sepsis, almost half of severe sepsis occurs outside the ICU, carrying with it many of the same clinical implications. Additionally, increased morbidity, mortality, and resource utilization are known to be true in all patients with severe sepsis, irrespective of where they receive treatment in the hospital.[4, 5, 6] Recent evidence has also shown that severe sepsis treated on the floor may be clinically, epidemiologically, and even prognostically unique from its ICU counterpart.[5, 58, 59] Therefore, it appears that research domains with tailored interventions to both ICU and non‐ICU severe sepsis patients are important areas of inquiry for clinicians. Such research may serve the purpose of assessing impact of early mobilization and unmasking any treatment heterogeneity that may exist when dealing with severe sepsis. Though trials of PT in ICU‐based severe sepsis are underway,[60] it is prudent that these also extend beyond the ICU‐setting.

Third, variability in early mobility practices and billing documentation for severe sepsis patients may exist, adding barriers to performing high‐quality research on this topic. In fact, administrative billing records for PT may offer insufficient granularity about services provided or therapies administered, particularly in the ICU where variability in early mobilization practices have been shown despite common employment of physiotherapists.[61]

Finally, many hospitalists may believe that patients with severe sepsis are simply too sick for early mobilization or PT, possibly limiting their participation in clinical or research‐based interventions. This perception has been well described in ICU populations, where it has been well studied and shown to be false.[41, 42, 43] Nevertheless, if severe sepsis patients are viewed as relatively sick hospitalized patients, it is plausible that resistance against early mobilization interventions may exist.[62] Understanding these biases and being mindful of such barriers when conducting studies in this area would be important.

CONCLUSION AND FUTURE DIRECTIONS

The cost burdens of severe sepsis are substantial. Elixhauser et al. suggest that it is currently the single most expensive cause of acute hospitalization in the United States.[63] Importantly, a large proportion of patients with severe sepsis receive care from hospitalists and/or floor teams on the general wards. Our integrative review has demonstrated a knowledge gap when it comes to rigorous assessments of PT and mobilization treatments in patients with severe sepsis within and beyond the ICU. Existing evidence provides a strong rationale for why functional decline occurs in patients with severe sepsis. A reasonable argument for PT‐based interventions to mitigate functional decline in this subset exists, but rigorous evaluation of such interventions is necessary. Physical and mobilization‐based treatments are routinely available and efficacious in several other settings and populations. It could be rapidly deployed and potentially improve outcomes in those with severe sepsis. Research would be welcomed to establish optimal dosing, efficacy, and cost effectiveness of PT and early mobilization for severe sepsis, particularly in patients treated on the general wards by hospitalists and floor teams.

How may such a research agenda be launched? A balanced multipronged approach is necessary. First, large‐scale epidemiological data to understand variation in practice are needed. Focused studies carried out by community and academic hospitalists on septic patients treated outside the ICU are the call of the hour. These data, in turn, can help create registries that assess for risk factors, quality of treatment, and long‐term outcomes among survivors of this condition. Second, evaluation and improvement of the coding and precision of physical and occupational therapy billing records is necessary so that their added value can be assessed and tracked using administrative data. Third, targeted prospective studies and clinical trials to directly evaluate the effect of PT in well‐defined patient populations with sepsis outside the ICU are needed. In this arena, hospitalist expertise and trained physical therapists will be crucial. The focus of this work should be directed toward both short‐term and long‐term functional outcomes, as well as mortality and morbidity assessments. Fourth, these patient‐centered efforts should loop back and inform the foundational biology of severe sepsis, thus illuminating patient‐centered end points, from biomarker analysis to physiometric measurements in basic and translational research.

In conclusion, this review sheds light on the fact that interventions that may mitigate the functional and cognitive decline in survivors of severe sepsis appear underdeveloped. Although the precise benefit of such interventions remains unclear, the low‐cost, widespread availability and generalizability of PT‐based interventions make it a worthy candidate for future research. As the numbers of survivors of sepsis expand, an unmet public health need for interventions to improve the long‐term outcomes of this population exists. Hospitalists and intensivists caring for severe sepsis patients must rise to meet this need. Together, we can help improve the lives of patients afflicted with severe sepsis, wherever they may receive care in the hospital.

Severe sepsis, defined as an infection leading to systemic inflammatory response and acute organ dysfunction, is a significant cause of morbidity and mortality.[1, 2, 3] Although it has been a condition classically attributed to patients in the intensive care unit (ICU), accumulating data suggest that a substantial proportion of patients with severe sepsis are managed by hospitalists and floor teams in non‐ICU, general ward settings.[1, 4, 5] Although the incidence of severe sepsis continues to rise both in the United States and other developed nations,[2, 6, 7] advances in early recognition, management, and care of this condition have resulted in improved rates of survival.[8] The resultant increase in a severe sepsis survivor population[6] make the long‐term sequelae of this condition an important public health problem.[9]

In both the ICU and on general wards, severe sepsis survivors suffer from decreased functional status, worsened quality of life, increased cognitive dysfunction, and sarcopenia.[4, 6, 10, 11, 12, 13, 14] Not surprisingly, many such patients are discharged to long‐term care facilities for physical rehabilitation,[15] with escalating utilization of resources[16] and cost.[17, 18] Inexpensive interventions that improve outcomes following sepsis would thus be welcomed.

It is well known that physical therapy (PT) and early mobilization are beneficial in mitigating functional decline in a number of conditions.[19, 20, 21, 22] PT can improve outcomes in several ways: prevention of bed rest deconditioning, mitigation of mechanisms that lead to sarcopenia, increased pulmonary and tissue aerobic capacity, and improved sense of well‐being. Indeed, among the population cared for in ICU settings, early mobility and PT lead to more ventilator‐free days, better functional status at discharge, shorter duration of delirium, and even a potentially reduced risk of central line‐associated bloodstream infection (CLABSI).[23, 24] However, whether initiating early PT can improve outcomes in patients with severe sepsis treated by either intensivists or hospitalists/floor teams outside the ICU is unknown.

