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Geriatric-Centered Interdisciplinary Care Pathway Reduces Delirium in Hospitalized Older Adults With Traumatic Injury
Study 1 Overview (Park et al)
Objective: To examine whether implementation of a geriatric trauma clinical pathway is associated with reduced rates of delirium in older adults with traumatic injury.
Design: Retrospective case-control study of electronic health records.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and did not undergo an operation. A Geriatric Trauma Care Pathway was developed by a multidisciplinary Stanford Quality Pathways team and formally launched on November 1, 2018. The clinical pathway was designed to incorporate geriatric best practices, which included order sets (eg, age-appropriate nonpharmacological interventions and pharmacological dosages), guidelines (eg, Institute for Healthcare Improvement Age-Friendly Health systems 4M framework), automated consultations (comprehensive geriatric assessment), and escalation pathways executed by a multidisciplinary team (eg, pain, bowel, and sleep regulation). The clinical pathway began with admission to the emergency department (ED) (ie, automatic trigger of geriatric trauma care admission order set), daily multidisciplinary team meetings during acute hospitalization, and a transitional care team consultation for postdischarge follow-up or home visit.
Main outcome measures: The primary outcome was delirium as determined by a positive Confusion Assessment Method (CAM) score or a diagnosis of delirium by the clinical team. The secondary outcome was hospital length of stay (LOS). Process measures for pathway compliance (eg, achieving adequate pain control, early mobilization, advance care planning) were assessed. Outcome measures were compared between patients who underwent the Geriatric Trauma Care Pathway intervention (postimplementation group) vs patients who were treated prior to pathway implementation (baseline pre-implementation group).
Main results: Of the 859 eligible patients, 712 were included in the analysis (442 [62.1%] in the baseline pre-implementation group and 270 [37.9%] in the postimplementation group); mean (SD) age was 81.4 (9.1) years, and 394 (55.3%) were women. The injury mechanism was similar between groups, with falls being the most common cause of injury (247 [55.9%] in the baseline group vs 162 [60.0%] in the postimplementation group; P = .43). Injuries as measured by Injury Severity Score (ISS) were minor or moderate in both groups (261 [59.0%] in baseline group vs 168 [62.2%] in postimplementation group; P = .87). The adjusted odds ratio (OR) for delirium in the postimplementation group was lower compared to the baseline pre-implementation group (OR, 0.54; 95% CI, 0.37-0.80; P < .001). Measures of advance care planning in the postimplementation group improved, including more frequent goals-of-care documentation (53.7% in postimplementation group vs 16.7% in baseline group; P < .001) and a shortened time to first goals-of-care discussion upon presenting to the ED (36 hours in postimplementation group vs 50 hours in baseline group; P = .03).
Conclusion: Implementation of a multidisciplinary geriatric trauma clinical pathway for older adults with traumatic injury at a single level I trauma center was associated with reduced rates of delirium.
Study 2 Overview (Bryant et al)
Objective: To determine whether an interdisciplinary care pathway for frail trauma patients can improve in-hospital mortality, complications, and 30-day readmissions.
Design: Retrospective cohort study of frail patients.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and survived more than 24 hours; admitted to and discharged from the trauma unit; and determined to be pre-frail or frail by a geriatrician’s assessment. A Frailty Identification and Care Pathway designed to reduce delirium and complications in frail older trauma patients was developed by a multidisciplinary team and implemented in 2016. The standardized evidence-based interdisciplinary care pathway included utilization of order sets and interventions for delirium prevention, early ambulation, bowel and pain regimens, nutrition and physical therapy consults, medication management, care-goal setting, and geriatric assessments.
Main outcome measures: The main outcomes were delirium as determined by a positive CAM score, major complications as defined by the Trauma Quality Improvement Project, in-hospital mortality, and 30-day hospital readmission. Outcome measures were compared between patients who underwent Frailty Identification and Care Pathway intervention (postintervention group) vs patients who were treated prior to pathway implementation (pre-intervention group).
Main results: A total of 269 frail patients were included in the analysis (125 in pre-intervention group vs 144 in postintervention group). Patient demographic and admission characteristics were similar between the 2 groups: mean age was 83.5 (7.1) years, 60.6% were women, and median ISS was 10 (interquartile range [IQR], 9-14). The injury mechanism was similar between groups, with falls accounting for 92.8% and 86.1% of injuries in the pre-intervention and postintervention groups, respectively (P = .07). In univariate analysis, the Frailty Identification and Care Pathway intervention was associated with a significant reduction in delirium (12.5% vs 21.6%, P = .04) and 30-day hospital readmission (2.7% vs 9.6%, P = .01) compared to patients in the pre-intervention group. However, rates of major complications (28.5% vs 28.0%, P = 0.93) and in-hospital mortality (4.2% vs 7.2%, P = .28) were similar between the pre-intervention and postintervention groups. In multivariate logistic regression models adjusted for patient characteristics (age, sex, race, ISS), patients in the postintervention group had lower delirium (OR, 0.44; 95% CI, 0.22-0.88; P = .02) and 30-day hospital readmission (OR, 0.25; 95% CI, 0.07-0.84; P = .02) rates compared to those in the pre-intervention group.
Conclusion: Implementation of an interdisciplinary care protocol for frail geriatric trauma patients significantly decreased their risks for in-hospital delirium and 30-day hospital readmission.
Commentary
Traumatic injuries in older adults are associated with higher morbidity and mortality compared to younger patients, with falls and motor vehicle accidents accounting for a majority of these injuries. Astoundingly, up to one-third of this vulnerable population presenting to hospitals with an ISS greater than 15 may die during hospitalization.1 As a result, a large number of studies and clinical trials have focused on interventions that are designed to reduce fall risks, and hence reduce adverse consequences of traumatic injuries that may arise after falls.2 However, this emphasis on falls prevention has overshadowed a need to develop effective geriatric-centered clinical interventions that aim to improve outcomes in older adults who present to hospitals with traumatic injuries. Furthermore, frailty—a geriatric syndrome indicative of an increased state of vulnerability and predictive of adverse outcomes such as delirium—is highly prevalent in older patients with traumatic injury.3 Thus, there is an urgent need to develop novel, hospital-based, traumatic injury–targeting strategies that incorporate a thoughtful redesign of the care framework that includes evidence-based interventions for geriatric syndromes such as delirium and frailty.
The study reported by Park et al (Study 1) represents the latest effort to evaluate inpatient management strategies designed to improve outcomes in hospitalized older adults who have sustained traumatic injury. Through the implementation of a novel multidisciplinary Geriatric Trauma Care Pathway that incorporates geriatric best practices, this intervention was found to be associated with a 46% lower risk of in-hospital delirium. Because of the inclusion of all age-eligible patients across all strata of traumatic injuries, rather than preselecting for those at the highest risk for poor clinical outcomes, the benefits of this intervention extend to those with minor or moderate injury severity. Furthermore, the improvement in delirium (ie, the primary outcome) is particularly meaningful given that delirium is one of the most common hospital-associated complications that increase hospital LOS, discharge to an institution, and mortality in older adults. Finally, the study’s observed reduced time to a first goals-of-care discussion and increased frequency of goals-of-care documentation after intervention should not be overlooked. The improvements in these 2 process measures are highly significant given that advanced care planning, an intervention that helps to align patients’ values, goals, and treatments, is completed at substantially lower rates in older adults in the acute hospital setting.4
Similarly, in an earlier published study, Bryant and colleagues (Study 2) also show that a geriatric-focused interdisciplinary trauma care pathway is associated with delirium risk reduction in hospitalized older trauma patients. Much like Study 1, the Frailty Identification and Care Pathway utilized in Study 2 is an evidence-based interdisciplinary care pathway that includes the use of geriatric assessments, order sets, and geriatric best practices. Moreover, its exclusive inclusion of pre-frail and frail older patients (ie, those at higher risk for poor outcomes) with moderate injury severity (median ISS of 10 [IQR, 9-14]) suggests that this type of care pathway benefits hospitalized older trauma patients, who are particularly vulnerable to adverse complications such as delirium. Moreover, the successful utilization of the FRAIL questionnaire, a validated frailty screening tool, by surgical residents in the ED to initiate this care pathway demonstrates the feasibility of its use in expediting frailty screening in older patients in trauma care.
Application for Clinical Practice and System Implementation
Findings from the 2 studies discussed in this review indicate that implementation of interdisciplinary clinical care pathways predicated on evidence-based geriatric principles and best practices is a promising approach to reduce delirium in hospitalized older trauma patients. These studies have helped to lay the groundwork in outlining the roadmaps (eg, processes and infrastructures) needed to create such clinical pathways. These key elements include: (1) integration of a multidisciplinary committee (eg, representation from trauma, emergency, and geriatric medicine, nursing, physical and occupational therapy, pharmacy, social work) in pathway design and implementation; (2) adaption of evidence-based geriatric best practices (eg, the Institute for Healthcare Improvement Age-Friendly Health System 4M framework [medication, mentation, mobility, what matters]) to prioritize interventions and to design a pathway that incorporates these features; (3) incorporation of comprehensive geriatric assessment by interdisciplinary providers; (4) utilization of validated clinical instruments to assess physical and cognitive functions, frailty, delirium, and social determinants of health; (5) modification of electronic health record systems to encompass order sets that incorporate evidence-based, nonpharmacological and pharmacological interventions to manage symptoms (eg, delirium, pain, bowel movement, sleep, immobility, polypharmacy) essential to quality geriatric care; and (6) integration of patient and caregiver preferences via goals-of-care discussions and corresponding documentation and communication of these goals.
Additionally, these 2 studies imparted some strategies that may facilitate the implementation of interdisciplinary clinical care pathways in trauma care. Examples of such facilitators include: (1) collaboration with champions within each specialty to reinforce education and buy-in; (2) creation of automatically triggered order sets upon patient presentation to the ED that unites distinct features of clinical pathways; (3) adaption and reorganization of existing hospital infrastructures and resources to meet the needs of clinical pathways implementation (eg, utilizing information technology resources to develop electronic health record order sets; using quality department to develop clinical pathway guidelines and electronic outcome dashboards); and (4) development of individualized patient and caregiver education materials based on care needs (eg, principles of delirium prevention and preservation of mobility during hospitalization) to prepare and engage these stakeholders in patient care and recovery.
Practice Points
- A geriatric interdisciplinary care model can be effectively applied to the management of acute trauma in older patients.
- Interdisciplinary clinical pathways should incorporate geriatric best practices and guidelines and age-appropriate order sets to prioritize and integrate care.
—Fred Ko, MD, MS
1. Hashmi A, Ibrahim-Zada I, Rhee P, et al. Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2014;76(3):894-901. doi:10.1097/TA.0b013e3182ab0763
2. Hopewell S, Adedire O, Copsey BJ, et al. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2018;7(7):CD012221. doi:10.1002/14651858.CD012221.pub2
3. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149(8):766-772. doi:10.1001/jamasurg.2014.296
4. Hopkins SA, Bentley A, Phillips V, Barclay S. Advance care plans and hospitalized frail older adults: a systematic review. BMJ Support Palliat Care. 2020;10(2):164-174. doi:10.1136/bmjspcare-2019-002093
Study 1 Overview (Park et al)
Objective: To examine whether implementation of a geriatric trauma clinical pathway is associated with reduced rates of delirium in older adults with traumatic injury.
Design: Retrospective case-control study of electronic health records.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and did not undergo an operation. A Geriatric Trauma Care Pathway was developed by a multidisciplinary Stanford Quality Pathways team and formally launched on November 1, 2018. The clinical pathway was designed to incorporate geriatric best practices, which included order sets (eg, age-appropriate nonpharmacological interventions and pharmacological dosages), guidelines (eg, Institute for Healthcare Improvement Age-Friendly Health systems 4M framework), automated consultations (comprehensive geriatric assessment), and escalation pathways executed by a multidisciplinary team (eg, pain, bowel, and sleep regulation). The clinical pathway began with admission to the emergency department (ED) (ie, automatic trigger of geriatric trauma care admission order set), daily multidisciplinary team meetings during acute hospitalization, and a transitional care team consultation for postdischarge follow-up or home visit.
Main outcome measures: The primary outcome was delirium as determined by a positive Confusion Assessment Method (CAM) score or a diagnosis of delirium by the clinical team. The secondary outcome was hospital length of stay (LOS). Process measures for pathway compliance (eg, achieving adequate pain control, early mobilization, advance care planning) were assessed. Outcome measures were compared between patients who underwent the Geriatric Trauma Care Pathway intervention (postimplementation group) vs patients who were treated prior to pathway implementation (baseline pre-implementation group).
Main results: Of the 859 eligible patients, 712 were included in the analysis (442 [62.1%] in the baseline pre-implementation group and 270 [37.9%] in the postimplementation group); mean (SD) age was 81.4 (9.1) years, and 394 (55.3%) were women. The injury mechanism was similar between groups, with falls being the most common cause of injury (247 [55.9%] in the baseline group vs 162 [60.0%] in the postimplementation group; P = .43). Injuries as measured by Injury Severity Score (ISS) were minor or moderate in both groups (261 [59.0%] in baseline group vs 168 [62.2%] in postimplementation group; P = .87). The adjusted odds ratio (OR) for delirium in the postimplementation group was lower compared to the baseline pre-implementation group (OR, 0.54; 95% CI, 0.37-0.80; P < .001). Measures of advance care planning in the postimplementation group improved, including more frequent goals-of-care documentation (53.7% in postimplementation group vs 16.7% in baseline group; P < .001) and a shortened time to first goals-of-care discussion upon presenting to the ED (36 hours in postimplementation group vs 50 hours in baseline group; P = .03).
Conclusion: Implementation of a multidisciplinary geriatric trauma clinical pathway for older adults with traumatic injury at a single level I trauma center was associated with reduced rates of delirium.
Study 2 Overview (Bryant et al)
Objective: To determine whether an interdisciplinary care pathway for frail trauma patients can improve in-hospital mortality, complications, and 30-day readmissions.
Design: Retrospective cohort study of frail patients.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and survived more than 24 hours; admitted to and discharged from the trauma unit; and determined to be pre-frail or frail by a geriatrician’s assessment. A Frailty Identification and Care Pathway designed to reduce delirium and complications in frail older trauma patients was developed by a multidisciplinary team and implemented in 2016. The standardized evidence-based interdisciplinary care pathway included utilization of order sets and interventions for delirium prevention, early ambulation, bowel and pain regimens, nutrition and physical therapy consults, medication management, care-goal setting, and geriatric assessments.
Main outcome measures: The main outcomes were delirium as determined by a positive CAM score, major complications as defined by the Trauma Quality Improvement Project, in-hospital mortality, and 30-day hospital readmission. Outcome measures were compared between patients who underwent Frailty Identification and Care Pathway intervention (postintervention group) vs patients who were treated prior to pathway implementation (pre-intervention group).
Main results: A total of 269 frail patients were included in the analysis (125 in pre-intervention group vs 144 in postintervention group). Patient demographic and admission characteristics were similar between the 2 groups: mean age was 83.5 (7.1) years, 60.6% were women, and median ISS was 10 (interquartile range [IQR], 9-14). The injury mechanism was similar between groups, with falls accounting for 92.8% and 86.1% of injuries in the pre-intervention and postintervention groups, respectively (P = .07). In univariate analysis, the Frailty Identification and Care Pathway intervention was associated with a significant reduction in delirium (12.5% vs 21.6%, P = .04) and 30-day hospital readmission (2.7% vs 9.6%, P = .01) compared to patients in the pre-intervention group. However, rates of major complications (28.5% vs 28.0%, P = 0.93) and in-hospital mortality (4.2% vs 7.2%, P = .28) were similar between the pre-intervention and postintervention groups. In multivariate logistic regression models adjusted for patient characteristics (age, sex, race, ISS), patients in the postintervention group had lower delirium (OR, 0.44; 95% CI, 0.22-0.88; P = .02) and 30-day hospital readmission (OR, 0.25; 95% CI, 0.07-0.84; P = .02) rates compared to those in the pre-intervention group.
Conclusion: Implementation of an interdisciplinary care protocol for frail geriatric trauma patients significantly decreased their risks for in-hospital delirium and 30-day hospital readmission.
Commentary
Traumatic injuries in older adults are associated with higher morbidity and mortality compared to younger patients, with falls and motor vehicle accidents accounting for a majority of these injuries. Astoundingly, up to one-third of this vulnerable population presenting to hospitals with an ISS greater than 15 may die during hospitalization.1 As a result, a large number of studies and clinical trials have focused on interventions that are designed to reduce fall risks, and hence reduce adverse consequences of traumatic injuries that may arise after falls.2 However, this emphasis on falls prevention has overshadowed a need to develop effective geriatric-centered clinical interventions that aim to improve outcomes in older adults who present to hospitals with traumatic injuries. Furthermore, frailty—a geriatric syndrome indicative of an increased state of vulnerability and predictive of adverse outcomes such as delirium—is highly prevalent in older patients with traumatic injury.3 Thus, there is an urgent need to develop novel, hospital-based, traumatic injury–targeting strategies that incorporate a thoughtful redesign of the care framework that includes evidence-based interventions for geriatric syndromes such as delirium and frailty.
The study reported by Park et al (Study 1) represents the latest effort to evaluate inpatient management strategies designed to improve outcomes in hospitalized older adults who have sustained traumatic injury. Through the implementation of a novel multidisciplinary Geriatric Trauma Care Pathway that incorporates geriatric best practices, this intervention was found to be associated with a 46% lower risk of in-hospital delirium. Because of the inclusion of all age-eligible patients across all strata of traumatic injuries, rather than preselecting for those at the highest risk for poor clinical outcomes, the benefits of this intervention extend to those with minor or moderate injury severity. Furthermore, the improvement in delirium (ie, the primary outcome) is particularly meaningful given that delirium is one of the most common hospital-associated complications that increase hospital LOS, discharge to an institution, and mortality in older adults. Finally, the study’s observed reduced time to a first goals-of-care discussion and increased frequency of goals-of-care documentation after intervention should not be overlooked. The improvements in these 2 process measures are highly significant given that advanced care planning, an intervention that helps to align patients’ values, goals, and treatments, is completed at substantially lower rates in older adults in the acute hospital setting.4
Similarly, in an earlier published study, Bryant and colleagues (Study 2) also show that a geriatric-focused interdisciplinary trauma care pathway is associated with delirium risk reduction in hospitalized older trauma patients. Much like Study 1, the Frailty Identification and Care Pathway utilized in Study 2 is an evidence-based interdisciplinary care pathway that includes the use of geriatric assessments, order sets, and geriatric best practices. Moreover, its exclusive inclusion of pre-frail and frail older patients (ie, those at higher risk for poor outcomes) with moderate injury severity (median ISS of 10 [IQR, 9-14]) suggests that this type of care pathway benefits hospitalized older trauma patients, who are particularly vulnerable to adverse complications such as delirium. Moreover, the successful utilization of the FRAIL questionnaire, a validated frailty screening tool, by surgical residents in the ED to initiate this care pathway demonstrates the feasibility of its use in expediting frailty screening in older patients in trauma care.