Therefore, to better understand this phenomenon, we systematically reviewed and integrated the literature regarding early mobilization and PT for severe sepsis outside the ICU. To be more inclusive, a secondary review including populations with any infectious etiology and severe sepsis treated within the ICU was also conducted. Our review begins by providing an overview of the pathophysiology behind functional decline in severe sepsis, along with existing evidence on early mobilization efficacy in other patient populations. We then proceed with a review of the extant literature on the aforementioned topic. We conclude with an evaluation of the current evidence on the subject, along with assertions regarding future research in the area.

PATHOPHYSIOLOGY OF DISABILITY FOLLOWING HOSPITALIZATION FOR SEVERE SEPSIS

The pathophysiology behind functional decline in patients hospitalized with severe sepsis is multifactorial (Figure 1). During hospitalization, it is well known that patients suffer from restricted mobility,[25] and that this impediment is linked to poor functional outcomes.[26] Described as far back as Hippocrates,[27] more recent studies have elucidated how prolonged bed rest leads to a multitude of physiological changes that promote deconditioning.[28] Specifically, skeletal muscle atrophy and decreased protein synthesis, independent of ongoing disease processes and acute illness, have been demonstrated in both animal and human models of prolonged inactivity.[29, 30] Additionally, bed rest leading to insensible fluid losses, a decline in stroke volume and effective cardiac output, bone loss, and decreased insulin sensitivity has been reported.[28, 31] There is little doubt that the aforementioned issues pertain to severe sepsis patients outside the ICU. In fact, nearly all of the acute mechanisms driving Creditor's hazards of hospitalization are noted among patients with severe sepsis.[32]

Figure 1

Furthermore, several factors preceding hospitalization may increase risk of disability. For example, Covinsky et al. described a number of risk factors, such as comorbid conditions, cognitive impairment, and various psychosocial aspects such as depression and limited social support, as being associated with increased risk of functional decline.[33] Thus, both in‐hospital and prehospital factors likely combine within an individual patient's context to determine risk of physical decline.

On this backdrop and the inherent immobilization associated with hospitalization, sepsis and inflammation catalyze physiologic changes that further propagate deconditioning.[7] Implicated pathways and proteins for this process include the mammalian target of rapamycin, human growth hormone, insulin‐like growth factors, interleukin‐1, and tumor necrosis factor‐. Through several metabolic alterations, sepsis independently promotes skeletal muscle breakdown and impairs skeletal muscle synthesis.[34, 35, 36] Inflammation associated with sepsis also increases oxidant burden, further leading to muscle dysfunction and dysregulation.[7, 31, 37, 38]

EFFECTS OF PHYSICAL THERAPY AND MOBILIZATION ON CLINICAL OUTCOMES

In patients with nonsepsis conditions who are at risk for functional decline, the effectiveness of physical therapy has been studied in multiple settings with positive outcomes. For example, in hospitalized elderly patients with general deconditioning, PT‐based interventions have demonstrated reductions in length of hospital stay.[39] Additionally, exercise in healthy subjects who have been subjected to bed rest has been shown to attenuate physiological changes, and maintain plasma and red cell volume and work capacity.[40] Adequate safety and improved outcomes have also been demonstrated in the general population of critically ill patients who receive early PT and mobilization. Improved functional capacity at discharge, decreases in duration of delirium, increased ventilator‐free days, decreased risk for CLABSI, and a better general sense of well‐being following these interventions have been widely reported in the literature.[14, 19, 23, 24, 41, 42, 43, 44, 45] Interestingly, critically ill patients may have a dose‐ and time‐dependent response to PT; that is, high intensity and early onset mobility‐based interventions are often associated with more ventilator‐free time and improved functional outcomes, resulting in shorter ICU and hospital length of stay.[42, 46, 47, 48]

Moderate intensity exercise has also been shown to improve 6‐minute walking distance in patients convalescing from coronary artery bypass grafting surgery.[49] Furthermore, in the postoperative setting, patients suffering traumatic hip fractures are known to benefit from physical and occupational therapies with shorter time to ambulation and improved locomotion in the recovery period.[21, 50, 51] Among patients with stroke, PT and gait training has led to improvements in speed, gait, independence during walking, activities of daily living, and extended activities of daily living.[52, 53, 54] A recent meta‐analysis also suggested that extra PT compared to regular treatment in patients with acute and subacute conditions such as stroke and postoperative states improved mobility and quality of life, while reducing length of hospital stay.[22]

Although this evidence suggests potential benefits for PT and mobilization, it is important to note that the effect of these treatments in dissimilar populations is unknown and may not necessarily be positive. For example, a recent study examining PT and its impact on patients with hip osteoarthritis showed no clinical benefit.[55] Mobilizing patients in severe illness may be associated with important risks, including falls, worsening of their clinical status, or moral discouragement in the setting of limited capacity. Therefore, understanding which elements of mobilization efforts create the greatest impact in the context of delivery of the intervention is critical to assessing the risk, benefit, and efficacy of PT‐based interventions.

EARLY PHYSICAL THERAPY FOR SEVERE SEPSIS OUTSIDE THE ICU: LITERATURE REVIEW

Given the functional decline associated with severe sepsis and the evidence of PT efficacy in other populations, we reviewed the current literature for studies evaluating physical therapy in severe sepsis patients outside the ICU. With the assistance of medical reference librarians, we searched MEDLINE via PubMed (1950present), EMBASE (1946present), Cochrane CENTRAL Register of Controlled Trials, and the Cochrane Database of Reviews of Effectiveness (1960present via Ovid). The search was last updated in June 2014.

We searched for studies that (1) involved human patients 18 years of age, (2) included patients with a primary diagnosis of sepsis or severe sepsis being treated outside the ICU, (3) featured a primary intervention that included PT or an early mobilization‐based initiative, and (4) reported a primary clinical or functional outcome of interest. Early was defined based on the included studies' definition. To be fully inclusive, we also conducted a secondary review with inclusion criteria expanded to studies of either any infectious pathology or severe sepsis patient in the ICU that employed PT interventions.