Application for Clinical Practice and System Implementation
Findings from the 2 studies discussed in this review indicate that implementation of interdisciplinary clinical care pathways predicated on evidence-based geriatric principles and best practices is a promising approach to reduce delirium in hospitalized older trauma patients. These studies have helped to lay the groundwork in outlining the roadmaps (eg, processes and infrastructures) needed to create such clinical pathways. These key elements include: (1) integration of a multidisciplinary committee (eg, representation from trauma, emergency, and geriatric medicine, nursing, physical and occupational therapy, pharmacy, social work) in pathway design and implementation; (2) adaption of evidence-based geriatric best practices (eg, the Institute for Healthcare Improvement Age-Friendly Health System 4M framework [medication, mentation, mobility, what matters]) to prioritize interventions and to design a pathway that incorporates these features; (3) incorporation of comprehensive geriatric assessment by interdisciplinary providers; (4) utilization of validated clinical instruments to assess physical and cognitive functions, frailty, delirium, and social determinants of health; (5) modification of electronic health record systems to encompass order sets that incorporate evidence-based, nonpharmacological and pharmacological interventions to manage symptoms (eg, delirium, pain, bowel movement, sleep, immobility, polypharmacy) essential to quality geriatric care; and (6) integration of patient and caregiver preferences via goals-of-care discussions and corresponding documentation and communication of these goals.
Additionally, these 2 studies imparted some strategies that may facilitate the implementation of interdisciplinary clinical care pathways in trauma care. Examples of such facilitators include: (1) collaboration with champions within each specialty to reinforce education and buy-in; (2) creation of automatically triggered order sets upon patient presentation to the ED that unites distinct features of clinical pathways; (3) adaption and reorganization of existing hospital infrastructures and resources to meet the needs of clinical pathways implementation (eg, utilizing information technology resources to develop electronic health record order sets; using quality department to develop clinical pathway guidelines and electronic outcome dashboards); and (4) development of individualized patient and caregiver education materials based on care needs (eg, principles of delirium prevention and preservation of mobility during hospitalization) to prepare and engage these stakeholders in patient care and recovery.
Practice Points
- A geriatric interdisciplinary care model can be effectively applied to the management of acute trauma in older patients.
- Interdisciplinary clinical pathways should incorporate geriatric best practices and guidelines and age-appropriate order sets to prioritize and integrate care.
—Fred Ko, MD, MS
Study 1 Overview (Park et al)
Objective: To examine whether implementation of a geriatric trauma clinical pathway is associated with reduced rates of delirium in older adults with traumatic injury.
Design: Retrospective case-control study of electronic health records.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and did not undergo an operation. A Geriatric Trauma Care Pathway was developed by a multidisciplinary Stanford Quality Pathways team and formally launched on November 1, 2018. The clinical pathway was designed to incorporate geriatric best practices, which included order sets (eg, age-appropriate nonpharmacological interventions and pharmacological dosages), guidelines (eg, Institute for Healthcare Improvement Age-Friendly Health systems 4M framework), automated consultations (comprehensive geriatric assessment), and escalation pathways executed by a multidisciplinary team (eg, pain, bowel, and sleep regulation). The clinical pathway began with admission to the emergency department (ED) (ie, automatic trigger of geriatric trauma care admission order set), daily multidisciplinary team meetings during acute hospitalization, and a transitional care team consultation for postdischarge follow-up or home visit.
Main outcome measures: The primary outcome was delirium as determined by a positive Confusion Assessment Method (CAM) score or a diagnosis of delirium by the clinical team. The secondary outcome was hospital length of stay (LOS). Process measures for pathway compliance (eg, achieving adequate pain control, early mobilization, advance care planning) were assessed. Outcome measures were compared between patients who underwent the Geriatric Trauma Care Pathway intervention (postimplementation group) vs patients who were treated prior to pathway implementation (baseline pre-implementation group).
Main results: Of the 859 eligible patients, 712 were included in the analysis (442 [62.1%] in the baseline pre-implementation group and 270 [37.9%] in the postimplementation group); mean (SD) age was 81.4 (9.1) years, and 394 (55.3%) were women. The injury mechanism was similar between groups, with falls being the most common cause of injury (247 [55.9%] in the baseline group vs 162 [60.0%] in the postimplementation group; P = .43). Injuries as measured by Injury Severity Score (ISS) were minor or moderate in both groups (261 [59.0%] in baseline group vs 168 [62.2%] in postimplementation group; P = .87). The adjusted odds ratio (OR) for delirium in the postimplementation group was lower compared to the baseline pre-implementation group (OR, 0.54; 95% CI, 0.37-0.80; P < .001). Measures of advance care planning in the postimplementation group improved, including more frequent goals-of-care documentation (53.7% in postimplementation group vs 16.7% in baseline group; P < .001) and a shortened time to first goals-of-care discussion upon presenting to the ED (36 hours in postimplementation group vs 50 hours in baseline group; P = .03).
Conclusion: Implementation of a multidisciplinary geriatric trauma clinical pathway for older adults with traumatic injury at a single level I trauma center was associated with reduced rates of delirium.
Study 2 Overview (Bryant et al)
Objective: To determine whether an interdisciplinary care pathway for frail trauma patients can improve in-hospital mortality, complications, and 30-day readmissions.
Design: Retrospective cohort study of frail patients.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and survived more than 24 hours; admitted to and discharged from the trauma unit; and determined to be pre-frail or frail by a geriatrician’s assessment. A Frailty Identification and Care Pathway designed to reduce delirium and complications in frail older trauma patients was developed by a multidisciplinary team and implemented in 2016. The standardized evidence-based interdisciplinary care pathway included utilization of order sets and interventions for delirium prevention, early ambulation, bowel and pain regimens, nutrition and physical therapy consults, medication management, care-goal setting, and geriatric assessments.
Main outcome measures: The main outcomes were delirium as determined by a positive CAM score, major complications as defined by the Trauma Quality Improvement Project, in-hospital mortality, and 30-day hospital readmission. Outcome measures were compared between patients who underwent Frailty Identification and Care Pathway intervention (postintervention group) vs patients who were treated prior to pathway implementation (pre-intervention group).
Main results: A total of 269 frail patients were included in the analysis (125 in pre-intervention group vs 144 in postintervention group). Patient demographic and admission characteristics were similar between the 2 groups: mean age was 83.5 (7.1) years, 60.6% were women, and median ISS was 10 (interquartile range [IQR], 9-14). The injury mechanism was similar between groups, with falls accounting for 92.8% and 86.1% of injuries in the pre-intervention and postintervention groups, respectively (P = .07). In univariate analysis, the Frailty Identification and Care Pathway intervention was associated with a significant reduction in delirium (12.5% vs 21.6%, P = .04) and 30-day hospital readmission (2.7% vs 9.6%, P = .01) compared to patients in the pre-intervention group. However, rates of major complications (28.5% vs 28.0%, P = 0.93) and in-hospital mortality (4.2% vs 7.2%, P = .28) were similar between the pre-intervention and postintervention groups. In multivariate logistic regression models adjusted for patient characteristics (age, sex, race, ISS), patients in the postintervention group had lower delirium (OR, 0.44; 95% CI, 0.22-0.88; P = .02) and 30-day hospital readmission (OR, 0.25; 95% CI, 0.07-0.84; P = .02) rates compared to those in the pre-intervention group.
Conclusion: Implementation of an interdisciplinary care protocol for frail geriatric trauma patients significantly decreased their risks for in-hospital delirium and 30-day hospital readmission.
Commentary
Traumatic injuries in older adults are associated with higher morbidity and mortality compared to younger patients, with falls and motor vehicle accidents accounting for a majority of these injuries. Astoundingly, up to one-third of this vulnerable population presenting to hospitals with an ISS greater than 15 may die during hospitalization.1 As a result, a large number of studies and clinical trials have focused on interventions that are designed to reduce fall risks, and hence reduce adverse consequences of traumatic injuries that may arise after falls.2 However, this emphasis on falls prevention has overshadowed a need to develop effective geriatric-centered clinical interventions that aim to improve outcomes in older adults who present to hospitals with traumatic injuries. Furthermore, frailty—a geriatric syndrome indicative of an increased state of vulnerability and predictive of adverse outcomes such as delirium—is highly prevalent in older patients with traumatic injury.3 Thus, there is an urgent need to develop novel, hospital-based, traumatic injury–targeting strategies that incorporate a thoughtful redesign of the care framework that includes evidence-based interventions for geriatric syndromes such as delirium and frailty.
The study reported by Park et al (Study 1) represents the latest effort to evaluate inpatient management strategies designed to improve outcomes in hospitalized older adults who have sustained traumatic injury. Through the implementation of a novel multidisciplinary Geriatric Trauma Care Pathway that incorporates geriatric best practices, this intervention was found to be associated with a 46% lower risk of in-hospital delirium. Because of the inclusion of all age-eligible patients across all strata of traumatic injuries, rather than preselecting for those at the highest risk for poor clinical outcomes, the benefits of this intervention extend to those with minor or moderate injury severity. Furthermore, the improvement in delirium (ie, the primary outcome) is particularly meaningful given that delirium is one of the most common hospital-associated complications that increase hospital LOS, discharge to an institution, and mortality in older adults. Finally, the study’s observed reduced time to a first goals-of-care discussion and increased frequency of goals-of-care documentation after intervention should not be overlooked. The improvements in these 2 process measures are highly significant given that advanced care planning, an intervention that helps to align patients’ values, goals, and treatments, is completed at substantially lower rates in older adults in the acute hospital setting.4
Similarly, in an earlier published study, Bryant and colleagues (Study 2) also show that a geriatric-focused interdisciplinary trauma care pathway is associated with delirium risk reduction in hospitalized older trauma patients. Much like Study 1, the Frailty Identification and Care Pathway utilized in Study 2 is an evidence-based interdisciplinary care pathway that includes the use of geriatric assessments, order sets, and geriatric best practices. Moreover, its exclusive inclusion of pre-frail and frail older patients (ie, those at higher risk for poor outcomes) with moderate injury severity (median ISS of 10 [IQR, 9-14]) suggests that this type of care pathway benefits hospitalized older trauma patients, who are particularly vulnerable to adverse complications such as delirium. Moreover, the successful utilization of the FRAIL questionnaire, a validated frailty screening tool, by surgical residents in the ED to initiate this care pathway demonstrates the feasibility of its use in expediting frailty screening in older patients in trauma care.
Application for Clinical Practice and System Implementation
Findings from the 2 studies discussed in this review indicate that implementation of interdisciplinary clinical care pathways predicated on evidence-based geriatric principles and best practices is a promising approach to reduce delirium in hospitalized older trauma patients. These studies have helped to lay the groundwork in outlining the roadmaps (eg, processes and infrastructures) needed to create such clinical pathways. These key elements include: (1) integration of a multidisciplinary committee (eg, representation from trauma, emergency, and geriatric medicine, nursing, physical and occupational therapy, pharmacy, social work) in pathway design and implementation; (2) adaption of evidence-based geriatric best practices (eg, the Institute for Healthcare Improvement Age-Friendly Health System 4M framework [medication, mentation, mobility, what matters]) to prioritize interventions and to design a pathway that incorporates these features; (3) incorporation of comprehensive geriatric assessment by interdisciplinary providers; (4) utilization of validated clinical instruments to assess physical and cognitive functions, frailty, delirium, and social determinants of health; (5) modification of electronic health record systems to encompass order sets that incorporate evidence-based, nonpharmacological and pharmacological interventions to manage symptoms (eg, delirium, pain, bowel movement, sleep, immobility, polypharmacy) essential to quality geriatric care; and (6) integration of patient and caregiver preferences via goals-of-care discussions and corresponding documentation and communication of these goals.
Additionally, these 2 studies imparted some strategies that may facilitate the implementation of interdisciplinary clinical care pathways in trauma care. Examples of such facilitators include: (1) collaboration with champions within each specialty to reinforce education and buy-in; (2) creation of automatically triggered order sets upon patient presentation to the ED that unites distinct features of clinical pathways; (3) adaption and reorganization of existing hospital infrastructures and resources to meet the needs of clinical pathways implementation (eg, utilizing information technology resources to develop electronic health record order sets; using quality department to develop clinical pathway guidelines and electronic outcome dashboards); and (4) development of individualized patient and caregiver education materials based on care needs (eg, principles of delirium prevention and preservation of mobility during hospitalization) to prepare and engage these stakeholders in patient care and recovery.
Practice Points
- A geriatric interdisciplinary care model can be effectively applied to the management of acute trauma in older patients.
- Interdisciplinary clinical pathways should incorporate geriatric best practices and guidelines and age-appropriate order sets to prioritize and integrate care.
—Fred Ko, MD, MS
1. Hashmi A, Ibrahim-Zada I, Rhee P, et al. Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2014;76(3):894-901. doi:10.1097/TA.0b013e3182ab0763
2. Hopewell S, Adedire O, Copsey BJ, et al. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2018;7(7):CD012221. doi:10.1002/14651858.CD012221.pub2
3. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149(8):766-772. doi:10.1001/jamasurg.2014.296
4. Hopkins SA, Bentley A, Phillips V, Barclay S. Advance care plans and hospitalized frail older adults: a systematic review. BMJ Support Palliat Care. 2020;10(2):164-174. doi:10.1136/bmjspcare-2019-002093
1. Hashmi A, Ibrahim-Zada I, Rhee P, et al. Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2014;76(3):894-901. doi:10.1097/TA.0b013e3182ab0763
2. Hopewell S, Adedire O, Copsey BJ, et al. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2018;7(7):CD012221. doi:10.1002/14651858.CD012221.pub2
3. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149(8):766-772. doi:10.1001/jamasurg.2014.296
4. Hopkins SA, Bentley A, Phillips V, Barclay S. Advance care plans and hospitalized frail older adults: a systematic review. BMJ Support Palliat Care. 2020;10(2):164-174. doi:10.1136/bmjspcare-2019-002093
Preoperative Code Status Discussion in Older Adults: Are We Doing Enough?
Study Overview
Objective. The objective of this study was to evaluate orders and documentation describing perioperative management of code status in adults.
Design. A retrospective case series of all adult inpatients admitted to hospitals at 1 academic health system in the US.
Setting and participants. This retrospective case series was conducted at 5 hospitals within the University of Pennsylvania Health System. Cases included all adult inpatients admitted to hospitals between March 2017 and September 2018 who had a Do-Not-Resuscitate (DNR) order placed in their medical record during admission and subsequently underwent a surgical procedure that required anesthesia care.
Main outcome measures. Medical records of included cases were manually reviewed by the authors to verify whether a DNR order was in place at the time surgical intervention was discussed with a patient. Clinical notes and DNR orders of eligible cases were reviewed to identify documentation and outcome of goals of care discussions that were conducted within 48 hours prior to the surgical procedure. Collected data included patient demographics (age, sex, race); case characteristics (American Society of Anesthesiologists [ASA] physical status score, anesthesia type [general vs others such as regional], emergency status [emergent vs elective surgery], procedures by service [surgical including hip fracture repair, gastrostomy or jejunostomy, or exploratory laparotomy vs medical including endoscopy, bronchoscopy, or transesophageal echocardiogram]); and hospital policy for perioperative management of DNR orders (written policy encouraging discussion vs written policy plus additional initiatives, including procedure-specific DNR form). The primary outcome was the presence of a preoperative order or note documenting code status discussion or change. Data were analyzed using χ2 and Fisher exact tests and the threshold for statistical significance was P < .05.
Main results. Of the 27 665 inpatient procedures identified across 5 hospitals, 444 (1.6%) cases met the inclusion criteria. Patients from these cases aged 75 (SD 13) years (95% CI, 72-77 years); 247 (56%, 95% CI, 55%-57%) were women; and 300 (68%, 95% CI, 65%-71%) were White. A total of 426 patients (96%, 95% CI, 90%-100%) had an ASA physical status score of 3 or higher and 237 (53%, 95% CI, 51%-56%) received general anesthesia. The most common procedures performed were endoscopy (148 [33%]), hip fracture repair (43 [10%]), and gastrostomy or jejunostomy (28 [6%]). Reevaluation of code status was documented in 126 cases (28%, 95% CI, 25%-31%); code status orders were changed in 20 of 126 cases (16%, 95% CI, 7%-24%); and a note was filed without a corresponding order for 106 of 126 cases (84%, 95% CI, 75%-95%). In the majority of cases (109 of 126 [87%], 95% CI, 78%-95%) in which documented discussion occurred, DNR orders were suspended. Of 126 cases in which a discussion was documented, participants of these discussions included surgeons 10% of the time (13 cases, 95% CI, 8%-13%), members of the anesthesia team 51% of the time (64 cases, 95% CI, 49%-53%), and medicine or palliative care clinicians 39% of the time (49 cases, 95% CI, 37%-41%).
The rate of documented preoperative code status discussion was higher in patients with higher ASA physical status score (35% in patients with an ASA physical status score ≥ 4 [55 of 155] vs 25% in those with an ASA physical status score ≤ 3 [71 of 289]; P = .02). The rates of documented preoperative code status discussion were similar by anesthesia type (29% for general anesthesia [69 of 237 cases] vs 28% [57 of 207 cases] for other modalities; P = .70). The hospitals involved in this study all had a written policy encouraging rediscussion of code status before surgery. However, only 1 hospital reported added measures (eg, provision of a procedure-specific DNR form) to increase documentation of preoperative code status discussions. In this specific hospital, documentation of preoperative code status discussions was higher compared to other hospitals (67% [37 of 55 cases] vs 23% [89 of 389 cases]; P < .01).
Conclusion. In a retrospective case series conducted at 5 hospitals within 1 academic health system in the US, fewer than 1 in 5 patients with preexisting DNR orders had a documented discussion of code status prior to undergoing surgery. Additional strategies including the development of institutional protocols that facilitate perioperative management of advance directives, identification of local champions, and patient education, should be explored as means to improve preoperative code status reevaulation per guideline recommendations.