Our electronic search retrieved 815 records (Figure 2). Despite this approach, no publications met our primary inclusion criteria as we found no study that implemented a mobility intervention directed toward patients with sepsis treated outside the ICU. Our expanded secondary review included patients with any infectious pathology or those with severe sepsis in the ICU treated with PT; in this review, 2 studies met eligibility criteria.[56] In a 2003 cluster‐randomized trial, Mundy and colleagues randomized patients admitted with pneumonia to receive early PT or usual care. The outcomes of interest were hospital length of stay, mortality, number of chest radiographs, emergency department visits, and readmissions at 30 and 90 days after hospital admission. Although the study has important limitations (including patient‐level difference between trial arms, subjective definition of early mobilization), the authors found a significant decrease in length of stay among patients with pneumonia who received early PT compared to controls (5.8 vs 6.9 days, absolute difference 1.1 days, 95% confidence interval: 02.2 days). The study also reported a substantial decrease in adjusted mean hospital charges for the early mobilization group versus the usual care group ($10,159 per patient vs. $12,868 per patient, P=0.05). In the second study, Sossdorf et al. retrospectively evaluated a cohort of 999 patients with severe sepsis and septic shock and assessed whether onset and frequency of PT‐based interventions was associated with clinical benefit. After multivariate analysis, the authors reported a small mortality benefit associated with the relative number of PT interventions (hazard ratio: 0.982, P<0.001).[45]

Figure 2

EXPLAINING THE VOID

Our integrative review of the current literature reveals a gap in our understanding of the role of early mobilization in severe sepsis both within and beyond the ICU. Given the promise of PT‐based interventions and the toll of severe sepsis, one must ask: why may this be so?

First, the understanding that severe sepsis leads to significant, long‐term consequences for survivors has only been identified recently. Thus, it is possible that the burden and consequences related to this condition have not been fully recognized in clinical settings, leading to a paucity of research and interventions. Although the association between sepsis and mortality has been known since the 1990s,[57] long‐term complications and enduring morbidity of this disease continue to be realized. Indeed, many studies delineating the longer‐term effects of sepsis have been only recently published.[6, 10, 11, 12, 13]

Second, it is likely that many clinicians ascribe to the viewpoint that severe sepsis is an ICU‐only condition, a myth that has been discounted by multiple studies.[1, 4, 5] Although our study shows a paucity of evidence in both ICU and nonICU‐based severe sepsis, almost half of severe sepsis occurs outside the ICU, carrying with it many of the same clinical implications. Additionally, increased morbidity, mortality, and resource utilization are known to be true in all patients with severe sepsis, irrespective of where they receive treatment in the hospital.[4, 5, 6] Recent evidence has also shown that severe sepsis treated on the floor may be clinically, epidemiologically, and even prognostically unique from its ICU counterpart.[5, 58, 59] Therefore, it appears that research domains with tailored interventions to both ICU and non‐ICU severe sepsis patients are important areas of inquiry for clinicians. Such research may serve the purpose of assessing impact of early mobilization and unmasking any treatment heterogeneity that may exist when dealing with severe sepsis. Though trials of PT in ICU‐based severe sepsis are underway,[60] it is prudent that these also extend beyond the ICU‐setting.

Third, variability in early mobility practices and billing documentation for severe sepsis patients may exist, adding barriers to performing high‐quality research on this topic. In fact, administrative billing records for PT may offer insufficient granularity about services provided or therapies administered, particularly in the ICU where variability in early mobilization practices have been shown despite common employment of physiotherapists.[61]

Finally, many hospitalists may believe that patients with severe sepsis are simply too sick for early mobilization or PT, possibly limiting their participation in clinical or research‐based interventions. This perception has been well described in ICU populations, where it has been well studied and shown to be false.[41, 42, 43] Nevertheless, if severe sepsis patients are viewed as relatively sick hospitalized patients, it is plausible that resistance against early mobilization interventions may exist.[62] Understanding these biases and being mindful of such barriers when conducting studies in this area would be important.

CONCLUSION AND FUTURE DIRECTIONS

The cost burdens of severe sepsis are substantial. Elixhauser et al. suggest that it is currently the single most expensive cause of acute hospitalization in the United States.[63] Importantly, a large proportion of patients with severe sepsis receive care from hospitalists and/or floor teams on the general wards. Our integrative review has demonstrated a knowledge gap when it comes to rigorous assessments of PT and mobilization treatments in patients with severe sepsis within and beyond the ICU. Existing evidence provides a strong rationale for why functional decline occurs in patients with severe sepsis. A reasonable argument for PT‐based interventions to mitigate functional decline in this subset exists, but rigorous evaluation of such interventions is necessary. Physical and mobilization‐based treatments are routinely available and efficacious in several other settings and populations. It could be rapidly deployed and potentially improve outcomes in those with severe sepsis. Research would be welcomed to establish optimal dosing, efficacy, and cost effectiveness of PT and early mobilization for severe sepsis, particularly in patients treated on the general wards by hospitalists and floor teams.

How may such a research agenda be launched? A balanced multipronged approach is necessary. First, large‐scale epidemiological data to understand variation in practice are needed. Focused studies carried out by community and academic hospitalists on septic patients treated outside the ICU are the call of the hour. These data, in turn, can help create registries that assess for risk factors, quality of treatment, and long‐term outcomes among survivors of this condition. Second, evaluation and improvement of the coding and precision of physical and occupational therapy billing records is necessary so that their added value can be assessed and tracked using administrative data. Third, targeted prospective studies and clinical trials to directly evaluate the effect of PT in well‐defined patient populations with sepsis outside the ICU are needed. In this arena, hospitalist expertise and trained physical therapists will be crucial. The focus of this work should be directed toward both short‐term and long‐term functional outcomes, as well as mortality and morbidity assessments. Fourth, these patient‐centered efforts should loop back and inform the foundational biology of severe sepsis, thus illuminating patient‐centered end points, from biomarker analysis to physiometric measurements in basic and translational research.

In conclusion, this review sheds light on the fact that interventions that may mitigate the functional and cognitive decline in survivors of severe sepsis appear underdeveloped. Although the precise benefit of such interventions remains unclear, the low‐cost, widespread availability and generalizability of PT‐based interventions make it a worthy candidate for future research. As the numbers of survivors of sepsis expand, an unmet public health need for interventions to improve the long‐term outcomes of this population exists. Hospitalists and intensivists caring for severe sepsis patients must rise to meet this need. Together, we can help improve the lives of patients afflicted with severe sepsis, wherever they may receive care in the hospital.