Commentary
It is not unusual that patients with a DNR order may require and undergo surgical interventions to treat reversible conditions, prevent progression of underlying disease, or mitigate distressing symptoms such as pain. For instance, intubation, mechanical ventilation, and administration of vasoactive drugs are resuscitative measures that may be needed to safely anesthetize and sedate a patient. As such, the American College of Surgeons1 has provided a statement on advance directives by patients with an existing DNR order to guide management. Specifically, the statement indicates that the best approach for these patients is a policy of “required reconsideration” of the existing DNR order. Required reconsideration means that “the patient or designated surrogate and the physicians who will be responsible for the patient’s care should, when possible, discuss the new intraoperative and perioperative risks associated with the surgical procedure, the patient’s treatment goals, and an approach for potentially life-threatening problems consistent with the patient’s values and preferences.” Moreover, the required reconsideration discussion needs to occur as early as it is practical once a decision is made to have surgery because the discussion “may result in the patient agreeing to suspend the DNR order during surgery and the perioperative period, retaining the original DNR order, or modifying the DNR order.” Given that surgical patients with DNR orders have significant comorbidities, many sustain postoperative complications, and nearly 1 in 4 die within 30 days of surgery, preoperative advance care planning (ACP) and code status discussions are particularly essential to delivering high quality surgical care.2
In the current study, Hadler et al3 conducted a retrospective analysis to evaluate orders and documentation describing perioperative management of code status in patients with existing DNR order at an academic health system in the US. The authors reported that fewer than 20% of patients with existing DNR orders had a documented discussion of code status prior to undergoing surgery. These findings add to the notion that compliance with such guidance on required reconsideration discussion is suboptimal in perioperative care in the US.4,5 A recently published study focused on patients aged more than 60 years undergoing high-risk oncologic or vascular surgeries similarly showed that the frequency of ACP discussions or advance directive documentations among older patients was low.6 This growing body of evidence is highly clinically relevant in that preoperative discussion on code status is highly relevant to the care of older adults, a population group that accounts for the majority of surgeries and is most vulnerable to poor surgical outcomes. Additionally, it highlights a disconnect between the shared recognition by surgeons and patients that ACP discussion is important in perioperative care and its low implementation rates.
Unsurprisingly, Hadler et al3 reported that added measures such as the provision of a procedure-specific DNR form led to an increase in the documentation of preoperative code status discussions in 1 of the hospitals studied. The authors suggested that strategies such as the development of institutional protocols aimed to facilitate perioperative advance directive discussions, identify local champions, and educate patients may be ways to improve preoperative code status reevaulation. The idea that institutional value and culture are key factors impacting surgeon behavior and may influence the practice of ACP discussion is not new. Thus, creative and adaptable strategies, resources, and trainings that are required by medical institutions and hospitals to support preoperative ACP discussions with patients undergoing surgeries need to be identified, validated, and implemented to optimize perioperative care in vulnerable patients.
Applications for Clinical Practice
The findings from the current study indicate that less than 20% of patients with preexisting DNR orders have a documented discussion of code status prior to undergoing surgery. Physicians and health care institutions need to identify barriers to, and implement strategies that, facilitate and optimize preoperative ACP discussions in order to provide patient-centered care in vulnerable surgical patients.
Financial disclosures: None.
1. American College of Surgeons Board of Regents. Statement on Advance Directives by Patients: “Do Not Resuscitate” in the Operating Room. American College of Surgeons. January 3, 2014. Accessed November 6, 2021. https://www.facs.org/about-acs/statements/19-advance-directives
2. Kazaure H, Roman S, Sosa JA. High mortality in surgical patients with do-not-resuscitate orders: analysis of 8256 patients. Arch Surg. 2011;146(8):922-928. doi:10.1001/archsurg.2011.69
3. Hadler RA, Fatuzzo M, Sahota G, Neuman MD. Perioperative Management of Do-Not-Resuscitate Orders at a Large Academic Health System. JAMA Surg. 2021;e214135. doi:10.1001/jamasurg.2021.4135
4. Coopmans VC, Gries CA. CRNA awareness and experience with perioperative DNR orders. AANA J. 2000;68(3):247-256.
5. Urman RD, Lilley EJ, Changala M, Lindvall C, Hepner DL, Bader AM. A Pilot Study to Evaluate Compliance with Guidelines for Preprocedural Reconsideration of Code Status Limitations. J Palliat Med. 2018;21(8):1152-1156. doi:10.1089/jpm.2017.0601
6. Kalbfell E, Kata A, Buffington AS, et al. Frequency of Preoperative Advance Care Planning for Older Adults Undergoing High-risk Surgery: A Secondary Analysis of a Randomized Clinical Trial. JAMA Surg. 2021;156(7):e211521. doi:10.1001/jamasurg.2021.1521
Study Overview
Objective. The objective of this study was to evaluate orders and documentation describing perioperative management of code status in adults.
Design. A retrospective case series of all adult inpatients admitted to hospitals at 1 academic health system in the US.
Setting and participants. This retrospective case series was conducted at 5 hospitals within the University of Pennsylvania Health System. Cases included all adult inpatients admitted to hospitals between March 2017 and September 2018 who had a Do-Not-Resuscitate (DNR) order placed in their medical record during admission and subsequently underwent a surgical procedure that required anesthesia care.
Main outcome measures. Medical records of included cases were manually reviewed by the authors to verify whether a DNR order was in place at the time surgical intervention was discussed with a patient. Clinical notes and DNR orders of eligible cases were reviewed to identify documentation and outcome of goals of care discussions that were conducted within 48 hours prior to the surgical procedure. Collected data included patient demographics (age, sex, race); case characteristics (American Society of Anesthesiologists [ASA] physical status score, anesthesia type [general vs others such as regional], emergency status [emergent vs elective surgery], procedures by service [surgical including hip fracture repair, gastrostomy or jejunostomy, or exploratory laparotomy vs medical including endoscopy, bronchoscopy, or transesophageal echocardiogram]); and hospital policy for perioperative management of DNR orders (written policy encouraging discussion vs written policy plus additional initiatives, including procedure-specific DNR form). The primary outcome was the presence of a preoperative order or note documenting code status discussion or change. Data were analyzed using χ2 and Fisher exact tests and the threshold for statistical significance was P < .05.
Main results. Of the 27 665 inpatient procedures identified across 5 hospitals, 444 (1.6%) cases met the inclusion criteria. Patients from these cases aged 75 (SD 13) years (95% CI, 72-77 years); 247 (56%, 95% CI, 55%-57%) were women; and 300 (68%, 95% CI, 65%-71%) were White. A total of 426 patients (96%, 95% CI, 90%-100%) had an ASA physical status score of 3 or higher and 237 (53%, 95% CI, 51%-56%) received general anesthesia. The most common procedures performed were endoscopy (148 [33%]), hip fracture repair (43 [10%]), and gastrostomy or jejunostomy (28 [6%]). Reevaluation of code status was documented in 126 cases (28%, 95% CI, 25%-31%); code status orders were changed in 20 of 126 cases (16%, 95% CI, 7%-24%); and a note was filed without a corresponding order for 106 of 126 cases (84%, 95% CI, 75%-95%). In the majority of cases (109 of 126 [87%], 95% CI, 78%-95%) in which documented discussion occurred, DNR orders were suspended. Of 126 cases in which a discussion was documented, participants of these discussions included surgeons 10% of the time (13 cases, 95% CI, 8%-13%), members of the anesthesia team 51% of the time (64 cases, 95% CI, 49%-53%), and medicine or palliative care clinicians 39% of the time (49 cases, 95% CI, 37%-41%).
The rate of documented preoperative code status discussion was higher in patients with higher ASA physical status score (35% in patients with an ASA physical status score ≥ 4 [55 of 155] vs 25% in those with an ASA physical status score ≤ 3 [71 of 289]; P = .02). The rates of documented preoperative code status discussion were similar by anesthesia type (29% for general anesthesia [69 of 237 cases] vs 28% [57 of 207 cases] for other modalities; P = .70). The hospitals involved in this study all had a written policy encouraging rediscussion of code status before surgery. However, only 1 hospital reported added measures (eg, provision of a procedure-specific DNR form) to increase documentation of preoperative code status discussions. In this specific hospital, documentation of preoperative code status discussions was higher compared to other hospitals (67% [37 of 55 cases] vs 23% [89 of 389 cases]; P < .01).
Conclusion. In a retrospective case series conducted at 5 hospitals within 1 academic health system in the US, fewer than 1 in 5 patients with preexisting DNR orders had a documented discussion of code status prior to undergoing surgery. Additional strategies including the development of institutional protocols that facilitate perioperative management of advance directives, identification of local champions, and patient education, should be explored as means to improve preoperative code status reevaulation per guideline recommendations.
Commentary
It is not unusual that patients with a DNR order may require and undergo surgical interventions to treat reversible conditions, prevent progression of underlying disease, or mitigate distressing symptoms such as pain. For instance, intubation, mechanical ventilation, and administration of vasoactive drugs are resuscitative measures that may be needed to safely anesthetize and sedate a patient. As such, the American College of Surgeons1 has provided a statement on advance directives by patients with an existing DNR order to guide management. Specifically, the statement indicates that the best approach for these patients is a policy of “required reconsideration” of the existing DNR order. Required reconsideration means that “the patient or designated surrogate and the physicians who will be responsible for the patient’s care should, when possible, discuss the new intraoperative and perioperative risks associated with the surgical procedure, the patient’s treatment goals, and an approach for potentially life-threatening problems consistent with the patient’s values and preferences.” Moreover, the required reconsideration discussion needs to occur as early as it is practical once a decision is made to have surgery because the discussion “may result in the patient agreeing to suspend the DNR order during surgery and the perioperative period, retaining the original DNR order, or modifying the DNR order.” Given that surgical patients with DNR orders have significant comorbidities, many sustain postoperative complications, and nearly 1 in 4 die within 30 days of surgery, preoperative advance care planning (ACP) and code status discussions are particularly essential to delivering high quality surgical care.2
In the current study, Hadler et al3 conducted a retrospective analysis to evaluate orders and documentation describing perioperative management of code status in patients with existing DNR order at an academic health system in the US. The authors reported that fewer than 20% of patients with existing DNR orders had a documented discussion of code status prior to undergoing surgery. These findings add to the notion that compliance with such guidance on required reconsideration discussion is suboptimal in perioperative care in the US.4,5 A recently published study focused on patients aged more than 60 years undergoing high-risk oncologic or vascular surgeries similarly showed that the frequency of ACP discussions or advance directive documentations among older patients was low.6 This growing body of evidence is highly clinically relevant in that preoperative discussion on code status is highly relevant to the care of older adults, a population group that accounts for the majority of surgeries and is most vulnerable to poor surgical outcomes. Additionally, it highlights a disconnect between the shared recognition by surgeons and patients that ACP discussion is important in perioperative care and its low implementation rates.
Unsurprisingly, Hadler et al3 reported that added measures such as the provision of a procedure-specific DNR form led to an increase in the documentation of preoperative code status discussions in 1 of the hospitals studied. The authors suggested that strategies such as the development of institutional protocols aimed to facilitate perioperative advance directive discussions, identify local champions, and educate patients may be ways to improve preoperative code status reevaulation. The idea that institutional value and culture are key factors impacting surgeon behavior and may influence the practice of ACP discussion is not new. Thus, creative and adaptable strategies, resources, and trainings that are required by medical institutions and hospitals to support preoperative ACP discussions with patients undergoing surgeries need to be identified, validated, and implemented to optimize perioperative care in vulnerable patients.
Applications for Clinical Practice
The findings from the current study indicate that less than 20% of patients with preexisting DNR orders have a documented discussion of code status prior to undergoing surgery. Physicians and health care institutions need to identify barriers to, and implement strategies that, facilitate and optimize preoperative ACP discussions in order to provide patient-centered care in vulnerable surgical patients.
Financial disclosures: None.
Study Overview
Objective. The objective of this study was to evaluate orders and documentation describing perioperative management of code status in adults.
Design. A retrospective case series of all adult inpatients admitted to hospitals at 1 academic health system in the US.
Setting and participants. This retrospective case series was conducted at 5 hospitals within the University of Pennsylvania Health System. Cases included all adult inpatients admitted to hospitals between March 2017 and September 2018 who had a Do-Not-Resuscitate (DNR) order placed in their medical record during admission and subsequently underwent a surgical procedure that required anesthesia care.
Main outcome measures. Medical records of included cases were manually reviewed by the authors to verify whether a DNR order was in place at the time surgical intervention was discussed with a patient. Clinical notes and DNR orders of eligible cases were reviewed to identify documentation and outcome of goals of care discussions that were conducted within 48 hours prior to the surgical procedure. Collected data included patient demographics (age, sex, race); case characteristics (American Society of Anesthesiologists [ASA] physical status score, anesthesia type [general vs others such as regional], emergency status [emergent vs elective surgery], procedures by service [surgical including hip fracture repair, gastrostomy or jejunostomy, or exploratory laparotomy vs medical including endoscopy, bronchoscopy, or transesophageal echocardiogram]); and hospital policy for perioperative management of DNR orders (written policy encouraging discussion vs written policy plus additional initiatives, including procedure-specific DNR form). The primary outcome was the presence of a preoperative order or note documenting code status discussion or change. Data were analyzed using χ2 and Fisher exact tests and the threshold for statistical significance was P < .05.
Main results. Of the 27 665 inpatient procedures identified across 5 hospitals, 444 (1.6%) cases met the inclusion criteria. Patients from these cases aged 75 (SD 13) years (95% CI, 72-77 years); 247 (56%, 95% CI, 55%-57%) were women; and 300 (68%, 95% CI, 65%-71%) were White. A total of 426 patients (96%, 95% CI, 90%-100%) had an ASA physical status score of 3 or higher and 237 (53%, 95% CI, 51%-56%) received general anesthesia. The most common procedures performed were endoscopy (148 [33%]), hip fracture repair (43 [10%]), and gastrostomy or jejunostomy (28 [6%]). Reevaluation of code status was documented in 126 cases (28%, 95% CI, 25%-31%); code status orders were changed in 20 of 126 cases (16%, 95% CI, 7%-24%); and a note was filed without a corresponding order for 106 of 126 cases (84%, 95% CI, 75%-95%). In the majority of cases (109 of 126 [87%], 95% CI, 78%-95%) in which documented discussion occurred, DNR orders were suspended. Of 126 cases in which a discussion was documented, participants of these discussions included surgeons 10% of the time (13 cases, 95% CI, 8%-13%), members of the anesthesia team 51% of the time (64 cases, 95% CI, 49%-53%), and medicine or palliative care clinicians 39% of the time (49 cases, 95% CI, 37%-41%).
The rate of documented preoperative code status discussion was higher in patients with higher ASA physical status score (35% in patients with an ASA physical status score ≥ 4 [55 of 155] vs 25% in those with an ASA physical status score ≤ 3 [71 of 289]; P = .02). The rates of documented preoperative code status discussion were similar by anesthesia type (29% for general anesthesia [69 of 237 cases] vs 28% [57 of 207 cases] for other modalities; P = .70). The hospitals involved in this study all had a written policy encouraging rediscussion of code status before surgery. However, only 1 hospital reported added measures (eg, provision of a procedure-specific DNR form) to increase documentation of preoperative code status discussions. In this specific hospital, documentation of preoperative code status discussions was higher compared to other hospitals (67% [37 of 55 cases] vs 23% [89 of 389 cases]; P < .01).
Conclusion. In a retrospective case series conducted at 5 hospitals within 1 academic health system in the US, fewer than 1 in 5 patients with preexisting DNR orders had a documented discussion of code status prior to undergoing surgery. Additional strategies including the development of institutional protocols that facilitate perioperative management of advance directives, identification of local champions, and patient education, should be explored as means to improve preoperative code status reevaulation per guideline recommendations.
Commentary
It is not unusual that patients with a DNR order may require and undergo surgical interventions to treat reversible conditions, prevent progression of underlying disease, or mitigate distressing symptoms such as pain. For instance, intubation, mechanical ventilation, and administration of vasoactive drugs are resuscitative measures that may be needed to safely anesthetize and sedate a patient. As such, the American College of Surgeons1 has provided a statement on advance directives by patients with an existing DNR order to guide management. Specifically, the statement indicates that the best approach for these patients is a policy of “required reconsideration” of the existing DNR order. Required reconsideration means that “the patient or designated surrogate and the physicians who will be responsible for the patient’s care should, when possible, discuss the new intraoperative and perioperative risks associated with the surgical procedure, the patient’s treatment goals, and an approach for potentially life-threatening problems consistent with the patient’s values and preferences.” Moreover, the required reconsideration discussion needs to occur as early as it is practical once a decision is made to have surgery because the discussion “may result in the patient agreeing to suspend the DNR order during surgery and the perioperative period, retaining the original DNR order, or modifying the DNR order.” Given that surgical patients with DNR orders have significant comorbidities, many sustain postoperative complications, and nearly 1 in 4 die within 30 days of surgery, preoperative advance care planning (ACP) and code status discussions are particularly essential to delivering high quality surgical care.2
In the current study, Hadler et al3 conducted a retrospective analysis to evaluate orders and documentation describing perioperative management of code status in patients with existing DNR order at an academic health system in the US. The authors reported that fewer than 20% of patients with existing DNR orders had a documented discussion of code status prior to undergoing surgery. These findings add to the notion that compliance with such guidance on required reconsideration discussion is suboptimal in perioperative care in the US.4,5 A recently published study focused on patients aged more than 60 years undergoing high-risk oncologic or vascular surgeries similarly showed that the frequency of ACP discussions or advance directive documentations among older patients was low.6 This growing body of evidence is highly clinically relevant in that preoperative discussion on code status is highly relevant to the care of older adults, a population group that accounts for the majority of surgeries and is most vulnerable to poor surgical outcomes. Additionally, it highlights a disconnect between the shared recognition by surgeons and patients that ACP discussion is important in perioperative care and its low implementation rates.
Unsurprisingly, Hadler et al3 reported that added measures such as the provision of a procedure-specific DNR form led to an increase in the documentation of preoperative code status discussions in 1 of the hospitals studied. The authors suggested that strategies such as the development of institutional protocols aimed to facilitate perioperative advance directive discussions, identify local champions, and educate patients may be ways to improve preoperative code status reevaulation. The idea that institutional value and culture are key factors impacting surgeon behavior and may influence the practice of ACP discussion is not new. Thus, creative and adaptable strategies, resources, and trainings that are required by medical institutions and hospitals to support preoperative ACP discussions with patients undergoing surgeries need to be identified, validated, and implemented to optimize perioperative care in vulnerable patients.
Applications for Clinical Practice
The findings from the current study indicate that less than 20% of patients with preexisting DNR orders have a documented discussion of code status prior to undergoing surgery. Physicians and health care institutions need to identify barriers to, and implement strategies that, facilitate and optimize preoperative ACP discussions in order to provide patient-centered care in vulnerable surgical patients.
Financial disclosures: None.