The International Consensus Conference (ICC) for sepsis defines severe sepsis as an infection leading to acute organ dysfunction.[1, 2] Severe sepsis afflicts over 1 million patients each year in Medicare alone, and is substantially more common among older Americans than acute myocardial infarction.[3, 4, 5] Recently, the Agency for Healthcare Research and Quality identified severe sepsis as the single most expensive cause of hospitalization in the United States.[6] The incidence of severe sepsis continues to rise.[4, 5]

Severe sepsis is often mischaracterized as a diagnosis cared for primarily in the intensive care unit (ICU). Yet, studies indicate that only 32% to 50% of patients with severe sepsis require ICU care, leaving the majority on the general care wards.[7, 8] These studies also reveal mortality rates of 26% to 30% among patients with severe sepsis who are not admitted to an ICU compared to 11% to 33% in the ICU.[7, 8]

Although a number of epidemiologic and interventional studies have focused on severe sepsis in the ICU,[3, 9, 10] much less is known about patients cared for on the general medicine wards. Without this information, clinicians cannot make informed choices about important management decisions such as targeted diagnostic testing, empirical antimicrobials, and other therapies. To this end, we sought to further characterize the infectious etiologies and resultant organ system dysfunctions in the subset of patients with severe sepsis admitted to non‐ICU medical services at a tertiary academic medical center.

METHODS

RESULTS

Of 23,288 hospitalizations examined from 2009 through 2010, the ICD‐9based automated screen for severe sepsis was positive for 3,146 (14 %). A random sample of 111 medical records, of which 92 had screened positive for severe sepsis and 19 had screened negative, was reviewed in detail. After review by the hospitalists, 64 of these 111 hospitalizations were judged to have severe sepsis, 61 of the 92 screened positive cases (66%), and 3 of the 19 screened negative cases (16%). The 3 reviewers had a kappa of 0.70, indicating good agreement.

Characteristics of the 64 patients with severe sepsis are shown in Table 2. The mean age was 63 years old (standard deviation [SD]=17.7), and 41% were male. The mean length of stay was 13.7 days (SD=20.8). Thirty‐nine percent (95% CI, 27%‐52%) of patients (25/64) were immunosuppressed. Of patients initially admitted to the general medical ward, 25% (16/64; 95% CI, 15%‐37%) ultimately required ICU care during their admission. The overall in‐hospital mortality rate was 13% (8/64; 95% CI, 6%‐23%). Immunosuppressed patients had a mortality rate of 20% and nonimmunosuppressed patients had a mortality rate of 8%. Only 47% (30/64; 95% CI, 34%‐60%) of the medical records had explicit clinician documentation of severe sepsis.

The most common site of infection was found to be the genitourinary system, occurring in 41% (26/64; 95% CI, 29%‐54%) of patients (Table 3). Pulmonary and intra‐abdominal sites were also common, accounting for 14% (95% CI, 6.6%‐25%) and 13% (95% CI, 5.6%‐23%) of sites, respectively. An infecting organism was identified by culture in 66% (42/64; 95% CI, 53%‐77%) of case patients with specific pathogens listed in Table 4. Among patients with positive culture results, the majority grew Gram‐negative organisms (57%; 95% CI, 41%‐72%). Non‐Clostridium difficile Gram‐positive organisms were also prominent and identified in 48% (95% CI, 32%‐64%) of positive cultures. Candida was less common (12%, 95% CI, 4.0%‐26%). Fourteen cases (22%, 95% CI, 10%‐30%) had 2 or more concomitant infectious pathogens.

All 64 patients had at least 1 organ dysfunction, as required by the ICC definition of severe sepsis. Organ dysfunction in 2 or more organ systems occurred in 77% (95% CI, 64%‐86%) of the cases (49/64). The incidence for each organ system dysfunction is presented in Table 5, as well as its relationship to both mortality and ICU admission. The most common organ system dysfunctions were found to be cardiovascular (hypotension) and renal dysfunction occurring in 66% and 64% of the cases, respectively. In this non‐ICU population, pulmonary dysfunction occurred in 30% of cases, but was frequently associated with transfer to the ICU, as 63% of the patients with pulmonary failure required ICU care. Patients with more organ systems affected were more likely to be transferred to the ICU and to die.

DISCUSSION

Severe sepsis was common among patients admitted to the general medical ward in this tertiary care center. Our patient cohort differed in important ways from previously described typical cases of severe sepsis among ICU populations. Severe sepsis on the general medical wards was more commonly associated with Gram‐negative pathogens in the setting of genitourinary tract infections. This is in contrast to Gram‐positive organisms and respiratory tract infections, which are more common in the ICU.[3, 10] Renal and cardiac dysfunction were commonly observed organ failures, whereas in the ICU, severe sepsis has been reported to more likely involve respiratory failure. These results suggest that hospitalists seeking to provide evidence‐based care to prevent postsepsis morbidity and mortality for their non‐ICU patients need to heighten their index of suspicion when caring for an infected patient and appreciate that many severe sepsis patients may not fit neatly into traditional sepsis treatment algorithms.

Studies characterizing severe sepsis in the ICU setting indicate a predominance of pulmonary infections and respiratory failure with occurrence rates of 74% to 95% and 54% to 61%, respectively.[3, 12, 13] Given that either shock or pulmonary dysfunction is often required for admission to many ICUs, it is perhaps not surprising that these rates are dramatically different on the general medicine ward, with a relative scarcity of pulmonary infections (14%) and respiratory dysfunction (30%). Instead, genitourinary infections were noted in 41% (95% CI, 29%‐54%) of the cases, in contrast to the rates of genitourinary infections in ICU patients with severe sepsis, which have rates of 5.4% to 9.1%.[3, 10] Likely as a result of this, a Gram‐negative predominance is noted in the associated microbiology. Furthermore, our study indicates that C difficile and vancomycin‐resistant Enterococcus (VRE) species appear to represent an emerging cause of severe sepsis on the general medicine wards, as they have not been noted to be causative micro‐organisms in previous studies of sepsis. This is concordant with other studies showing increases in incidence and severity of disease for C difficile as well as VRE.[14, 15]

Previous epidemiologic studies of severe sepsis originating outside the ICU are lacking, but some work has been done. One study on the epidemiology of sepsis both with and without organ dysfunction aggregated all hospitalized patients and included those both admitted to the general medicine wards and directly to the ICU.[7] Similar to our study, this study also found a predominance of Gram‐negative causative organisms, as well as comparable in‐hospital mortality rates (12.8% vs 13%). Additionally, genitourinary infections were noted in 20% of the patients, notably higher than rates reported to have been found in patients with severe sepsis in the ICU, but not the magnitude found in our study, perhaps as a result of the combined ICU‐ward population studied. A similar high prevalence of genitourinary infections was also noted in a recent administrative data‐based study of emergency medical services‐transported patients with severe sepsis, half of whom required intensive care during their hospitalization.[16]

Our study is unique in that it focuses on severe sepsis in patients, commonly cared for by hospitalists, who were admitted to the general medical ward, and uses patient level data to elucidate more characteristics of the defining organ dysfunction. Furthermore, our results suggest that severe sepsis was poorly documented in this setting, indicating a potential impact on billing, coding, case mix index, and hospital mortality statistics that rely on very specific wording, as well as a possible need for increased awareness among hospitalists. Without this awareness, an opportunity may be missed for improved patient care via specific sepsis‐targeted measures,[13, 17, 18] including more aggressive resuscitative measures[19] or intensive physical and occupational therapy interventions aimed at impacting the cognitive and functional debilities[20] that result from severe sepsis. Highlighting this growing need to better assist clinicians assess the severity of septic patients and recognize these complex cases on the general medicine wards, 1 recent study evaluated the fitness of several clinical disease‐severity scoring systems for patients with sepsis in general internal medicine departments.[21] Perhaps with the help of tools such as these, which are being piloted in some hospitals, the care of this growing population can be enhanced.

Our study has a number of limitations that should be kept in mind. First, this is a single center study performed at an academic tertiary care center with a relatively high incidence of immunosuppression, which may influence the spectrum of infecting organisms. Our center also has a relatively large, closed‐model ICU, which often operates at near capacity, potentially affecting the severity of our non‐ICU population. Second, although we screened a large number of patients, as necessitated by our intensive and detailed review of clinical information, our sample size with hospitalist‐validated severe sepsis is relatively small. With this small sample size, less prevalent infections, patient characteristics, and organ dysfunctions may by chance have been under or over‐represented, and one could expect some variance in the occurrence rates of organ system dysfunction and infection rates by sampling error alone. Further larger scale studies are warranted to confirm these data and their generalizability. Third, the data necessary to calculate sequential organ failure assessment or multiple organ dysfunction score were not collected. This may limit the ability to directly compare the organ dysfunction noted in this study with others. Additionally, given the ICC definitions of organ dysfunction, some of the organ dysfunction noted, particularly for neurological dysfunction, was reliant on subjective clinical findings documented in the record. Finally, we relied on the lack of specific terminology to indicate a lack of documentation of sepsis, which does not necessarily indicate a lack of recognition or undertreatment of this condition. However, these limitations are offset by the strengths of this study, including the patient‐level medical record validation of severe sepsis by trained hospitalist physicians, high kappa statistic, and strict application of guideline‐based definitions.

This work has important implications for both clinicians and for future research on severe sepsis. The results suggest that severe sepsis may be quite common outside the ICU, and that patients presenting with this condition who are admitted to general medical wards are not routinely characterized by the profound hypoxemia and refractory shock of iconic cases. Certainly, further study looking at larger numbers of cases is needed to better understand the specifics and nuances of this important topic as well as to further evaluate clinicians' ability to recognize and treat such patients in this setting. Furthermore, future research on the treatment of severe sepsis, including both antimicrobials and disease‐modifying agents (eg, anti‐inflammatories) must continue to include and even focus on this large population of non‐ICU patients with severe sepsis, as the risk/benefit ratios of such potential treatments may vary with severity of illness.

In conclusion, severe sepsis was commonly found in patients admitted on the general medicine wards. The epidemiology of the infections and resultant organ dysfunction appears to differ from that found in the ICU. More studies are needed to provide a deeper understanding of this disease process, as this will enable clinicians to better recognize and treat patients thus afflicted, no matter the setting.

The International Consensus Conference (ICC) for sepsis defines severe sepsis as an infection leading to acute organ dysfunction.[1, 2] Severe sepsis afflicts over 1 million patients each year in Medicare alone, and is substantially more common among older Americans than acute myocardial infarction.[3, 4, 5] Recently, the Agency for Healthcare Research and Quality identified severe sepsis as the single most expensive cause of hospitalization in the United States.[6] The incidence of severe sepsis continues to rise.[4, 5]

Severe sepsis is often mischaracterized as a diagnosis cared for primarily in the intensive care unit (ICU). Yet, studies indicate that only 32% to 50% of patients with severe sepsis require ICU care, leaving the majority on the general care wards.[7, 8] These studies also reveal mortality rates of 26% to 30% among patients with severe sepsis who are not admitted to an ICU compared to 11% to 33% in the ICU.[7, 8]

Although a number of epidemiologic and interventional studies have focused on severe sepsis in the ICU,[3, 9, 10] much less is known about patients cared for on the general medicine wards. Without this information, clinicians cannot make informed choices about important management decisions such as targeted diagnostic testing, empirical antimicrobials, and other therapies. To this end, we sought to further characterize the infectious etiologies and resultant organ system dysfunctions in the subset of patients with severe sepsis admitted to non‐ICU medical services at a tertiary academic medical center.

METHODS

RESULTS

Of 23,288 hospitalizations examined from 2009 through 2010, the ICD‐9based automated screen for severe sepsis was positive for 3,146 (14 %). A random sample of 111 medical records, of which 92 had screened positive for severe sepsis and 19 had screened negative, was reviewed in detail. After review by the hospitalists, 64 of these 111 hospitalizations were judged to have severe sepsis, 61 of the 92 screened positive cases (66%), and 3 of the 19 screened negative cases (16%). The 3 reviewers had a kappa of 0.70, indicating good agreement.