1. American College of Surgeons Board of Regents. Statement on Advance Directives by Patients: “Do Not Resuscitate” in the Operating Room. American College of Surgeons. January 3, 2014. Accessed November 6, 2021. https://www.facs.org/about-acs/statements/19-advance-directives
2. Kazaure H, Roman S, Sosa JA. High mortality in surgical patients with do-not-resuscitate orders: analysis of 8256 patients. Arch Surg. 2011;146(8):922-928. doi:10.1001/archsurg.2011.69
3. Hadler RA, Fatuzzo M, Sahota G, Neuman MD. Perioperative Management of Do-Not-Resuscitate Orders at a Large Academic Health System. JAMA Surg. 2021;e214135. doi:10.1001/jamasurg.2021.4135
4. Coopmans VC, Gries CA. CRNA awareness and experience with perioperative DNR orders. AANA J. 2000;68(3):247-256.
5. Urman RD, Lilley EJ, Changala M, Lindvall C, Hepner DL, Bader AM. A Pilot Study to Evaluate Compliance with Guidelines for Preprocedural Reconsideration of Code Status Limitations. J Palliat Med. 2018;21(8):1152-1156. doi:10.1089/jpm.2017.0601
6. Kalbfell E, Kata A, Buffington AS, et al. Frequency of Preoperative Advance Care Planning for Older Adults Undergoing High-risk Surgery: A Secondary Analysis of a Randomized Clinical Trial. JAMA Surg. 2021;156(7):e211521. doi:10.1001/jamasurg.2021.1521
1. American College of Surgeons Board of Regents. Statement on Advance Directives by Patients: “Do Not Resuscitate” in the Operating Room. American College of Surgeons. January 3, 2014. Accessed November 6, 2021. https://www.facs.org/about-acs/statements/19-advance-directives
2. Kazaure H, Roman S, Sosa JA. High mortality in surgical patients with do-not-resuscitate orders: analysis of 8256 patients. Arch Surg. 2011;146(8):922-928. doi:10.1001/archsurg.2011.69
3. Hadler RA, Fatuzzo M, Sahota G, Neuman MD. Perioperative Management of Do-Not-Resuscitate Orders at a Large Academic Health System. JAMA Surg. 2021;e214135. doi:10.1001/jamasurg.2021.4135
4. Coopmans VC, Gries CA. CRNA awareness and experience with perioperative DNR orders. AANA J. 2000;68(3):247-256.
5. Urman RD, Lilley EJ, Changala M, Lindvall C, Hepner DL, Bader AM. A Pilot Study to Evaluate Compliance with Guidelines for Preprocedural Reconsideration of Code Status Limitations. J Palliat Med. 2018;21(8):1152-1156. doi:10.1089/jpm.2017.0601
6. Kalbfell E, Kata A, Buffington AS, et al. Frequency of Preoperative Advance Care Planning for Older Adults Undergoing High-risk Surgery: A Secondary Analysis of a Randomized Clinical Trial. JAMA Surg. 2021;156(7):e211521. doi:10.1001/jamasurg.2021.1521
Dapagliflozin Reduces Adverse Renal and Cardiovascular Events in Patients With Chronic Kidney Disease
Study Overview
Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.
Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.
Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m2 of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.
Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.
Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).
Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m2, the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.
The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.
Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.
Commentary
Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,1 canagliflozin,2 and dapagliflozin,3 showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.4 Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.5 As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.
The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.8 Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.
The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.
The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,9 the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.
Applications for Clinical Practice
This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m2 and lowering the costs of this class of drugs.
—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
4. Zelniker TA, Wiviott SD, Raz I, Sabatine MS. SGLT-2 inhibitors for people with type 2 diabetes - Authors’ reply. Lancet. 2019;394:560-561.
5. American Diabetes Association 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S111-S34.
6. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-1424.
7. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819-829.
8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295-2306.
9. Strandberg TE, Petrovic M, Benetos A. SGLT-2 inhibitors for people with type 2 diabetes. Lancet. 2019;394:560.
Study Overview
Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.
Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.
Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m2 of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.
Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.
Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).
Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m2, the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.
The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.
Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.
Commentary
Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,1 canagliflozin,2 and dapagliflozin,3 showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.4 Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.5 As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.
The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.8 Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.
The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.
The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,9 the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.
Applications for Clinical Practice
This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m2 and lowering the costs of this class of drugs.
—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS
Study Overview
Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.
Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.
Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m2 of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.
Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.
Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).
Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m2, the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.
The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.
Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.
Commentary
Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,1 canagliflozin,2 and dapagliflozin,3 showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.4 Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.5 As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.
The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.8 Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.
The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.
The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,9 the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.
Applications for Clinical Practice
This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m2 and lowering the costs of this class of drugs.
—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
4. Zelniker TA, Wiviott SD, Raz I, Sabatine MS. SGLT-2 inhibitors for people with type 2 diabetes - Authors’ reply. Lancet. 2019;394:560-561.
5. American Diabetes Association 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S111-S34.
6. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-1424.
7. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819-829.
8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295-2306.
9. Strandberg TE, Petrovic M, Benetos A. SGLT-2 inhibitors for people with type 2 diabetes. Lancet. 2019;394:560.
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
4. Zelniker TA, Wiviott SD, Raz I, Sabatine MS. SGLT-2 inhibitors for people with type 2 diabetes - Authors’ reply. Lancet. 2019;394:560-561.
5. American Diabetes Association 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S111-S34.
6. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-1424.
7. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819-829.
8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295-2306.
9. Strandberg TE, Petrovic M, Benetos A. SGLT-2 inhibitors for people with type 2 diabetes. Lancet. 2019;394:560.
Systemic Corticosteroids in Critically Ill Patients With COVID-19
Study Overview
Objective. To assess the association between administration of systemic corticosteroids, compared with usual care or placebo, and 28-day all-cause mortality in critically ill patients with coronavirus disease 2019 (COVID-19).
Design. Prospective meta-analysis with data from 7 randomized clinical trials conducted in 12 countries.
Setting and participants. This prospective meta-analysis included randomized clinical trials conducted between February 26, 2020, and June 9, 2020, that examined the clinical efficacy of administration of corticosteroids in hospitalized COVID-19 patients who were critically ill. Trials were systematically identified from ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the EU Clinical Trials Register, using the search terms COVID-19, corticosteroids, and steroids. Additional trials were identified by experts from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Senior investigators of these identified trials were asked to participate in weekly calls to develop a protocol for the prospective meta-analysis.1 Subsequently, trials that had randomly assigned critically ill patients to receive corticosteroids versus usual care or placebo were invited to participate in this meta-analysis. Data were pooled from patients recruited to the participating trials through June 9, 2020, and aggregated in overall and in predefined subgroups.
Main outcome measures. The primary outcome was all-cause mortality up to 30 days after randomization. Because 5 of the included trials reported mortality at 28 days after randomization, the primary outcome was reported as 28-day all-cause mortality. The secondary outcome was serious adverse events (SAEs). The authors also gathered data on the demographic and clinical characteristics of patients, the number of patients lost to follow-up, and outcomes according to intervention group, overall, and in subgroups (ie, patients receiving invasive mechanical ventilation or vasoactive medication; age ≤ 60 years or > 60 years [the median across trials]; sex [male or female]; and the duration patients were symptomatic [≤ 7 days or > 7 days]). For each trial, the risk of bias was assessed independently by 4 investigators using the Cochrane Risk of Bias Assessment Tool for the overall effects of corticosteroids on mortality and SAEs and the effect of assignment and allocated interventions. Inconsistency between trial results was evaluated using the I2 statistic. The trials were classified according to the corticosteroids used in the intervention group and the dose administered using a priori-defined cutoffs (15 mg/day of dexamethasone, 400 mg/day of hydrocortisone, and 1 mg/kg/day of methylprednisolone). The primary analysis utilized was an inverse variance-weighted fixed-effect meta-analysis of odds ratios (ORs) for overall mortality. Random-effects meta-analyses with Paule-Mandel estimate of heterogeneity were also performed.
Main results. Seven trials (DEXA-COVID 19, CoDEX, RECOVERY, CAPE COVID, COVID STEROID, REMAP-CAP, and Steroids-SARI) were included in the final meta-analysis. The enrolled patients were from Australia, Brazil, Canada, China, Denmark, France, Ireland, the Netherlands, New Zealand, Spain, the United Kingdom, and the United States. The date of final follow-up was July 6, 2020. The corticosteroids groups included dexamethasone at low (6 mg/day orally or intravenously [IV]) and high (20 mg/day IV) doses; low-dose hydrocortisone (200 mg/day IV or 50 mg every 6 hr IV); and high-dose methylprednisolone (40 mg every 12 hr IV). In total, 1703 patients were randomized, with 678 assigned to the corticosteroids group and 1025 to the usual-care or placebo group. The median age of patients was 60 years (interquartile range, 52-68 years), and 29% were women. The larger number of patients in the usual-care/placebo group was a result of the 1:2 randomization (corticosteroids versus usual care or placebo) in the RECOVERY trial, which contributed 59.1% of patients included in this prospective meta-analysis. The majority of patients were receiving invasive mechanical ventilation at randomization (1559 patients). The administration of adjunctive treatments, such as azithromycin or antiviral agents, varied among the trials. The risk of bias was determined as low for 6 of the 7 mortality results.
A total of 222 of 678 patients in the corticosteroids group died, and 425 of 1025 patients in the usual care or placebo group died. The summary OR was 0.66 (95% confidence interval [CI], 0.53-0.82; P < 0.001) based on a fixed-effect meta-analysis, and 0.70 (95% CI, 0.48-1.01; P = 0.053) based on the random-effects meta-analysis, for 28-day all-cause mortality comparing all corticosteroids with usual care or placebo. There was little inconsistency between trial results (I2 = 15.6%; P = 0.31). The fixed-effect summary OR for the association with 28-day all-cause mortality was 0.64 (95% CI, 0.50-0.82; P < 0.001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths); the OR was 0.69 (95% CI, 0.43-1.12; P = 0.13) for hydrocortisone (3 trials, 374 patients, and 94 deaths); and the OR was 0.91 (95% CI, 0.29-2.87; P = 0.87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Moreover, in trials that administered low-dose corticosteroids, the overall fixed-effect OR for 28-day all-cause mortality was 0.61 (95% CI, 0.48-0.78; P < 0.001). In the subgroup analysis, the overall fixed-effect OR was 0.69 (95% CI, 0.55-0.86) in patients who were receiving invasive mechanical ventilation at randomization, and the OR was 0.41 (95% CI, 0.19-0.88) in patients who were not receiving invasive mechanical ventilation at randomization.
Six trials (all except the RECOVERY trial) reported SAEs, with 64 events occurring among 354 patients assigned to the corticosteroids group and 80 SAEs occurring among 342 patients assigned to the usual-care or placebo group. There was no suggestion that the risk of SAEs was higher in patients who were administered corticosteroids.
Conclusion. The administration of systemic corticosteroids was associated with a lower 28-day all-cause mortality in critically ill patients with COVID-19 compared to those who received usual care or placebo.
Commentary
Corticosteroids are anti-inflammatory and vasoconstrictive medications that have long been used in intensive care units for the treatment of acute respiratory distress syndrome and septic shock. However, the therapeutic role of corticosteroids for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was uncertain at the outset of the COVID-19 pandemic due to concerns that this class of medications may cause an impaired immune response in the setting of a life-threatening SARS-CoV-2 infection. Evidence supporting this notion included prior studies showing that corticosteroid therapy was associated with delayed viral clearance of Middle East respiratory syndrome or a higher viral load of SARS-CoV.2,3 The uncertainty surrounding the therapeutic use of corticosteroids in treating COVID-19 led to a simultaneous global effort to conduct randomized controlled trials to urgently examine this important clinical question. The open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, conducted in the UK, was the first large-scale randomized clinical trial that reported the clinical benefit of corticosteroids in treating patients hospitalized with COVID-19. Specifically, it showed that low-dose dexamethasone (6 mg/day) administered orally or IV for up to 10 days resulted in a 2.8% absolute reduction in 28-day mortality, with the greatest benefit, an absolute risk reduction of 12.1%, conferred to patients who were receiving invasive mechanical ventilation at the time of randomization.4 In response to these findings, the National Institutes of Health COVID-19 Treatment Guidelines Panel recommended the use of dexamethasone in patients with COVID-19 who are on mechanical ventilation or who require supplemental oxygen, and recommended against the use of dexamethasone for those not requiring supplemental oxygen.5
The meta-analysis discussed in this commentary, conducted by the WHO REACT Working Group, has replicated initial findings from the RECOVERY trial. This prospective meta-analysis pooled data from 7 randomized controlled trials of corticosteroid therapy in 1703 critically ill patients hospitalized with COVID-19. Similar to findings from the RECOVERY trial, corticosteroids were associated with lower all-cause mortality at 28 days after randomization, and this benefit was observed both in critically ill patients who were receiving mechanical ventilation or supplemental oxygen without mechanical ventilation. Interestingly, while the OR estimates were imprecise, the reduction in mortality rates was similar between patients who were administered dexamethasone and hydrocortisone, which may suggest a general drug class effect. In addition, the mortality benefit of corticosteroids appeared similar for those aged ≤ 60 years and those aged > 60 years, between female and male patients, and those who were symptomatic for ≤ 7 days or > 7 days before randomization. Moreover, the administration of corticosteroids did not appear to increase the risk of SAEs. While more data are needed, results from the RECOVERY trial and this prospective meta-analysis indicate that corticosteroids should be an essential pharmacologic treatment for COVID-19, and suggest its potential role as a standard of care for critically ill patients with COVID-19.
This study has several limitations. First, not all trials systematically identified participated in the meta-analysis. Second, long-term outcomes after hospital discharge were not captured, and thus the effect of corticosteroids on long-term mortality and other adverse outcomes, such as hospital readmission, remain unknown. Third, because children were excluded from study participation, the effect of corticosteroids on pediatric COVID-19 patients is unknown. Fourth, the RECOVERY trial contributed more than 50% of patients in the current analysis, although there was little inconsistency in the effects of corticosteroids on mortality between individual trials. Last, the meta-analysis was unable to establish the optimal dose or duration of corticosteroid intervention in critically ill COVID-19 patients, or determine its efficacy in patients with mild-to-moderate COVID-19, all of which are key clinical questions that will need to be addressed with further clinical investigations.
The development of effective treatments for COVID-19 is critical to mitigating the devastating consequences of SARS-CoV-2 infection. Several recent COVID-19 clinical trials have shown promise in this endeavor. For instance, the Adaptive COVID-19 Treatment Trial (ACCT-1) found that intravenous remdesivir, as compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.6 Moreover, there is some evidence to suggest that convalescent plasma and aerosol inhalation of IFN-κ may have beneficial effects in treating COVID-19.7,8 Thus, clinical trials designed to investigate combination therapy approaches including corticosteroids, remdesivir, convalescent plasma, and others are urgently needed to help identify interventions that most effectively treat COVID-19.
Applications for Clinical Practice
The use of corticosteroids in critically ill patients with COVID-19 reduces overall mortality. This treatment is inexpensive and available in most care settings, including low-resource regions, and provides hope for better outcomes in the COVID-19 pandemic.
Katerina Oikonomou, MD, PhD
General Hospital of Larissa, Larissa, Greece
Fred Ko, MD, MS
1. Sterne JAC, Diaz J, Villar J, et al. Corticosteroid therapy for critically ill patients with COVID-19: A structured summary of a study protocol for a prospective meta-analysis of randomized trials. Trials. 2020;21:734.
2. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31:304-309.
3. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for citically Ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197:757-767.
4. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report [published online ahead of print, 2020 Jul 17]. N Engl J Med. 2020;NEJMoa2021436.
5. NIH COVID-19 Treatment Guidelines. National Institutes of Health. www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/. Accessed September 11, 2020.
6. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19--preliminary report [published online ahead of print, 2020 May 22]. N Engl J Med. 2020;NEJMoa2007764.
7. Casadevall A, Joyner MJ, Pirofski LA. A randomized trial of convalescent plasma for covid-19-potentially hopeful signals. JAMA. 2020;324:455-457.
8. Fu W, Liu Y, Xia L, et al. A clinical pilot study on the safety and efficacy of aerosol inhalation treatment of IFN-κ plus TFF2 in patients with moderate COVID-19. EClinicalMedicine. 2020;25:100478.
Study Overview
Objective. To assess the association between administration of systemic corticosteroids, compared with usual care or placebo, and 28-day all-cause mortality in critically ill patients with coronavirus disease 2019 (COVID-19).
Design. Prospective meta-analysis with data from 7 randomized clinical trials conducted in 12 countries.
Setting and participants. This prospective meta-analysis included randomized clinical trials conducted between February 26, 2020, and June 9, 2020, that examined the clinical efficacy of administration of corticosteroids in hospitalized COVID-19 patients who were critically ill. Trials were systematically identified from ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the EU Clinical Trials Register, using the search terms COVID-19, corticosteroids, and steroids. Additional trials were identified by experts from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Senior investigators of these identified trials were asked to participate in weekly calls to develop a protocol for the prospective meta-analysis.1 Subsequently, trials that had randomly assigned critically ill patients to receive corticosteroids versus usual care or placebo were invited to participate in this meta-analysis. Data were pooled from patients recruited to the participating trials through June 9, 2020, and aggregated in overall and in predefined subgroups.
Main outcome measures. The primary outcome was all-cause mortality up to 30 days after randomization. Because 5 of the included trials reported mortality at 28 days after randomization, the primary outcome was reported as 28-day all-cause mortality. The secondary outcome was serious adverse events (SAEs). The authors also gathered data on the demographic and clinical characteristics of patients, the number of patients lost to follow-up, and outcomes according to intervention group, overall, and in subgroups (ie, patients receiving invasive mechanical ventilation or vasoactive medication; age ≤ 60 years or > 60 years [the median across trials]; sex [male or female]; and the duration patients were symptomatic [≤ 7 days or > 7 days]). For each trial, the risk of bias was assessed independently by 4 investigators using the Cochrane Risk of Bias Assessment Tool for the overall effects of corticosteroids on mortality and SAEs and the effect of assignment and allocated interventions. Inconsistency between trial results was evaluated using the I2 statistic. The trials were classified according to the corticosteroids used in the intervention group and the dose administered using a priori-defined cutoffs (15 mg/day of dexamethasone, 400 mg/day of hydrocortisone, and 1 mg/kg/day of methylprednisolone). The primary analysis utilized was an inverse variance-weighted fixed-effect meta-analysis of odds ratios (ORs) for overall mortality. Random-effects meta-analyses with Paule-Mandel estimate of heterogeneity were also performed.
Main results. Seven trials (DEXA-COVID 19, CoDEX, RECOVERY, CAPE COVID, COVID STEROID, REMAP-CAP, and Steroids-SARI) were included in the final meta-analysis. The enrolled patients were from Australia, Brazil, Canada, China, Denmark, France, Ireland, the Netherlands, New Zealand, Spain, the United Kingdom, and the United States. The date of final follow-up was July 6, 2020. The corticosteroids groups included dexamethasone at low (6 mg/day orally or intravenously [IV]) and high (20 mg/day IV) doses; low-dose hydrocortisone (200 mg/day IV or 50 mg every 6 hr IV); and high-dose methylprednisolone (40 mg every 12 hr IV). In total, 1703 patients were randomized, with 678 assigned to the corticosteroids group and 1025 to the usual-care or placebo group. The median age of patients was 60 years (interquartile range, 52-68 years), and 29% were women. The larger number of patients in the usual-care/placebo group was a result of the 1:2 randomization (corticosteroids versus usual care or placebo) in the RECOVERY trial, which contributed 59.1% of patients included in this prospective meta-analysis. The majority of patients were receiving invasive mechanical ventilation at randomization (1559 patients). The administration of adjunctive treatments, such as azithromycin or antiviral agents, varied among the trials. The risk of bias was determined as low for 6 of the 7 mortality results.