Characteristics of the 64 patients with severe sepsis are shown in Table 2. The mean age was 63 years old (standard deviation [SD]=17.7), and 41% were male. The mean length of stay was 13.7 days (SD=20.8). Thirty‐nine percent (95% CI, 27%‐52%) of patients (25/64) were immunosuppressed. Of patients initially admitted to the general medical ward, 25% (16/64; 95% CI, 15%‐37%) ultimately required ICU care during their admission. The overall in‐hospital mortality rate was 13% (8/64; 95% CI, 6%‐23%). Immunosuppressed patients had a mortality rate of 20% and nonimmunosuppressed patients had a mortality rate of 8%. Only 47% (30/64; 95% CI, 34%‐60%) of the medical records had explicit clinician documentation of severe sepsis.

The most common site of infection was found to be the genitourinary system, occurring in 41% (26/64; 95% CI, 29%‐54%) of patients (Table 3). Pulmonary and intra‐abdominal sites were also common, accounting for 14% (95% CI, 6.6%‐25%) and 13% (95% CI, 5.6%‐23%) of sites, respectively. An infecting organism was identified by culture in 66% (42/64; 95% CI, 53%‐77%) of case patients with specific pathogens listed in Table 4. Among patients with positive culture results, the majority grew Gram‐negative organisms (57%; 95% CI, 41%‐72%). Non‐Clostridium difficile Gram‐positive organisms were also prominent and identified in 48% (95% CI, 32%‐64%) of positive cultures. Candida was less common (12%, 95% CI, 4.0%‐26%). Fourteen cases (22%, 95% CI, 10%‐30%) had 2 or more concomitant infectious pathogens.

All 64 patients had at least 1 organ dysfunction, as required by the ICC definition of severe sepsis. Organ dysfunction in 2 or more organ systems occurred in 77% (95% CI, 64%‐86%) of the cases (49/64). The incidence for each organ system dysfunction is presented in Table 5, as well as its relationship to both mortality and ICU admission. The most common organ system dysfunctions were found to be cardiovascular (hypotension) and renal dysfunction occurring in 66% and 64% of the cases, respectively. In this non‐ICU population, pulmonary dysfunction occurred in 30% of cases, but was frequently associated with transfer to the ICU, as 63% of the patients with pulmonary failure required ICU care. Patients with more organ systems affected were more likely to be transferred to the ICU and to die.

DISCUSSION

Severe sepsis was common among patients admitted to the general medical ward in this tertiary care center. Our patient cohort differed in important ways from previously described typical cases of severe sepsis among ICU populations. Severe sepsis on the general medical wards was more commonly associated with Gram‐negative pathogens in the setting of genitourinary tract infections. This is in contrast to Gram‐positive organisms and respiratory tract infections, which are more common in the ICU.[3, 10] Renal and cardiac dysfunction were commonly observed organ failures, whereas in the ICU, severe sepsis has been reported to more likely involve respiratory failure. These results suggest that hospitalists seeking to provide evidence‐based care to prevent postsepsis morbidity and mortality for their non‐ICU patients need to heighten their index of suspicion when caring for an infected patient and appreciate that many severe sepsis patients may not fit neatly into traditional sepsis treatment algorithms.

Studies characterizing severe sepsis in the ICU setting indicate a predominance of pulmonary infections and respiratory failure with occurrence rates of 74% to 95% and 54% to 61%, respectively.[3, 12, 13] Given that either shock or pulmonary dysfunction is often required for admission to many ICUs, it is perhaps not surprising that these rates are dramatically different on the general medicine ward, with a relative scarcity of pulmonary infections (14%) and respiratory dysfunction (30%). Instead, genitourinary infections were noted in 41% (95% CI, 29%‐54%) of the cases, in contrast to the rates of genitourinary infections in ICU patients with severe sepsis, which have rates of 5.4% to 9.1%.[3, 10] Likely as a result of this, a Gram‐negative predominance is noted in the associated microbiology. Furthermore, our study indicates that C difficile and vancomycin‐resistant Enterococcus (VRE) species appear to represent an emerging cause of severe sepsis on the general medicine wards, as they have not been noted to be causative micro‐organisms in previous studies of sepsis. This is concordant with other studies showing increases in incidence and severity of disease for C difficile as well as VRE.[14, 15]

Previous epidemiologic studies of severe sepsis originating outside the ICU are lacking, but some work has been done. One study on the epidemiology of sepsis both with and without organ dysfunction aggregated all hospitalized patients and included those both admitted to the general medicine wards and directly to the ICU.[7] Similar to our study, this study also found a predominance of Gram‐negative causative organisms, as well as comparable in‐hospital mortality rates (12.8% vs 13%). Additionally, genitourinary infections were noted in 20% of the patients, notably higher than rates reported to have been found in patients with severe sepsis in the ICU, but not the magnitude found in our study, perhaps as a result of the combined ICU‐ward population studied. A similar high prevalence of genitourinary infections was also noted in a recent administrative data‐based study of emergency medical services‐transported patients with severe sepsis, half of whom required intensive care during their hospitalization.[16]

Our study is unique in that it focuses on severe sepsis in patients, commonly cared for by hospitalists, who were admitted to the general medical ward, and uses patient level data to elucidate more characteristics of the defining organ dysfunction. Furthermore, our results suggest that severe sepsis was poorly documented in this setting, indicating a potential impact on billing, coding, case mix index, and hospital mortality statistics that rely on very specific wording, as well as a possible need for increased awareness among hospitalists. Without this awareness, an opportunity may be missed for improved patient care via specific sepsis‐targeted measures,[13, 17, 18] including more aggressive resuscitative measures[19] or intensive physical and occupational therapy interventions aimed at impacting the cognitive and functional debilities[20] that result from severe sepsis. Highlighting this growing need to better assist clinicians assess the severity of septic patients and recognize these complex cases on the general medicine wards, 1 recent study evaluated the fitness of several clinical disease‐severity scoring systems for patients with sepsis in general internal medicine departments.[21] Perhaps with the help of tools such as these, which are being piloted in some hospitals, the care of this growing population can be enhanced.