A total of 222 of 678 patients in the corticosteroids group died, and 425 of 1025 patients in the usual care or placebo group died. The summary OR was 0.66 (95% confidence interval [CI], 0.53-0.82; P < 0.001) based on a fixed-effect meta-analysis, and 0.70 (95% CI, 0.48-1.01; P = 0.053) based on the random-effects meta-analysis, for 28-day all-cause mortality comparing all corticosteroids with usual care or placebo. There was little inconsistency between trial results (I2 = 15.6%; P = 0.31). The fixed-effect summary OR for the association with 28-day all-cause mortality was 0.64 (95% CI, 0.50-0.82; P < 0.001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths); the OR was 0.69 (95% CI, 0.43-1.12; P = 0.13) for hydrocortisone (3 trials, 374 patients, and 94 deaths); and the OR was 0.91 (95% CI, 0.29-2.87; P = 0.87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Moreover, in trials that administered low-dose corticosteroids, the overall fixed-effect OR for 28-day all-cause mortality was 0.61 (95% CI, 0.48-0.78; P < 0.001). In the subgroup analysis, the overall fixed-effect OR was 0.69 (95% CI, 0.55-0.86) in patients who were receiving invasive mechanical ventilation at randomization, and the OR was 0.41 (95% CI, 0.19-0.88) in patients who were not receiving invasive mechanical ventilation at randomization.
Six trials (all except the RECOVERY trial) reported SAEs, with 64 events occurring among 354 patients assigned to the corticosteroids group and 80 SAEs occurring among 342 patients assigned to the usual-care or placebo group. There was no suggestion that the risk of SAEs was higher in patients who were administered corticosteroids.
Conclusion. The administration of systemic corticosteroids was associated with a lower 28-day all-cause mortality in critically ill patients with COVID-19 compared to those who received usual care or placebo.
Commentary
Corticosteroids are anti-inflammatory and vasoconstrictive medications that have long been used in intensive care units for the treatment of acute respiratory distress syndrome and septic shock. However, the therapeutic role of corticosteroids for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was uncertain at the outset of the COVID-19 pandemic due to concerns that this class of medications may cause an impaired immune response in the setting of a life-threatening SARS-CoV-2 infection. Evidence supporting this notion included prior studies showing that corticosteroid therapy was associated with delayed viral clearance of Middle East respiratory syndrome or a higher viral load of SARS-CoV.2,3 The uncertainty surrounding the therapeutic use of corticosteroids in treating COVID-19 led to a simultaneous global effort to conduct randomized controlled trials to urgently examine this important clinical question. The open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, conducted in the UK, was the first large-scale randomized clinical trial that reported the clinical benefit of corticosteroids in treating patients hospitalized with COVID-19. Specifically, it showed that low-dose dexamethasone (6 mg/day) administered orally or IV for up to 10 days resulted in a 2.8% absolute reduction in 28-day mortality, with the greatest benefit, an absolute risk reduction of 12.1%, conferred to patients who were receiving invasive mechanical ventilation at the time of randomization.4 In response to these findings, the National Institutes of Health COVID-19 Treatment Guidelines Panel recommended the use of dexamethasone in patients with COVID-19 who are on mechanical ventilation or who require supplemental oxygen, and recommended against the use of dexamethasone for those not requiring supplemental oxygen.5
The meta-analysis discussed in this commentary, conducted by the WHO REACT Working Group, has replicated initial findings from the RECOVERY trial. This prospective meta-analysis pooled data from 7 randomized controlled trials of corticosteroid therapy in 1703 critically ill patients hospitalized with COVID-19. Similar to findings from the RECOVERY trial, corticosteroids were associated with lower all-cause mortality at 28 days after randomization, and this benefit was observed both in critically ill patients who were receiving mechanical ventilation or supplemental oxygen without mechanical ventilation. Interestingly, while the OR estimates were imprecise, the reduction in mortality rates was similar between patients who were administered dexamethasone and hydrocortisone, which may suggest a general drug class effect. In addition, the mortality benefit of corticosteroids appeared similar for those aged ≤ 60 years and those aged > 60 years, between female and male patients, and those who were symptomatic for ≤ 7 days or > 7 days before randomization. Moreover, the administration of corticosteroids did not appear to increase the risk of SAEs. While more data are needed, results from the RECOVERY trial and this prospective meta-analysis indicate that corticosteroids should be an essential pharmacologic treatment for COVID-19, and suggest its potential role as a standard of care for critically ill patients with COVID-19.
This study has several limitations. First, not all trials systematically identified participated in the meta-analysis. Second, long-term outcomes after hospital discharge were not captured, and thus the effect of corticosteroids on long-term mortality and other adverse outcomes, such as hospital readmission, remain unknown. Third, because children were excluded from study participation, the effect of corticosteroids on pediatric COVID-19 patients is unknown. Fourth, the RECOVERY trial contributed more than 50% of patients in the current analysis, although there was little inconsistency in the effects of corticosteroids on mortality between individual trials. Last, the meta-analysis was unable to establish the optimal dose or duration of corticosteroid intervention in critically ill COVID-19 patients, or determine its efficacy in patients with mild-to-moderate COVID-19, all of which are key clinical questions that will need to be addressed with further clinical investigations.
The development of effective treatments for COVID-19 is critical to mitigating the devastating consequences of SARS-CoV-2 infection. Several recent COVID-19 clinical trials have shown promise in this endeavor. For instance, the Adaptive COVID-19 Treatment Trial (ACCT-1) found that intravenous remdesivir, as compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.6 Moreover, there is some evidence to suggest that convalescent plasma and aerosol inhalation of IFN-κ may have beneficial effects in treating COVID-19.7,8 Thus, clinical trials designed to investigate combination therapy approaches including corticosteroids, remdesivir, convalescent plasma, and others are urgently needed to help identify interventions that most effectively treat COVID-19.
Applications for Clinical Practice
The use of corticosteroids in critically ill patients with COVID-19 reduces overall mortality. This treatment is inexpensive and available in most care settings, including low-resource regions, and provides hope for better outcomes in the COVID-19 pandemic.
Katerina Oikonomou, MD, PhD
General Hospital of Larissa, Larissa, Greece
Fred Ko, MD, MS
Study Overview
Objective. To assess the association between administration of systemic corticosteroids, compared with usual care or placebo, and 28-day all-cause mortality in critically ill patients with coronavirus disease 2019 (COVID-19).
Design. Prospective meta-analysis with data from 7 randomized clinical trials conducted in 12 countries.
Setting and participants. This prospective meta-analysis included randomized clinical trials conducted between February 26, 2020, and June 9, 2020, that examined the clinical efficacy of administration of corticosteroids in hospitalized COVID-19 patients who were critically ill. Trials were systematically identified from ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the EU Clinical Trials Register, using the search terms COVID-19, corticosteroids, and steroids. Additional trials were identified by experts from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Senior investigators of these identified trials were asked to participate in weekly calls to develop a protocol for the prospective meta-analysis.1 Subsequently, trials that had randomly assigned critically ill patients to receive corticosteroids versus usual care or placebo were invited to participate in this meta-analysis. Data were pooled from patients recruited to the participating trials through June 9, 2020, and aggregated in overall and in predefined subgroups.
Main outcome measures. The primary outcome was all-cause mortality up to 30 days after randomization. Because 5 of the included trials reported mortality at 28 days after randomization, the primary outcome was reported as 28-day all-cause mortality. The secondary outcome was serious adverse events (SAEs). The authors also gathered data on the demographic and clinical characteristics of patients, the number of patients lost to follow-up, and outcomes according to intervention group, overall, and in subgroups (ie, patients receiving invasive mechanical ventilation or vasoactive medication; age ≤ 60 years or > 60 years [the median across trials]; sex [male or female]; and the duration patients were symptomatic [≤ 7 days or > 7 days]). For each trial, the risk of bias was assessed independently by 4 investigators using the Cochrane Risk of Bias Assessment Tool for the overall effects of corticosteroids on mortality and SAEs and the effect of assignment and allocated interventions. Inconsistency between trial results was evaluated using the I2 statistic. The trials were classified according to the corticosteroids used in the intervention group and the dose administered using a priori-defined cutoffs (15 mg/day of dexamethasone, 400 mg/day of hydrocortisone, and 1 mg/kg/day of methylprednisolone). The primary analysis utilized was an inverse variance-weighted fixed-effect meta-analysis of odds ratios (ORs) for overall mortality. Random-effects meta-analyses with Paule-Mandel estimate of heterogeneity were also performed.
Main results. Seven trials (DEXA-COVID 19, CoDEX, RECOVERY, CAPE COVID, COVID STEROID, REMAP-CAP, and Steroids-SARI) were included in the final meta-analysis. The enrolled patients were from Australia, Brazil, Canada, China, Denmark, France, Ireland, the Netherlands, New Zealand, Spain, the United Kingdom, and the United States. The date of final follow-up was July 6, 2020. The corticosteroids groups included dexamethasone at low (6 mg/day orally or intravenously [IV]) and high (20 mg/day IV) doses; low-dose hydrocortisone (200 mg/day IV or 50 mg every 6 hr IV); and high-dose methylprednisolone (40 mg every 12 hr IV). In total, 1703 patients were randomized, with 678 assigned to the corticosteroids group and 1025 to the usual-care or placebo group. The median age of patients was 60 years (interquartile range, 52-68 years), and 29% were women. The larger number of patients in the usual-care/placebo group was a result of the 1:2 randomization (corticosteroids versus usual care or placebo) in the RECOVERY trial, which contributed 59.1% of patients included in this prospective meta-analysis. The majority of patients were receiving invasive mechanical ventilation at randomization (1559 patients). The administration of adjunctive treatments, such as azithromycin or antiviral agents, varied among the trials. The risk of bias was determined as low for 6 of the 7 mortality results.
A total of 222 of 678 patients in the corticosteroids group died, and 425 of 1025 patients in the usual care or placebo group died. The summary OR was 0.66 (95% confidence interval [CI], 0.53-0.82; P < 0.001) based on a fixed-effect meta-analysis, and 0.70 (95% CI, 0.48-1.01; P = 0.053) based on the random-effects meta-analysis, for 28-day all-cause mortality comparing all corticosteroids with usual care or placebo. There was little inconsistency between trial results (I2 = 15.6%; P = 0.31). The fixed-effect summary OR for the association with 28-day all-cause mortality was 0.64 (95% CI, 0.50-0.82; P < 0.001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths); the OR was 0.69 (95% CI, 0.43-1.12; P = 0.13) for hydrocortisone (3 trials, 374 patients, and 94 deaths); and the OR was 0.91 (95% CI, 0.29-2.87; P = 0.87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Moreover, in trials that administered low-dose corticosteroids, the overall fixed-effect OR for 28-day all-cause mortality was 0.61 (95% CI, 0.48-0.78; P < 0.001). In the subgroup analysis, the overall fixed-effect OR was 0.69 (95% CI, 0.55-0.86) in patients who were receiving invasive mechanical ventilation at randomization, and the OR was 0.41 (95% CI, 0.19-0.88) in patients who were not receiving invasive mechanical ventilation at randomization.
Six trials (all except the RECOVERY trial) reported SAEs, with 64 events occurring among 354 patients assigned to the corticosteroids group and 80 SAEs occurring among 342 patients assigned to the usual-care or placebo group. There was no suggestion that the risk of SAEs was higher in patients who were administered corticosteroids.
Conclusion. The administration of systemic corticosteroids was associated with a lower 28-day all-cause mortality in critically ill patients with COVID-19 compared to those who received usual care or placebo.
Commentary
Corticosteroids are anti-inflammatory and vasoconstrictive medications that have long been used in intensive care units for the treatment of acute respiratory distress syndrome and septic shock. However, the therapeutic role of corticosteroids for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was uncertain at the outset of the COVID-19 pandemic due to concerns that this class of medications may cause an impaired immune response in the setting of a life-threatening SARS-CoV-2 infection. Evidence supporting this notion included prior studies showing that corticosteroid therapy was associated with delayed viral clearance of Middle East respiratory syndrome or a higher viral load of SARS-CoV.2,3 The uncertainty surrounding the therapeutic use of corticosteroids in treating COVID-19 led to a simultaneous global effort to conduct randomized controlled trials to urgently examine this important clinical question. The open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, conducted in the UK, was the first large-scale randomized clinical trial that reported the clinical benefit of corticosteroids in treating patients hospitalized with COVID-19. Specifically, it showed that low-dose dexamethasone (6 mg/day) administered orally or IV for up to 10 days resulted in a 2.8% absolute reduction in 28-day mortality, with the greatest benefit, an absolute risk reduction of 12.1%, conferred to patients who were receiving invasive mechanical ventilation at the time of randomization.4 In response to these findings, the National Institutes of Health COVID-19 Treatment Guidelines Panel recommended the use of dexamethasone in patients with COVID-19 who are on mechanical ventilation or who require supplemental oxygen, and recommended against the use of dexamethasone for those not requiring supplemental oxygen.5
The meta-analysis discussed in this commentary, conducted by the WHO REACT Working Group, has replicated initial findings from the RECOVERY trial. This prospective meta-analysis pooled data from 7 randomized controlled trials of corticosteroid therapy in 1703 critically ill patients hospitalized with COVID-19. Similar to findings from the RECOVERY trial, corticosteroids were associated with lower all-cause mortality at 28 days after randomization, and this benefit was observed both in critically ill patients who were receiving mechanical ventilation or supplemental oxygen without mechanical ventilation. Interestingly, while the OR estimates were imprecise, the reduction in mortality rates was similar between patients who were administered dexamethasone and hydrocortisone, which may suggest a general drug class effect. In addition, the mortality benefit of corticosteroids appeared similar for those aged ≤ 60 years and those aged > 60 years, between female and male patients, and those who were symptomatic for ≤ 7 days or > 7 days before randomization. Moreover, the administration of corticosteroids did not appear to increase the risk of SAEs. While more data are needed, results from the RECOVERY trial and this prospective meta-analysis indicate that corticosteroids should be an essential pharmacologic treatment for COVID-19, and suggest its potential role as a standard of care for critically ill patients with COVID-19.
This study has several limitations. First, not all trials systematically identified participated in the meta-analysis. Second, long-term outcomes after hospital discharge were not captured, and thus the effect of corticosteroids on long-term mortality and other adverse outcomes, such as hospital readmission, remain unknown. Third, because children were excluded from study participation, the effect of corticosteroids on pediatric COVID-19 patients is unknown. Fourth, the RECOVERY trial contributed more than 50% of patients in the current analysis, although there was little inconsistency in the effects of corticosteroids on mortality between individual trials. Last, the meta-analysis was unable to establish the optimal dose or duration of corticosteroid intervention in critically ill COVID-19 patients, or determine its efficacy in patients with mild-to-moderate COVID-19, all of which are key clinical questions that will need to be addressed with further clinical investigations.
The development of effective treatments for COVID-19 is critical to mitigating the devastating consequences of SARS-CoV-2 infection. Several recent COVID-19 clinical trials have shown promise in this endeavor. For instance, the Adaptive COVID-19 Treatment Trial (ACCT-1) found that intravenous remdesivir, as compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.6 Moreover, there is some evidence to suggest that convalescent plasma and aerosol inhalation of IFN-κ may have beneficial effects in treating COVID-19.7,8 Thus, clinical trials designed to investigate combination therapy approaches including corticosteroids, remdesivir, convalescent plasma, and others are urgently needed to help identify interventions that most effectively treat COVID-19.
Applications for Clinical Practice
The use of corticosteroids in critically ill patients with COVID-19 reduces overall mortality. This treatment is inexpensive and available in most care settings, including low-resource regions, and provides hope for better outcomes in the COVID-19 pandemic.
Katerina Oikonomou, MD, PhD
General Hospital of Larissa, Larissa, Greece
Fred Ko, MD, MS
1. Sterne JAC, Diaz J, Villar J, et al. Corticosteroid therapy for critically ill patients with COVID-19: A structured summary of a study protocol for a prospective meta-analysis of randomized trials. Trials. 2020;21:734.
2. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31:304-309.
3. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for citically Ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197:757-767.
4. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report [published online ahead of print, 2020 Jul 17]. N Engl J Med. 2020;NEJMoa2021436.
5. NIH COVID-19 Treatment Guidelines. National Institutes of Health. www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/. Accessed September 11, 2020.
6. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19--preliminary report [published online ahead of print, 2020 May 22]. N Engl J Med. 2020;NEJMoa2007764.
7. Casadevall A, Joyner MJ, Pirofski LA. A randomized trial of convalescent plasma for covid-19-potentially hopeful signals. JAMA. 2020;324:455-457.
8. Fu W, Liu Y, Xia L, et al. A clinical pilot study on the safety and efficacy of aerosol inhalation treatment of IFN-κ plus TFF2 in patients with moderate COVID-19. EClinicalMedicine. 2020;25:100478.
1. Sterne JAC, Diaz J, Villar J, et al. Corticosteroid therapy for critically ill patients with COVID-19: A structured summary of a study protocol for a prospective meta-analysis of randomized trials. Trials. 2020;21:734.
2. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31:304-309.
3. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for citically Ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197:757-767.
4. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report [published online ahead of print, 2020 Jul 17]. N Engl J Med. 2020;NEJMoa2021436.
5. NIH COVID-19 Treatment Guidelines. National Institutes of Health. www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/. Accessed September 11, 2020.
6. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19--preliminary report [published online ahead of print, 2020 May 22]. N Engl J Med. 2020;NEJMoa2007764.
7. Casadevall A, Joyner MJ, Pirofski LA. A randomized trial of convalescent plasma for covid-19-potentially hopeful signals. JAMA. 2020;324:455-457.
8. Fu W, Liu Y, Xia L, et al. A clinical pilot study on the safety and efficacy of aerosol inhalation treatment of IFN-κ plus TFF2 in patients with moderate COVID-19. EClinicalMedicine. 2020;25:100478.
Remdesivir Reduces Time to Recovery in Adults Hospitalized With COVID-19: A Meaningful Step in Therapeutic Discovery
Study Overview
Objective. To assess the clinical efficacy and safety of remdesivir in hospitalized adults with laboratory-confirmed COVID-19 and with evidence of lower respiratory tract involvement.
Design. Double-blinded, randomized, placebo-controlled, multicenter trial.
Setting and participants. Enrollment for the study took place between February 21, 2020, and April 19, 2020, at 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Study participants included patients aged ≥ 18 years who were hospitalized and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as determined by a positive reverse transcription polymerase chain reaction assay on a respiratory specimen. Participants had evidence of lower respiratory tract infection at the time of enrollment; this was defined as radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO2) ≤ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Exclusion criteria for study participation included abnormal liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than 5 times the upper limit of normal range; impaired renal function or need for hemodialysis or hemofiltration; pregnancy or breastfeeding; or anticipated hospital discharge or transfer to another hospital within 72 hours of enrollment.