Our study has a number of limitations that should be kept in mind. First, this is a single center study performed at an academic tertiary care center with a relatively high incidence of immunosuppression, which may influence the spectrum of infecting organisms. Our center also has a relatively large, closed‐model ICU, which often operates at near capacity, potentially affecting the severity of our non‐ICU population. Second, although we screened a large number of patients, as necessitated by our intensive and detailed review of clinical information, our sample size with hospitalist‐validated severe sepsis is relatively small. With this small sample size, less prevalent infections, patient characteristics, and organ dysfunctions may by chance have been under or over‐represented, and one could expect some variance in the occurrence rates of organ system dysfunction and infection rates by sampling error alone. Further larger scale studies are warranted to confirm these data and their generalizability. Third, the data necessary to calculate sequential organ failure assessment or multiple organ dysfunction score were not collected. This may limit the ability to directly compare the organ dysfunction noted in this study with others. Additionally, given the ICC definitions of organ dysfunction, some of the organ dysfunction noted, particularly for neurological dysfunction, was reliant on subjective clinical findings documented in the record. Finally, we relied on the lack of specific terminology to indicate a lack of documentation of sepsis, which does not necessarily indicate a lack of recognition or undertreatment of this condition. However, these limitations are offset by the strengths of this study, including the patient‐level medical record validation of severe sepsis by trained hospitalist physicians, high kappa statistic, and strict application of guideline‐based definitions.

This work has important implications for both clinicians and for future research on severe sepsis. The results suggest that severe sepsis may be quite common outside the ICU, and that patients presenting with this condition who are admitted to general medical wards are not routinely characterized by the profound hypoxemia and refractory shock of iconic cases. Certainly, further study looking at larger numbers of cases is needed to better understand the specifics and nuances of this important topic as well as to further evaluate clinicians' ability to recognize and treat such patients in this setting. Furthermore, future research on the treatment of severe sepsis, including both antimicrobials and disease‐modifying agents (eg, anti‐inflammatories) must continue to include and even focus on this large population of non‐ICU patients with severe sepsis, as the risk/benefit ratios of such potential treatments may vary with severity of illness.

In conclusion, severe sepsis was commonly found in patients admitted on the general medicine wards. The epidemiology of the infections and resultant organ dysfunction appears to differ from that found in the ICU. More studies are needed to provide a deeper understanding of this disease process, as this will enable clinicians to better recognize and treat patients thus afflicted, no matter the setting.

The International Consensus Conference (ICC) for sepsis defines severe sepsis as an infection leading to acute organ dysfunction.[1, 2] Severe sepsis afflicts over 1 million patients each year in Medicare alone, and is substantially more common among older Americans than acute myocardial infarction.[3, 4, 5] Recently, the Agency for Healthcare Research and Quality identified severe sepsis as the single most expensive cause of hospitalization in the United States.[6] The incidence of severe sepsis continues to rise.[4, 5]

Severe sepsis is often mischaracterized as a diagnosis cared for primarily in the intensive care unit (ICU). Yet, studies indicate that only 32% to 50% of patients with severe sepsis require ICU care, leaving the majority on the general care wards.[7, 8] These studies also reveal mortality rates of 26% to 30% among patients with severe sepsis who are not admitted to an ICU compared to 11% to 33% in the ICU.[7, 8]

Although a number of epidemiologic and interventional studies have focused on severe sepsis in the ICU,[3, 9, 10] much less is known about patients cared for on the general medicine wards. Without this information, clinicians cannot make informed choices about important management decisions such as targeted diagnostic testing, empirical antimicrobials, and other therapies. To this end, we sought to further characterize the infectious etiologies and resultant organ system dysfunctions in the subset of patients with severe sepsis admitted to non‐ICU medical services at a tertiary academic medical center.

METHODS

RESULTS

Of 23,288 hospitalizations examined from 2009 through 2010, the ICD‐9based automated screen for severe sepsis was positive for 3,146 (14 %). A random sample of 111 medical records, of which 92 had screened positive for severe sepsis and 19 had screened negative, was reviewed in detail. After review by the hospitalists, 64 of these 111 hospitalizations were judged to have severe sepsis, 61 of the 92 screened positive cases (66%), and 3 of the 19 screened negative cases (16%). The 3 reviewers had a kappa of 0.70, indicating good agreement.

Characteristics of the 64 patients with severe sepsis are shown in Table 2. The mean age was 63 years old (standard deviation [SD]=17.7), and 41% were male. The mean length of stay was 13.7 days (SD=20.8). Thirty‐nine percent (95% CI, 27%‐52%) of patients (25/64) were immunosuppressed. Of patients initially admitted to the general medical ward, 25% (16/64; 95% CI, 15%‐37%) ultimately required ICU care during their admission. The overall in‐hospital mortality rate was 13% (8/64; 95% CI, 6%‐23%). Immunosuppressed patients had a mortality rate of 20% and nonimmunosuppressed patients had a mortality rate of 8%. Only 47% (30/64; 95% CI, 34%‐60%) of the medical records had explicit clinician documentation of severe sepsis.

The most common site of infection was found to be the genitourinary system, occurring in 41% (26/64; 95% CI, 29%‐54%) of patients (Table 3). Pulmonary and intra‐abdominal sites were also common, accounting for 14% (95% CI, 6.6%‐25%) and 13% (95% CI, 5.6%‐23%) of sites, respectively. An infecting organism was identified by culture in 66% (42/64; 95% CI, 53%‐77%) of case patients with specific pathogens listed in Table 4. Among patients with positive culture results, the majority grew Gram‐negative organisms (57%; 95% CI, 41%‐72%). Non‐Clostridium difficile Gram‐positive organisms were also prominent and identified in 48% (95% CI, 32%‐64%) of positive cultures. Candida was less common (12%, 95% CI, 4.0%‐26%). Fourteen cases (22%, 95% CI, 10%‐30%) had 2 or more concomitant infectious pathogens.

All 64 patients had at least 1 organ dysfunction, as required by the ICC definition of severe sepsis. Organ dysfunction in 2 or more organ systems occurred in 77% (95% CI, 64%‐86%) of the cases (49/64). The incidence for each organ system dysfunction is presented in Table 5, as well as its relationship to both mortality and ICU admission. The most common organ system dysfunctions were found to be cardiovascular (hypotension) and renal dysfunction occurring in 66% and 64% of the cases, respectively. In this non‐ICU population, pulmonary dysfunction occurred in 30% of cases, but was frequently associated with transfer to the ICU, as 63% of the patients with pulmonary failure required ICU care. Patients with more organ systems affected were more likely to be transferred to the ICU and to die.