Intervention. Participants were randomized in a 1:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200-mg loading dose on day 1, followed by a 100-mg maintenance dose daily on days 2 through 10, or until hospital discharge or death) or placebo for up to 10 days. Blinding was maintained by masking infusions with an opaque bag and tubing. Randomization was stratified by study site and disease severity at enrollment. Supportive care was delivered to all participants according to the standard of care at each trial site hospital. Clinical status, determined using an 8-category ordinal scale and the National Early Warning Score, was assessed daily for each participant while hospitalized (day 1 through day 29).
Blood samples for safety laboratory tests were collected, and oropharyngeal or nasopharyngeal swab testing was performed for viral RNA detection and quantification on days 1, 3, 5, 8, and 11. All serious adverse events (AEs) and grade 3/4 AEs that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions associated with the study drug or placebo administration were recorded.
Main outcome measures. The primary endpoint measure of this study was time to recovery, defined as the first day during the 28 days after enrollment on which a participant satisfied category 1 (ie, not hospitalized, no limitations of activities), 2 (ie, not hospitalized, limitation of activities, home oxygen requirement, or both), or 3 (ie, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; hospitalization was extended for infection-control reason) on the 8-category ordinal scale. Secondary outcomes included all-cause mortality at 14 and 28 days after enrollment and grade 3/4 AEs and serious AEs that occurred during trial participation. Analysis of the primary outcome was performed using a log-rank test of the time to recovery comparing remdesivir with placebo group, stratified by disease severity.
The study’s primary outcome was initially defined as a difference in clinical status as ascertained by the 8-category ordinal scale between groups of participants who were administered remdesivir versus placebo on day 15. Because of new knowledge gained external to the study about a more protracted COVID-19 clinical course than previously recognized, a change in primary outcome to time to recovery was proposed by trial statisticians, who were unaware of treatment assignments (72 participants had been enrolled) or outcome data (no interim data) on March 22, 2020, with subsequent amendment approval on April 2, 2020. On April 27, 2020, the Data and Safety Monitoring Board (DSMB) reviewed the interim study analysis (with data cutoff date of April 22, 2020) and recommended the report and mortality data to be provided to trial team members from the National Institute of Allergy and Infectious Diseases; these findings were subsequently made public.
Main results. A total of 1107 patients were assessed for eligibility, of whom 1063 underwent randomization, with 541 assigned to remdesivir and 522 to placebo. Results were unblinded early at the recommendation of DSMB due to findings from the interim analysis that showed reduced time to recovery in the group that received remdesivir. As of April 28, 2020, a total of 391 participants in the remdesivir group and 340 participants in the placebo group had completed the trial (day 29), recovered, or died. The mean age of participants was 58.9 ± 15.0 years, the majority were men (64.3%) and were White (53.2%), and the most common prespecified coexisting conditions were hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The vast majority of participants (88.7%) had severe COVID-19 disease at enrollment, defined as requiring invasive or noninvasive mechanical ventilation, requiring supplemental oxygen, SpO2 ≤ 94% on room air, or tachypnea (respiratory rate ≥ 24 breaths per minute).
Based on available data from 1059 participants (538 from the remdesivir group and 521 from the placebo group), those in the remdesivir group had a shorter median recovery time of 11 days (95% confidence interval [CI], 9-12) as compared to 15 days (95% CI, 13-19) in the placebo group, with a rate ratio for recovery of 1.32 (95% CI, 1.12-1.55; P < 0.001). Moreover, the odds of improvement on day 15 in the 8-category ordinal scale score were higher in the remdesivir group, compared to the placebo group (proportional odds model; odds ratio, 1.50; 95% CI, 1.18-1.91; P = 0.001; 844 participants).
Mortality rate by 14 days was numerically lower in the remdesivir group (7.1%) compared to the placebo group (11.9%), but the difference was not statistically significant (Kaplan-Meier, hazard ratio for death, 0.70; 95% CI, 0.47-1.04). Serious AEs were reported in 114 of the 541 (21.1%) participants in the remdesivir group and 141 of the 522 (27.0%) participants in the placebo group. Moreover, grade 3/4 AEs occurred in 156 (28.8%) participants in the remdesivir group and in 172 (33.0%) in the placebo group.
Conclusion. The study found that remdesivir, compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.
Commentary
Since the initial reporting of a cluster of cases of pneumonia in Wuhan, China, on December 31, 2019, SARS-CoV-2 has been identified as the cause of this new disease (COVID-19), and to-date SARS-CoV-2 infection has affected more than 15.2 million people globally, with more than 3.9 million cases in the United States alone.1 Despite an unprecedented global research effort, as well as public-private research partnerships, both in terms of scale and scope, an effective pharmacologic therapy for COVID-19 has so far eluded the scientific and medical community. Early trials of hydroxychloroquine and lopinavir-ritonavir did not demonstrate a clinical benefit in patients with COVID-19.2,3 Moreover, the first randomized controlled trial of remdesivir in COVID-19, a nucleoside analogue prodrug and a broad-spectrum antiviral agent previously shown to have inhibitory effects on pathogenic coronaviruses, was an underpowered study, and thus inconclusive.4 Thus, given the persistence of the COVID-19 pandemic and a current lack of effective vaccines or curative treatments, the study reported by Beigel and colleagues is timely and provides much needed knowledge in developing potential therapies for COVID-19.
The present report described the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACCT-1), which aimed to evaluate the clinical efficacy and safety of intravenous remdesivir, as compared to placebo, in hospitalized adults with laboratory-confirmed COVID-19. The study itself was well-designed and conducted. The successful enrollment of more than 1000 participants randomized in a 1:1 ratio within a 2-month recruitment window, involving 60 international trial sites, shortly after the emergence of a new global pandemic was remarkable. This study provided the first evidence that remdesivir, an antiviral, can shorten time to recovery by approximately 31% compared to placebo in COVID-19 patients with lower respiratory tract involvement.
Interestingly, this beneficial effect of remdesivir on time to recovery was primarily observed in participants within the severe disease stratum (those requiring supplemental oxygen) at baseline (12 days in remdesivir group versus 18 days in placebo group), but not in those with mild-moderate disease at the time of study enrollment (5 days in either remdesivir or placebo group). Moreover, the beneficial effects of remdesivir on reducing time to recovery was not observed in participants who required mechanical ventilation or ECMO at enrollment. Thus, these preliminary results suggest that COVID-19 disease severity and timing, particularly in patients who require supplemental oxygen but prior to disease progression towards requiring mechanical ventilation, may present a window of opportunity to initiate remdesivir treatment in order to improve outcomes. Further analysis utilizing data from the entire cohort, including outcomes data from the full 28-day follow-up period, may better delineate the subgroup of hospitalized COVID-19 patients who may benefit most from remdesivir. Last, safety data from the present study, along with that reported by Wang and colleagues,4 provides evidence that intravenous remdesivir administration is likely safe in adults during the treatment period.
The preliminary results from the ACCT-1 provide early evidence that remdesivir shortens time to recovery in adult patients hospitalized for COVID-19 with pulmonary involvement. In light of these results, the US Food and Drug Administration issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.5 In addition, remdesivir has also recently been approved as a therapy for COVID-19 in Japan, Taiwan, India, Singapore, and the United Arab Emirates, and has received conditional approval for use by the European Commission.6
Although these are encouraging developments in the race to identify effective therapeutics for COVID-19, a number of unanswered questions regarding the administration of remdesivir in the treatment of this disease remain. For instance, in an open-label, randomized, multicenter trial of patients with severe COVID-19 not requiring mechanical ventilation, treatment with a 5-day course versus a 10-day course of intravenous remdesivir did not result in a significant difference in efficacy.7 Thus, more studies are needed to better determine the shortest effective duration of remdesivir therapy in COVID-19 patients with different disease severity. Also, the mortality rate in COVID-19 patients who were treated with remdesivir remained high in the current study. Therefore, there is ample opportunity to evaluate treatment strategies, including multidrug interventions with remdesivir, to reduce mortality and improve clinical outcomes in patients hospitalized with COVID-19.
Applications for Clinical Practice
Remdesivir shortens time to recovery in adult patients hospitalized with COVID-19 who require supplemental oxygen therapy. While much needs to be learned in order to optimize treatment of COVID-19, preliminary findings from the current study provide an important first step towards these discoveries.
–Fred Ko, MD, MS
1. Johns Hopkins University Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html. Accessed July 16, 2020.
2. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial [published online April 14, 2020]. medRxiv 2020; doi:10.1101/2020.04.10.20060558.
3. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;382:1787-1799.
4. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578.
5. Coronavirus (COVID-19) update: FDA issues Emergency Use Authorization for potential COVID-19 treatment. www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment. Accessed July 16, 2020.
6. Gilead’s COVID-19 antiviral remdesivir gets conditional EU clearance. www.reuters.com/article/us-health-coronavirus-eu-remdesivir/gileads-covid-19-antiviral-remdesivir-gets-conditional-eu-clearance-idUSKBN2441GK. Accessed July 6, 2020.
7. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020 May 27.doi: 10.1056/NEJMoa2015301. Online ahead of print.
Study Overview
Objective. To assess the clinical efficacy and safety of remdesivir in hospitalized adults with laboratory-confirmed COVID-19 and with evidence of lower respiratory tract involvement.
Design. Double-blinded, randomized, placebo-controlled, multicenter trial.
Setting and participants. Enrollment for the study took place between February 21, 2020, and April 19, 2020, at 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Study participants included patients aged ≥ 18 years who were hospitalized and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as determined by a positive reverse transcription polymerase chain reaction assay on a respiratory specimen. Participants had evidence of lower respiratory tract infection at the time of enrollment; this was defined as radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO2) ≤ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Exclusion criteria for study participation included abnormal liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than 5 times the upper limit of normal range; impaired renal function or need for hemodialysis or hemofiltration; pregnancy or breastfeeding; or anticipated hospital discharge or transfer to another hospital within 72 hours of enrollment.
Intervention. Participants were randomized in a 1:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200-mg loading dose on day 1, followed by a 100-mg maintenance dose daily on days 2 through 10, or until hospital discharge or death) or placebo for up to 10 days. Blinding was maintained by masking infusions with an opaque bag and tubing. Randomization was stratified by study site and disease severity at enrollment. Supportive care was delivered to all participants according to the standard of care at each trial site hospital. Clinical status, determined using an 8-category ordinal scale and the National Early Warning Score, was assessed daily for each participant while hospitalized (day 1 through day 29).
Blood samples for safety laboratory tests were collected, and oropharyngeal or nasopharyngeal swab testing was performed for viral RNA detection and quantification on days 1, 3, 5, 8, and 11. All serious adverse events (AEs) and grade 3/4 AEs that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions associated with the study drug or placebo administration were recorded.
Main outcome measures. The primary endpoint measure of this study was time to recovery, defined as the first day during the 28 days after enrollment on which a participant satisfied category 1 (ie, not hospitalized, no limitations of activities), 2 (ie, not hospitalized, limitation of activities, home oxygen requirement, or both), or 3 (ie, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; hospitalization was extended for infection-control reason) on the 8-category ordinal scale. Secondary outcomes included all-cause mortality at 14 and 28 days after enrollment and grade 3/4 AEs and serious AEs that occurred during trial participation. Analysis of the primary outcome was performed using a log-rank test of the time to recovery comparing remdesivir with placebo group, stratified by disease severity.
The study’s primary outcome was initially defined as a difference in clinical status as ascertained by the 8-category ordinal scale between groups of participants who were administered remdesivir versus placebo on day 15. Because of new knowledge gained external to the study about a more protracted COVID-19 clinical course than previously recognized, a change in primary outcome to time to recovery was proposed by trial statisticians, who were unaware of treatment assignments (72 participants had been enrolled) or outcome data (no interim data) on March 22, 2020, with subsequent amendment approval on April 2, 2020. On April 27, 2020, the Data and Safety Monitoring Board (DSMB) reviewed the interim study analysis (with data cutoff date of April 22, 2020) and recommended the report and mortality data to be provided to trial team members from the National Institute of Allergy and Infectious Diseases; these findings were subsequently made public.
Main results. A total of 1107 patients were assessed for eligibility, of whom 1063 underwent randomization, with 541 assigned to remdesivir and 522 to placebo. Results were unblinded early at the recommendation of DSMB due to findings from the interim analysis that showed reduced time to recovery in the group that received remdesivir. As of April 28, 2020, a total of 391 participants in the remdesivir group and 340 participants in the placebo group had completed the trial (day 29), recovered, or died. The mean age of participants was 58.9 ± 15.0 years, the majority were men (64.3%) and were White (53.2%), and the most common prespecified coexisting conditions were hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The vast majority of participants (88.7%) had severe COVID-19 disease at enrollment, defined as requiring invasive or noninvasive mechanical ventilation, requiring supplemental oxygen, SpO2 ≤ 94% on room air, or tachypnea (respiratory rate ≥ 24 breaths per minute).
Based on available data from 1059 participants (538 from the remdesivir group and 521 from the placebo group), those in the remdesivir group had a shorter median recovery time of 11 days (95% confidence interval [CI], 9-12) as compared to 15 days (95% CI, 13-19) in the placebo group, with a rate ratio for recovery of 1.32 (95% CI, 1.12-1.55; P < 0.001). Moreover, the odds of improvement on day 15 in the 8-category ordinal scale score were higher in the remdesivir group, compared to the placebo group (proportional odds model; odds ratio, 1.50; 95% CI, 1.18-1.91; P = 0.001; 844 participants).
Mortality rate by 14 days was numerically lower in the remdesivir group (7.1%) compared to the placebo group (11.9%), but the difference was not statistically significant (Kaplan-Meier, hazard ratio for death, 0.70; 95% CI, 0.47-1.04). Serious AEs were reported in 114 of the 541 (21.1%) participants in the remdesivir group and 141 of the 522 (27.0%) participants in the placebo group. Moreover, grade 3/4 AEs occurred in 156 (28.8%) participants in the remdesivir group and in 172 (33.0%) in the placebo group.
Conclusion. The study found that remdesivir, compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.
Commentary
Since the initial reporting of a cluster of cases of pneumonia in Wuhan, China, on December 31, 2019, SARS-CoV-2 has been identified as the cause of this new disease (COVID-19), and to-date SARS-CoV-2 infection has affected more than 15.2 million people globally, with more than 3.9 million cases in the United States alone.1 Despite an unprecedented global research effort, as well as public-private research partnerships, both in terms of scale and scope, an effective pharmacologic therapy for COVID-19 has so far eluded the scientific and medical community. Early trials of hydroxychloroquine and lopinavir-ritonavir did not demonstrate a clinical benefit in patients with COVID-19.2,3 Moreover, the first randomized controlled trial of remdesivir in COVID-19, a nucleoside analogue prodrug and a broad-spectrum antiviral agent previously shown to have inhibitory effects on pathogenic coronaviruses, was an underpowered study, and thus inconclusive.4 Thus, given the persistence of the COVID-19 pandemic and a current lack of effective vaccines or curative treatments, the study reported by Beigel and colleagues is timely and provides much needed knowledge in developing potential therapies for COVID-19.
The present report described the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACCT-1), which aimed to evaluate the clinical efficacy and safety of intravenous remdesivir, as compared to placebo, in hospitalized adults with laboratory-confirmed COVID-19. The study itself was well-designed and conducted. The successful enrollment of more than 1000 participants randomized in a 1:1 ratio within a 2-month recruitment window, involving 60 international trial sites, shortly after the emergence of a new global pandemic was remarkable. This study provided the first evidence that remdesivir, an antiviral, can shorten time to recovery by approximately 31% compared to placebo in COVID-19 patients with lower respiratory tract involvement.
Interestingly, this beneficial effect of remdesivir on time to recovery was primarily observed in participants within the severe disease stratum (those requiring supplemental oxygen) at baseline (12 days in remdesivir group versus 18 days in placebo group), but not in those with mild-moderate disease at the time of study enrollment (5 days in either remdesivir or placebo group). Moreover, the beneficial effects of remdesivir on reducing time to recovery was not observed in participants who required mechanical ventilation or ECMO at enrollment. Thus, these preliminary results suggest that COVID-19 disease severity and timing, particularly in patients who require supplemental oxygen but prior to disease progression towards requiring mechanical ventilation, may present a window of opportunity to initiate remdesivir treatment in order to improve outcomes. Further analysis utilizing data from the entire cohort, including outcomes data from the full 28-day follow-up period, may better delineate the subgroup of hospitalized COVID-19 patients who may benefit most from remdesivir. Last, safety data from the present study, along with that reported by Wang and colleagues,4 provides evidence that intravenous remdesivir administration is likely safe in adults during the treatment period.
The preliminary results from the ACCT-1 provide early evidence that remdesivir shortens time to recovery in adult patients hospitalized for COVID-19 with pulmonary involvement. In light of these results, the US Food and Drug Administration issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.5 In addition, remdesivir has also recently been approved as a therapy for COVID-19 in Japan, Taiwan, India, Singapore, and the United Arab Emirates, and has received conditional approval for use by the European Commission.6
Although these are encouraging developments in the race to identify effective therapeutics for COVID-19, a number of unanswered questions regarding the administration of remdesivir in the treatment of this disease remain. For instance, in an open-label, randomized, multicenter trial of patients with severe COVID-19 not requiring mechanical ventilation, treatment with a 5-day course versus a 10-day course of intravenous remdesivir did not result in a significant difference in efficacy.7 Thus, more studies are needed to better determine the shortest effective duration of remdesivir therapy in COVID-19 patients with different disease severity. Also, the mortality rate in COVID-19 patients who were treated with remdesivir remained high in the current study. Therefore, there is ample opportunity to evaluate treatment strategies, including multidrug interventions with remdesivir, to reduce mortality and improve clinical outcomes in patients hospitalized with COVID-19.
Applications for Clinical Practice
Remdesivir shortens time to recovery in adult patients hospitalized with COVID-19 who require supplemental oxygen therapy. While much needs to be learned in order to optimize treatment of COVID-19, preliminary findings from the current study provide an important first step towards these discoveries.
–Fred Ko, MD, MS
Study Overview
Objective. To assess the clinical efficacy and safety of remdesivir in hospitalized adults with laboratory-confirmed COVID-19 and with evidence of lower respiratory tract involvement.
Design. Double-blinded, randomized, placebo-controlled, multicenter trial.
Setting and participants. Enrollment for the study took place between February 21, 2020, and April 19, 2020, at 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Study participants included patients aged ≥ 18 years who were hospitalized and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as determined by a positive reverse transcription polymerase chain reaction assay on a respiratory specimen. Participants had evidence of lower respiratory tract infection at the time of enrollment; this was defined as radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO2) ≤ 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Exclusion criteria for study participation included abnormal liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than 5 times the upper limit of normal range; impaired renal function or need for hemodialysis or hemofiltration; pregnancy or breastfeeding; or anticipated hospital discharge or transfer to another hospital within 72 hours of enrollment.