DISCUSSION

Severe sepsis was common among patients admitted to the general medical ward in this tertiary care center. Our patient cohort differed in important ways from previously described typical cases of severe sepsis among ICU populations. Severe sepsis on the general medical wards was more commonly associated with Gram‐negative pathogens in the setting of genitourinary tract infections. This is in contrast to Gram‐positive organisms and respiratory tract infections, which are more common in the ICU.[3, 10] Renal and cardiac dysfunction were commonly observed organ failures, whereas in the ICU, severe sepsis has been reported to more likely involve respiratory failure. These results suggest that hospitalists seeking to provide evidence‐based care to prevent postsepsis morbidity and mortality for their non‐ICU patients need to heighten their index of suspicion when caring for an infected patient and appreciate that many severe sepsis patients may not fit neatly into traditional sepsis treatment algorithms.

Studies characterizing severe sepsis in the ICU setting indicate a predominance of pulmonary infections and respiratory failure with occurrence rates of 74% to 95% and 54% to 61%, respectively.[3, 12, 13] Given that either shock or pulmonary dysfunction is often required for admission to many ICUs, it is perhaps not surprising that these rates are dramatically different on the general medicine ward, with a relative scarcity of pulmonary infections (14%) and respiratory dysfunction (30%). Instead, genitourinary infections were noted in 41% (95% CI, 29%‐54%) of the cases, in contrast to the rates of genitourinary infections in ICU patients with severe sepsis, which have rates of 5.4% to 9.1%.[3, 10] Likely as a result of this, a Gram‐negative predominance is noted in the associated microbiology. Furthermore, our study indicates that C difficile and vancomycin‐resistant Enterococcus (VRE) species appear to represent an emerging cause of severe sepsis on the general medicine wards, as they have not been noted to be causative micro‐organisms in previous studies of sepsis. This is concordant with other studies showing increases in incidence and severity of disease for C difficile as well as VRE.[14, 15]

Previous epidemiologic studies of severe sepsis originating outside the ICU are lacking, but some work has been done. One study on the epidemiology of sepsis both with and without organ dysfunction aggregated all hospitalized patients and included those both admitted to the general medicine wards and directly to the ICU.[7] Similar to our study, this study also found a predominance of Gram‐negative causative organisms, as well as comparable in‐hospital mortality rates (12.8% vs 13%). Additionally, genitourinary infections were noted in 20% of the patients, notably higher than rates reported to have been found in patients with severe sepsis in the ICU, but not the magnitude found in our study, perhaps as a result of the combined ICU‐ward population studied. A similar high prevalence of genitourinary infections was also noted in a recent administrative data‐based study of emergency medical services‐transported patients with severe sepsis, half of whom required intensive care during their hospitalization.[16]

Our study is unique in that it focuses on severe sepsis in patients, commonly cared for by hospitalists, who were admitted to the general medical ward, and uses patient level data to elucidate more characteristics of the defining organ dysfunction. Furthermore, our results suggest that severe sepsis was poorly documented in this setting, indicating a potential impact on billing, coding, case mix index, and hospital mortality statistics that rely on very specific wording, as well as a possible need for increased awareness among hospitalists. Without this awareness, an opportunity may be missed for improved patient care via specific sepsis‐targeted measures,[13, 17, 18] including more aggressive resuscitative measures[19] or intensive physical and occupational therapy interventions aimed at impacting the cognitive and functional debilities[20] that result from severe sepsis. Highlighting this growing need to better assist clinicians assess the severity of septic patients and recognize these complex cases on the general medicine wards, 1 recent study evaluated the fitness of several clinical disease‐severity scoring systems for patients with sepsis in general internal medicine departments.[21] Perhaps with the help of tools such as these, which are being piloted in some hospitals, the care of this growing population can be enhanced.

Our study has a number of limitations that should be kept in mind. First, this is a single center study performed at an academic tertiary care center with a relatively high incidence of immunosuppression, which may influence the spectrum of infecting organisms. Our center also has a relatively large, closed‐model ICU, which often operates at near capacity, potentially affecting the severity of our non‐ICU population. Second, although we screened a large number of patients, as necessitated by our intensive and detailed review of clinical information, our sample size with hospitalist‐validated severe sepsis is relatively small. With this small sample size, less prevalent infections, patient characteristics, and organ dysfunctions may by chance have been under or over‐represented, and one could expect some variance in the occurrence rates of organ system dysfunction and infection rates by sampling error alone. Further larger scale studies are warranted to confirm these data and their generalizability. Third, the data necessary to calculate sequential organ failure assessment or multiple organ dysfunction score were not collected. This may limit the ability to directly compare the organ dysfunction noted in this study with others. Additionally, given the ICC definitions of organ dysfunction, some of the organ dysfunction noted, particularly for neurological dysfunction, was reliant on subjective clinical findings documented in the record. Finally, we relied on the lack of specific terminology to indicate a lack of documentation of sepsis, which does not necessarily indicate a lack of recognition or undertreatment of this condition. However, these limitations are offset by the strengths of this study, including the patient‐level medical record validation of severe sepsis by trained hospitalist physicians, high kappa statistic, and strict application of guideline‐based definitions.

This work has important implications for both clinicians and for future research on severe sepsis. The results suggest that severe sepsis may be quite common outside the ICU, and that patients presenting with this condition who are admitted to general medical wards are not routinely characterized by the profound hypoxemia and refractory shock of iconic cases. Certainly, further study looking at larger numbers of cases is needed to better understand the specifics and nuances of this important topic as well as to further evaluate clinicians' ability to recognize and treat such patients in this setting. Furthermore, future research on the treatment of severe sepsis, including both antimicrobials and disease‐modifying agents (eg, anti‐inflammatories) must continue to include and even focus on this large population of non‐ICU patients with severe sepsis, as the risk/benefit ratios of such potential treatments may vary with severity of illness.

In conclusion, severe sepsis was commonly found in patients admitted on the general medicine wards. The epidemiology of the infections and resultant organ dysfunction appears to differ from that found in the ICU. More studies are needed to provide a deeper understanding of this disease process, as this will enable clinicians to better recognize and treat patients thus afflicted, no matter the setting.