Intervention. Participants were randomized in a 1:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200-mg loading dose on day 1, followed by a 100-mg maintenance dose daily on days 2 through 10, or until hospital discharge or death) or placebo for up to 10 days. Blinding was maintained by masking infusions with an opaque bag and tubing. Randomization was stratified by study site and disease severity at enrollment. Supportive care was delivered to all participants according to the standard of care at each trial site hospital. Clinical status, determined using an 8-category ordinal scale and the National Early Warning Score, was assessed daily for each participant while hospitalized (day 1 through day 29).
Blood samples for safety laboratory tests were collected, and oropharyngeal or nasopharyngeal swab testing was performed for viral RNA detection and quantification on days 1, 3, 5, 8, and 11. All serious adverse events (AEs) and grade 3/4 AEs that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions associated with the study drug or placebo administration were recorded.
Main outcome measures. The primary endpoint measure of this study was time to recovery, defined as the first day during the 28 days after enrollment on which a participant satisfied category 1 (ie, not hospitalized, no limitations of activities), 2 (ie, not hospitalized, limitation of activities, home oxygen requirement, or both), or 3 (ie, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; hospitalization was extended for infection-control reason) on the 8-category ordinal scale. Secondary outcomes included all-cause mortality at 14 and 28 days after enrollment and grade 3/4 AEs and serious AEs that occurred during trial participation. Analysis of the primary outcome was performed using a log-rank test of the time to recovery comparing remdesivir with placebo group, stratified by disease severity.
The study’s primary outcome was initially defined as a difference in clinical status as ascertained by the 8-category ordinal scale between groups of participants who were administered remdesivir versus placebo on day 15. Because of new knowledge gained external to the study about a more protracted COVID-19 clinical course than previously recognized, a change in primary outcome to time to recovery was proposed by trial statisticians, who were unaware of treatment assignments (72 participants had been enrolled) or outcome data (no interim data) on March 22, 2020, with subsequent amendment approval on April 2, 2020. On April 27, 2020, the Data and Safety Monitoring Board (DSMB) reviewed the interim study analysis (with data cutoff date of April 22, 2020) and recommended the report and mortality data to be provided to trial team members from the National Institute of Allergy and Infectious Diseases; these findings were subsequently made public.
Main results. A total of 1107 patients were assessed for eligibility, of whom 1063 underwent randomization, with 541 assigned to remdesivir and 522 to placebo. Results were unblinded early at the recommendation of DSMB due to findings from the interim analysis that showed reduced time to recovery in the group that received remdesivir. As of April 28, 2020, a total of 391 participants in the remdesivir group and 340 participants in the placebo group had completed the trial (day 29), recovered, or died. The mean age of participants was 58.9 ± 15.0 years, the majority were men (64.3%) and were White (53.2%), and the most common prespecified coexisting conditions were hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The vast majority of participants (88.7%) had severe COVID-19 disease at enrollment, defined as requiring invasive or noninvasive mechanical ventilation, requiring supplemental oxygen, SpO2 ≤ 94% on room air, or tachypnea (respiratory rate ≥ 24 breaths per minute).
Based on available data from 1059 participants (538 from the remdesivir group and 521 from the placebo group), those in the remdesivir group had a shorter median recovery time of 11 days (95% confidence interval [CI], 9-12) as compared to 15 days (95% CI, 13-19) in the placebo group, with a rate ratio for recovery of 1.32 (95% CI, 1.12-1.55; P < 0.001). Moreover, the odds of improvement on day 15 in the 8-category ordinal scale score were higher in the remdesivir group, compared to the placebo group (proportional odds model; odds ratio, 1.50; 95% CI, 1.18-1.91; P = 0.001; 844 participants).
Mortality rate by 14 days was numerically lower in the remdesivir group (7.1%) compared to the placebo group (11.9%), but the difference was not statistically significant (Kaplan-Meier, hazard ratio for death, 0.70; 95% CI, 0.47-1.04). Serious AEs were reported in 114 of the 541 (21.1%) participants in the remdesivir group and 141 of the 522 (27.0%) participants in the placebo group. Moreover, grade 3/4 AEs occurred in 156 (28.8%) participants in the remdesivir group and in 172 (33.0%) in the placebo group.
Conclusion. The study found that remdesivir, compared to placebo, significantly shortened time to recovery in adult patients hospitalized with COVID-19 who had evidence of lower respiratory tract infection.
Commentary
Since the initial reporting of a cluster of cases of pneumonia in Wuhan, China, on December 31, 2019, SARS-CoV-2 has been identified as the cause of this new disease (COVID-19), and to-date SARS-CoV-2 infection has affected more than 15.2 million people globally, with more than 3.9 million cases in the United States alone.1 Despite an unprecedented global research effort, as well as public-private research partnerships, both in terms of scale and scope, an effective pharmacologic therapy for COVID-19 has so far eluded the scientific and medical community. Early trials of hydroxychloroquine and lopinavir-ritonavir did not demonstrate a clinical benefit in patients with COVID-19.2,3 Moreover, the first randomized controlled trial of remdesivir in COVID-19, a nucleoside analogue prodrug and a broad-spectrum antiviral agent previously shown to have inhibitory effects on pathogenic coronaviruses, was an underpowered study, and thus inconclusive.4 Thus, given the persistence of the COVID-19 pandemic and a current lack of effective vaccines or curative treatments, the study reported by Beigel and colleagues is timely and provides much needed knowledge in developing potential therapies for COVID-19.
The present report described the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACCT-1), which aimed to evaluate the clinical efficacy and safety of intravenous remdesivir, as compared to placebo, in hospitalized adults with laboratory-confirmed COVID-19. The study itself was well-designed and conducted. The successful enrollment of more than 1000 participants randomized in a 1:1 ratio within a 2-month recruitment window, involving 60 international trial sites, shortly after the emergence of a new global pandemic was remarkable. This study provided the first evidence that remdesivir, an antiviral, can shorten time to recovery by approximately 31% compared to placebo in COVID-19 patients with lower respiratory tract involvement.
Interestingly, this beneficial effect of remdesivir on time to recovery was primarily observed in participants within the severe disease stratum (those requiring supplemental oxygen) at baseline (12 days in remdesivir group versus 18 days in placebo group), but not in those with mild-moderate disease at the time of study enrollment (5 days in either remdesivir or placebo group). Moreover, the beneficial effects of remdesivir on reducing time to recovery was not observed in participants who required mechanical ventilation or ECMO at enrollment. Thus, these preliminary results suggest that COVID-19 disease severity and timing, particularly in patients who require supplemental oxygen but prior to disease progression towards requiring mechanical ventilation, may present a window of opportunity to initiate remdesivir treatment in order to improve outcomes. Further analysis utilizing data from the entire cohort, including outcomes data from the full 28-day follow-up period, may better delineate the subgroup of hospitalized COVID-19 patients who may benefit most from remdesivir. Last, safety data from the present study, along with that reported by Wang and colleagues,4 provides evidence that intravenous remdesivir administration is likely safe in adults during the treatment period.
The preliminary results from the ACCT-1 provide early evidence that remdesivir shortens time to recovery in adult patients hospitalized for COVID-19 with pulmonary involvement. In light of these results, the US Food and Drug Administration issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.5 In addition, remdesivir has also recently been approved as a therapy for COVID-19 in Japan, Taiwan, India, Singapore, and the United Arab Emirates, and has received conditional approval for use by the European Commission.6
Although these are encouraging developments in the race to identify effective therapeutics for COVID-19, a number of unanswered questions regarding the administration of remdesivir in the treatment of this disease remain. For instance, in an open-label, randomized, multicenter trial of patients with severe COVID-19 not requiring mechanical ventilation, treatment with a 5-day course versus a 10-day course of intravenous remdesivir did not result in a significant difference in efficacy.7 Thus, more studies are needed to better determine the shortest effective duration of remdesivir therapy in COVID-19 patients with different disease severity. Also, the mortality rate in COVID-19 patients who were treated with remdesivir remained high in the current study. Therefore, there is ample opportunity to evaluate treatment strategies, including multidrug interventions with remdesivir, to reduce mortality and improve clinical outcomes in patients hospitalized with COVID-19.
Applications for Clinical Practice
Remdesivir shortens time to recovery in adult patients hospitalized with COVID-19 who require supplemental oxygen therapy. While much needs to be learned in order to optimize treatment of COVID-19, preliminary findings from the current study provide an important first step towards these discoveries.
–Fred Ko, MD, MS
1. Johns Hopkins University Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html. Accessed July 16, 2020.
2. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial [published online April 14, 2020]. medRxiv 2020; doi:10.1101/2020.04.10.20060558.
3. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;382:1787-1799.
4. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578.
5. Coronavirus (COVID-19) update: FDA issues Emergency Use Authorization for potential COVID-19 treatment. www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment. Accessed July 16, 2020.
6. Gilead’s COVID-19 antiviral remdesivir gets conditional EU clearance. www.reuters.com/article/us-health-coronavirus-eu-remdesivir/gileads-covid-19-antiviral-remdesivir-gets-conditional-eu-clearance-idUSKBN2441GK. Accessed July 6, 2020.
7. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020 May 27.doi: 10.1056/NEJMoa2015301. Online ahead of print.
1. Johns Hopkins University Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html. Accessed July 16, 2020.
2. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial [published online April 14, 2020]. medRxiv 2020; doi:10.1101/2020.04.10.20060558.
3. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;382:1787-1799.
4. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578.
5. Coronavirus (COVID-19) update: FDA issues Emergency Use Authorization for potential COVID-19 treatment. www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment. Accessed July 16, 2020.
6. Gilead’s COVID-19 antiviral remdesivir gets conditional EU clearance. www.reuters.com/article/us-health-coronavirus-eu-remdesivir/gileads-covid-19-antiviral-remdesivir-gets-conditional-eu-clearance-idUSKBN2441GK. Accessed July 6, 2020.
7. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020 May 27.doi: 10.1056/NEJMoa2015301. Online ahead of print.
Long-Term Exercise Training in Older Adults Is Associated with Reduced Injurious Falls and Fractures
Study Overview
Objective. To evaluate the association between long-term exercise interventions (duration ≥ 1 year) and risks of falls, injurious falls, multiple falls, fractures, hospitalization, and mortality in older adults.
Design. A systematic review of randomized controlled trials (RCTs) with preplanned meta-analysis was conducted to investigate the association between long-term exercise interventions and falls and fall-related adverse outcomes in adults older than 60 years. A literature search using electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, SportDiscus, PsychInfo, and Ageline, was performed between February 20 and March 5, 2018. Studies selected were RCTs with exercise duration of 1 year or longer, where effects of exercise intervention were compared with a comparator group of participants aged 60 years or older. Articles were independently screened, abstracted, and assessed for risk of bias by 2 raters, who resolved divergences in data extraction and synthesis via in-person meetings.
Setting and participants. A total of 46 studies (22,709 participants; median of 203 participants per study) were included in the review and 40 studies (21,868 participants) were included in the meta-analysis. The participants’ mean age was 73.1 ± 7.1 years, and 66.3% (15,054 participants) were women. Studies were mostly conducted in Europe (n = 15), North America (n = 13), and Oceania (n = 10). Multicomponent training involving multiple exercises (eg, aerobic, strength and balance; 29 RCTs) was the most common intervention modality, followed by aerobic (8 RCTs) and strength (5 RCTs) training. Exercise interventions had a mean frequency of 3 times/week, with each session lasting approximately 50 minutes, and were administered at a moderate intensity. The average compliance rate with exercise training was 65%. Comparator groups were often active controls that ranged from attention controls to more intensive interventions.
Main outcome measures. The 6 binary outcomes investigated were fallers who fell at least once, multiple times, or at least twice; fractures; hospitalization; and mortality. Estimates of outcomes were combined using risk ratios (RRs) using DerSimonian and Laird’s random-effects model (Mantel-Haenszel method). Heterogeneity was evaluated using I2 statistics, and trials with low rates of compliance (< 30%) with exercise intervention or high attrition (> 40%) were excluded in primary analyses.
Main results. Exercise training significantly reduced the risk of falls by 12% (n = 20 RCTs; 4420 participants; RR, 0.88; 95% confidence interval [CI], 0.79-0.98) and injurious falls by 26% (9 RCTs; 4481 participants; RR, 0.74; 95% CI, 0.62-0.88), and reduced the risk of fractures by 16% (19 RCTs; 8410 participants; RR, 0.84; 95% CI, 0.71-1.00; P = 0.05). Exercise training did not decrease the risk of multiple falls (13 RCTs; 3060 participants; RR, 0.86; 95% CI, 0.68-1.08), hospitalization (12 RCTs; 5639 participants; RR 0.94; 95% CI, 0.80-1.12), or mortality (29 RCTs; 11,441 participants; RR 0.96; 95% CI, 0.85-1.09). Sensitivity analyses yielded similar results, with the exception of the fixed-effect meta-analysis for the risk of fracture that showed a significant effect of long-term exercise training (RR, 0.84; 95% CI, 0.70-1.00; P = 0.047). Meta-regression analysis on mortality and falls suggested that exercise frequency between 2 and 3 times per week was optimal and beneficial.
Conclusion. Long-term exercise training of 1 year or longer in duration is associated with a reduction in falls, injurious falls, and fractures in older adults. Moreover, moderate intensity, multicomponent exercise training performed 2 to 3 times weekly is likely safe and effective in this vulnerable population.
Commentary
Falls are exceedingly common (1 in 3 older Americans fall each year) and are the leading cause of fatal and nonfatal injuries in persons over the age of 65 years.1,2 While fall prevention is a public health priority and a topic of interest in many research studies, there are important gaps in knowledge regarding optimal strategies to prevent falls and fall-related injuries in this high-risk population. The study reported by de Souto Barreto and colleagues provides new insights to address several of these gaps and may have a significant impact on the clinical practice of fall prevention in geriatric medicine.
Studies show that a single exercise intervention of short- to medium-term duration can prevent falls in community-dwelling older adults.3 However, the effects of long-term exercise training (ie, intervention lasting longer than a year) on fall prevention in this population is less well characterized. This study is the first meta-analysis that aimed to evaluate the potential beneficial impact of long-term exercise training on falls and adverse fall-related outcomes in adults ≥ 60 years of age who are prone to falls. The study’s findings indicate that long-term exercise training reduces the risk of falling by 12%, injurious falls by 26%, and factures by 16%. These results are important in that they add compelling evidence that exercise training of any duration can reduce falls and some fall-related adverse outcomes. Furthermore, the positive effects of long-term exercise training appear to mitigate some of the fatal and nonfatal injuries attributable to falls—the leading cause of such injuries in older adults.
The modality (type) and dose (frequency) of exercise training are important components of “exercise prescription” for older adults. However, there is a lack of research evidence to help clearly define these exercise parameters to better guide development of consensus exercise recommendations for older patients. This gap in knowledge limits the clinicians’ ability to recommend evidence-based treatment regimens to older adults who are at higher risk for falls. Moreover, although exercise programs are rarely associated with serious adverse events, recent findings from the Lifestyle Interventions and Independence for Elders (LIFE) study found a modest and nonstatistically significant association between long-term, moderate-intensity physical activity programs and an increase in hospitalizations and mortality in older adults.4,5 Taken together, these gaps in knowledge highlight the urgent need to better understand the optimal methods for administering exercise programs in older adults as well as the need for critical appraisals of the benefits and harms associated with long-term exercise training in this vulnerable population.
The results reported by de Souto Barreto and colleagues helped to address these questions. In this study, the authors found that long-term multicomponent training, particularly moderate intensity with balance exercises performed 2 to 3 times a week, appears to be a safe and effective intervention for reducing falls and injurious falls in older adults. Importantly, this type of long-term exercise regimen does not increase hospitalization and mortality, and thus supports the notion that exercise therapy is safe in older adults. Therefore, information gained from this meta-analysis should help to guide clinicians to devise a patient-centered exercise prescription for fall prevention.
The current study was well designed and has a number of strengths. The design of the systematic review and meta-analysis allowed aggregation of data from multiple trials, resulting in a more robust point estimate to evaluate the effects of long-term exercise training on falls and fall-related outcomes that otherwise cannot be achieved with individual trials. In addition, the emphasis on long-term exercise training in older adults in the setting of falls and adverse fall-related outcomes addresses a key area of research that currently lacks a sufficient evidence base. There are also several limitations in this study, primarily due to the nature of its meta-analysis design. For instance, the study populations included in the analysis are highly heterogeneous and range from those with dementia to healthy participants. In addition, long-term exercise training, defined as a duration ≥ 1 year, was arbitrarily established as the minimum period of intervention. Thus, potential important studies that include interventions of significant duration, but less than 1 year, may not have been captured in this analysis.
Applications for Clinical Practice
Falls in older adults are common and may lead to devastating health consequences. The implementation of a long-term, multicomponent, moderate-intensity exercise regimen performed 2 to 3 times weekly can reduce falls and injurious falls in older adults.
—Fred Ko, MD, MS
1. Schiller JS, Kramarow EA, Dey AN. Fall injury episodes among noninstitutionalized older adults: United States, 2001-2003. Adv Data. 2007(392);1-16.
2. Sterling DA, O’Connor JA, Bonadies J. Geriatric falls: injury severity is high and disproportionate to mechanism. J Trauma. 2001;50:116-119.
3. Sherrington C, Michaleff ZA, Fairhall N, et al. Exercise to prevent falls in older adults: an updated systematic review and meta-analysis. Br J Sports Med. 2017;51:1750-1758.
4. Liu CJ, Latham, NK. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev. 2009;CD002759.
5. Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311:2387-2396.
Study Overview
Objective. To evaluate the association between long-term exercise interventions (duration ≥ 1 year) and risks of falls, injurious falls, multiple falls, fractures, hospitalization, and mortality in older adults.
Design. A systematic review of randomized controlled trials (RCTs) with preplanned meta-analysis was conducted to investigate the association between long-term exercise interventions and falls and fall-related adverse outcomes in adults older than 60 years. A literature search using electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, SportDiscus, PsychInfo, and Ageline, was performed between February 20 and March 5, 2018. Studies selected were RCTs with exercise duration of 1 year or longer, where effects of exercise intervention were compared with a comparator group of participants aged 60 years or older. Articles were independently screened, abstracted, and assessed for risk of bias by 2 raters, who resolved divergences in data extraction and synthesis via in-person meetings.
Setting and participants. A total of 46 studies (22,709 participants; median of 203 participants per study) were included in the review and 40 studies (21,868 participants) were included in the meta-analysis. The participants’ mean age was 73.1 ± 7.1 years, and 66.3% (15,054 participants) were women. Studies were mostly conducted in Europe (n = 15), North America (n = 13), and Oceania (n = 10). Multicomponent training involving multiple exercises (eg, aerobic, strength and balance; 29 RCTs) was the most common intervention modality, followed by aerobic (8 RCTs) and strength (5 RCTs) training. Exercise interventions had a mean frequency of 3 times/week, with each session lasting approximately 50 minutes, and were administered at a moderate intensity. The average compliance rate with exercise training was 65%. Comparator groups were often active controls that ranged from attention controls to more intensive interventions.
Main outcome measures. The 6 binary outcomes investigated were fallers who fell at least once, multiple times, or at least twice; fractures; hospitalization; and mortality. Estimates of outcomes were combined using risk ratios (RRs) using DerSimonian and Laird’s random-effects model (Mantel-Haenszel method). Heterogeneity was evaluated using I2 statistics, and trials with low rates of compliance (< 30%) with exercise intervention or high attrition (> 40%) were excluded in primary analyses.
Main results. Exercise training significantly reduced the risk of falls by 12% (n = 20 RCTs; 4420 participants; RR, 0.88; 95% confidence interval [CI], 0.79-0.98) and injurious falls by 26% (9 RCTs; 4481 participants; RR, 0.74; 95% CI, 0.62-0.88), and reduced the risk of fractures by 16% (19 RCTs; 8410 participants; RR, 0.84; 95% CI, 0.71-1.00; P = 0.05). Exercise training did not decrease the risk of multiple falls (13 RCTs; 3060 participants; RR, 0.86; 95% CI, 0.68-1.08), hospitalization (12 RCTs; 5639 participants; RR 0.94; 95% CI, 0.80-1.12), or mortality (29 RCTs; 11,441 participants; RR 0.96; 95% CI, 0.85-1.09). Sensitivity analyses yielded similar results, with the exception of the fixed-effect meta-analysis for the risk of fracture that showed a significant effect of long-term exercise training (RR, 0.84; 95% CI, 0.70-1.00; P = 0.047). Meta-regression analysis on mortality and falls suggested that exercise frequency between 2 and 3 times per week was optimal and beneficial.
Conclusion. Long-term exercise training of 1 year or longer in duration is associated with a reduction in falls, injurious falls, and fractures in older adults. Moreover, moderate intensity, multicomponent exercise training performed 2 to 3 times weekly is likely safe and effective in this vulnerable population.
Commentary
Falls are exceedingly common (1 in 3 older Americans fall each year) and are the leading cause of fatal and nonfatal injuries in persons over the age of 65 years.1,2 While fall prevention is a public health priority and a topic of interest in many research studies, there are important gaps in knowledge regarding optimal strategies to prevent falls and fall-related injuries in this high-risk population. The study reported by de Souto Barreto and colleagues provides new insights to address several of these gaps and may have a significant impact on the clinical practice of fall prevention in geriatric medicine.
Studies show that a single exercise intervention of short- to medium-term duration can prevent falls in community-dwelling older adults.3 However, the effects of long-term exercise training (ie, intervention lasting longer than a year) on fall prevention in this population is less well characterized. This study is the first meta-analysis that aimed to evaluate the potential beneficial impact of long-term exercise training on falls and adverse fall-related outcomes in adults ≥ 60 years of age who are prone to falls. The study’s findings indicate that long-term exercise training reduces the risk of falling by 12%, injurious falls by 26%, and factures by 16%. These results are important in that they add compelling evidence that exercise training of any duration can reduce falls and some fall-related adverse outcomes. Furthermore, the positive effects of long-term exercise training appear to mitigate some of the fatal and nonfatal injuries attributable to falls—the leading cause of such injuries in older adults.
The modality (type) and dose (frequency) of exercise training are important components of “exercise prescription” for older adults. However, there is a lack of research evidence to help clearly define these exercise parameters to better guide development of consensus exercise recommendations for older patients. This gap in knowledge limits the clinicians’ ability to recommend evidence-based treatment regimens to older adults who are at higher risk for falls. Moreover, although exercise programs are rarely associated with serious adverse events, recent findings from the Lifestyle Interventions and Independence for Elders (LIFE) study found a modest and nonstatistically significant association between long-term, moderate-intensity physical activity programs and an increase in hospitalizations and mortality in older adults.4,5 Taken together, these gaps in knowledge highlight the urgent need to better understand the optimal methods for administering exercise programs in older adults as well as the need for critical appraisals of the benefits and harms associated with long-term exercise training in this vulnerable population.
The results reported by de Souto Barreto and colleagues helped to address these questions. In this study, the authors found that long-term multicomponent training, particularly moderate intensity with balance exercises performed 2 to 3 times a week, appears to be a safe and effective intervention for reducing falls and injurious falls in older adults. Importantly, this type of long-term exercise regimen does not increase hospitalization and mortality, and thus supports the notion that exercise therapy is safe in older adults. Therefore, information gained from this meta-analysis should help to guide clinicians to devise a patient-centered exercise prescription for fall prevention.
The current study was well designed and has a number of strengths. The design of the systematic review and meta-analysis allowed aggregation of data from multiple trials, resulting in a more robust point estimate to evaluate the effects of long-term exercise training on falls and fall-related outcomes that otherwise cannot be achieved with individual trials. In addition, the emphasis on long-term exercise training in older adults in the setting of falls and adverse fall-related outcomes addresses a key area of research that currently lacks a sufficient evidence base. There are also several limitations in this study, primarily due to the nature of its meta-analysis design. For instance, the study populations included in the analysis are highly heterogeneous and range from those with dementia to healthy participants. In addition, long-term exercise training, defined as a duration ≥ 1 year, was arbitrarily established as the minimum period of intervention. Thus, potential important studies that include interventions of significant duration, but less than 1 year, may not have been captured in this analysis.
Applications for Clinical Practice
Falls in older adults are common and may lead to devastating health consequences. The implementation of a long-term, multicomponent, moderate-intensity exercise regimen performed 2 to 3 times weekly can reduce falls and injurious falls in older adults.
—Fred Ko, MD, MS
Study Overview
Objective. To evaluate the association between long-term exercise interventions (duration ≥ 1 year) and risks of falls, injurious falls, multiple falls, fractures, hospitalization, and mortality in older adults.
Design. A systematic review of randomized controlled trials (RCTs) with preplanned meta-analysis was conducted to investigate the association between long-term exercise interventions and falls and fall-related adverse outcomes in adults older than 60 years. A literature search using electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, SportDiscus, PsychInfo, and Ageline, was performed between February 20 and March 5, 2018. Studies selected were RCTs with exercise duration of 1 year or longer, where effects of exercise intervention were compared with a comparator group of participants aged 60 years or older. Articles were independently screened, abstracted, and assessed for risk of bias by 2 raters, who resolved divergences in data extraction and synthesis via in-person meetings.
Setting and participants. A total of 46 studies (22,709 participants; median of 203 participants per study) were included in the review and 40 studies (21,868 participants) were included in the meta-analysis. The participants’ mean age was 73.1 ± 7.1 years, and 66.3% (15,054 participants) were women. Studies were mostly conducted in Europe (n = 15), North America (n = 13), and Oceania (n = 10). Multicomponent training involving multiple exercises (eg, aerobic, strength and balance; 29 RCTs) was the most common intervention modality, followed by aerobic (8 RCTs) and strength (5 RCTs) training. Exercise interventions had a mean frequency of 3 times/week, with each session lasting approximately 50 minutes, and were administered at a moderate intensity. The average compliance rate with exercise training was 65%. Comparator groups were often active controls that ranged from attention controls to more intensive interventions.
Main outcome measures. The 6 binary outcomes investigated were fallers who fell at least once, multiple times, or at least twice; fractures; hospitalization; and mortality. Estimates of outcomes were combined using risk ratios (RRs) using DerSimonian and Laird’s random-effects model (Mantel-Haenszel method). Heterogeneity was evaluated using I2 statistics, and trials with low rates of compliance (< 30%) with exercise intervention or high attrition (> 40%) were excluded in primary analyses.
Main results. Exercise training significantly reduced the risk of falls by 12% (n = 20 RCTs; 4420 participants; RR, 0.88; 95% confidence interval [CI], 0.79-0.98) and injurious falls by 26% (9 RCTs; 4481 participants; RR, 0.74; 95% CI, 0.62-0.88), and reduced the risk of fractures by 16% (19 RCTs; 8410 participants; RR, 0.84; 95% CI, 0.71-1.00; P = 0.05). Exercise training did not decrease the risk of multiple falls (13 RCTs; 3060 participants; RR, 0.86; 95% CI, 0.68-1.08), hospitalization (12 RCTs; 5639 participants; RR 0.94; 95% CI, 0.80-1.12), or mortality (29 RCTs; 11,441 participants; RR 0.96; 95% CI, 0.85-1.09). Sensitivity analyses yielded similar results, with the exception of the fixed-effect meta-analysis for the risk of fracture that showed a significant effect of long-term exercise training (RR, 0.84; 95% CI, 0.70-1.00; P = 0.047). Meta-regression analysis on mortality and falls suggested that exercise frequency between 2 and 3 times per week was optimal and beneficial.
Conclusion. Long-term exercise training of 1 year or longer in duration is associated with a reduction in falls, injurious falls, and fractures in older adults. Moreover, moderate intensity, multicomponent exercise training performed 2 to 3 times weekly is likely safe and effective in this vulnerable population.
Commentary
Falls are exceedingly common (1 in 3 older Americans fall each year) and are the leading cause of fatal and nonfatal injuries in persons over the age of 65 years.1,2 While fall prevention is a public health priority and a topic of interest in many research studies, there are important gaps in knowledge regarding optimal strategies to prevent falls and fall-related injuries in this high-risk population. The study reported by de Souto Barreto and colleagues provides new insights to address several of these gaps and may have a significant impact on the clinical practice of fall prevention in geriatric medicine.
Studies show that a single exercise intervention of short- to medium-term duration can prevent falls in community-dwelling older adults.3 However, the effects of long-term exercise training (ie, intervention lasting longer than a year) on fall prevention in this population is less well characterized. This study is the first meta-analysis that aimed to evaluate the potential beneficial impact of long-term exercise training on falls and adverse fall-related outcomes in adults ≥ 60 years of age who are prone to falls. The study’s findings indicate that long-term exercise training reduces the risk of falling by 12%, injurious falls by 26%, and factures by 16%. These results are important in that they add compelling evidence that exercise training of any duration can reduce falls and some fall-related adverse outcomes. Furthermore, the positive effects of long-term exercise training appear to mitigate some of the fatal and nonfatal injuries attributable to falls—the leading cause of such injuries in older adults.
The modality (type) and dose (frequency) of exercise training are important components of “exercise prescription” for older adults. However, there is a lack of research evidence to help clearly define these exercise parameters to better guide development of consensus exercise recommendations for older patients. This gap in knowledge limits the clinicians’ ability to recommend evidence-based treatment regimens to older adults who are at higher risk for falls. Moreover, although exercise programs are rarely associated with serious adverse events, recent findings from the Lifestyle Interventions and Independence for Elders (LIFE) study found a modest and nonstatistically significant association between long-term, moderate-intensity physical activity programs and an increase in hospitalizations and mortality in older adults.4,5 Taken together, these gaps in knowledge highlight the urgent need to better understand the optimal methods for administering exercise programs in older adults as well as the need for critical appraisals of the benefits and harms associated with long-term exercise training in this vulnerable population.
The results reported by de Souto Barreto and colleagues helped to address these questions. In this study, the authors found that long-term multicomponent training, particularly moderate intensity with balance exercises performed 2 to 3 times a week, appears to be a safe and effective intervention for reducing falls and injurious falls in older adults. Importantly, this type of long-term exercise regimen does not increase hospitalization and mortality, and thus supports the notion that exercise therapy is safe in older adults. Therefore, information gained from this meta-analysis should help to guide clinicians to devise a patient-centered exercise prescription for fall prevention.
The current study was well designed and has a number of strengths. The design of the systematic review and meta-analysis allowed aggregation of data from multiple trials, resulting in a more robust point estimate to evaluate the effects of long-term exercise training on falls and fall-related outcomes that otherwise cannot be achieved with individual trials. In addition, the emphasis on long-term exercise training in older adults in the setting of falls and adverse fall-related outcomes addresses a key area of research that currently lacks a sufficient evidence base. There are also several limitations in this study, primarily due to the nature of its meta-analysis design. For instance, the study populations included in the analysis are highly heterogeneous and range from those with dementia to healthy participants. In addition, long-term exercise training, defined as a duration ≥ 1 year, was arbitrarily established as the minimum period of intervention. Thus, potential important studies that include interventions of significant duration, but less than 1 year, may not have been captured in this analysis.
Applications for Clinical Practice
Falls in older adults are common and may lead to devastating health consequences. The implementation of a long-term, multicomponent, moderate-intensity exercise regimen performed 2 to 3 times weekly can reduce falls and injurious falls in older adults.
—Fred Ko, MD, MS
1. Schiller JS, Kramarow EA, Dey AN. Fall injury episodes among noninstitutionalized older adults: United States, 2001-2003. Adv Data. 2007(392);1-16.
2. Sterling DA, O’Connor JA, Bonadies J. Geriatric falls: injury severity is high and disproportionate to mechanism. J Trauma. 2001;50:116-119.
3. Sherrington C, Michaleff ZA, Fairhall N, et al. Exercise to prevent falls in older adults: an updated systematic review and meta-analysis. Br J Sports Med. 2017;51:1750-1758.
4. Liu CJ, Latham, NK. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev. 2009;CD002759.
5. Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311:2387-2396.
1. Schiller JS, Kramarow EA, Dey AN. Fall injury episodes among noninstitutionalized older adults: United States, 2001-2003. Adv Data. 2007(392);1-16.
2. Sterling DA, O’Connor JA, Bonadies J. Geriatric falls: injury severity is high and disproportionate to mechanism. J Trauma. 2001;50:116-119.
3. Sherrington C, Michaleff ZA, Fairhall N, et al. Exercise to prevent falls in older adults: an updated systematic review and meta-analysis. Br J Sports Med. 2017;51:1750-1758.
4. Liu CJ, Latham, NK. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev. 2009;CD002759.
5. Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311:2387-2396.
Multicomponent Exercise Program Can Reverse Hospitalization-Associated Functional Decline in Elderly Patients
Study Overview
Objective. To assess the effects of an individualized, multicomponent exercise intervention on the functional status of very elderly patients who were acutely hospitalized compared with those who received usual care.
Design. A single-center, single-blind randomized clinical trial comparing elderly (≥ 75 years old) hospitalized patients who received in-hospital exercise (ie, individualized low-intensity resistance, balance, and walking exercises) versus control (ie, usual care that included physical rehabilitation if needed) interventions. The exercise intervention was adapted from the multicomponent physical exercise program Vivifrail and was supervised and conducted by a fitness specialist in 2 daily (1 morning and 1 evening) sessions lasting 20 minutes for 5 to 7 consecutive days. The morning session consisted of supervised and individualized progressive resistance, balance, and walking exercises. The evening session consisted of functional unsupervised exercises including light weights, extension and flexion of knee and hip, and walking.
Setting and participants. The study was conducted in an acute care unit in a tertiary public hospital in Navarra, Spain, between 1 February 2015 and 30 August 2017. A total of 370 elderly patients undergoing acute care hospitalization were enrolled in the study and randomly assigned to receive in-hospital exercise or control intervention. Inclusion criteria were: age ≥ 75 years, Barthel Index score ≥ 60, and ambulatory with or without assistance.
Main outcome measures. The primary outcome was change in functional capacity from baseline (beginning of exercise or control intervention) to hospital discharge as assessed by the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary outcomes were changes in cognitive capacity (Mini-Mental State Examination [MMSE]) and mood status (Yesavage Geriatric Depression Scale [GDS]), quality of life (QoL; EuroQol-5D), handgrip strength (dominant hand), incident delirium (Confusion Assessment Method), length of stay (LOS), falls during hospitalization, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Intention-to-treat analysis was conducted.
Main results. Of the 370 patients included in the study’s analyses, 209 (56.5%) were women, mean age was 87.3 ± 4.9 years (range, 75-101 years; 130 [35.1%] nonagenarians). The median LOS was 8 days in both groups (interquartile range [IQR], 4 and 4 days, respectively). The median duration of the intervention was 5 days (IQR, 0 days), with 5 ± 1 morning and 4 ± 1 evening sessions in the exercise group. Adherence to the exercise intervention was high (95.8% for morning sessions; 83.4% for evening sessions), and no adverse effects were observed with the intervention.
The in-hospital exercise intervention program yielded significant benefits over usual care in functional outcomes in elderly patients. The exercise group had an increased change in measures of functional capacity compared to the usual care group (ie, Barthel Index, 6.9 points; 95% confidence interval [CI], 4.4-9.5; SPPB score, 2.2 points; 95% CI, 1.7-2.6). Furthermore, acute hospitalization led to an impairment in functional capacity from baseline to discharge in the Barthel Index (−5.0 points; 95% CI, −6.8 to −3.2) in the usual care group. In contrast, exercise intervention reversed this decline and improved functional outcomes as assessed by Barthel Index (1.9 points; 95% CI, 0.2-3.7) and SPPB score (2.4 points; 95% CI, 2.1-2.7).
The beneficial effects of the in-hospital exercise intervention extended to secondary end points indicative of cognitive capacity (MMSE, 1.8 points; 95% CI, 1.3-2.3), mood status (GDS, −2.0 points; 95% CI, −2.5 to −1.6), QoL (EuroQol-5D, 13.2 points; 95% CI, 8.2-18.2), and handgrip strength (2.3 kg; 95% CI, 1.8-2.8) compared to those who received usual care. In contrast, no differences were observed between groups that received exercise intervention and usual care in incident delirium, LOS, falls during hospitalization, transfer after discharge, and 3-month hospital readmission rate and mortality.
Conclusion. An individualized, multicomponent physical exercise program that includes low-intensity resistance, balance, and walking exercises performed during the course of hospitalization (average of 5 days) can reverse functional decline associated with acute hospitalization in very elderly patients. Furthermore, this in-hospital exercise intervention is safe and has a high adherence rate, and thus represents an opportunity to improve quality of care in this vulnerable population.
Commentary
Frail elderly patients are highly susceptible to adverse outcomes of acute hospitalization, including functional decline, disability, nursing home placement, rehospitalization, and mortality.1 Mobility limitation, a major hazard of hospitalization, has been associated with poorer functional recovery and increased vulnerability to these major adverse events after hospital discharge.2-4 Interdisciplinary care models delivered during hospitalization (eg, Geriatric Evaluation Unit, Acute Care for Elders) that emphasize functional independence and provide protocols for exercise and rehabilitation have demonstrated reduced hospital LOS, discharge to nursing home, and mortality, and improved functional status in elderly patients.5-7 Despite this evidence, significant gaps in knowledge exist in understanding whether early implementation of an individualized, multicomponent exercise training program can benefit the oldest old patients who are acutely hospitalized.
This study reported by Martinez-Velilla and colleagues provides an important and timely investigation in examining the effects of an individualized, multicomponent (ie, low-intensity resistance, balance, and walking) in-hospital exercise intervention on functional outcomes of hospitalized octogenarians and nonagenarians. The authors reported that such an intervention, administered 2 sessions per day for 5 to 7 consecutive days, can be safely implemented and reverse functional decline (ie, improvement in Barthel Index and SPPB score over course of hospital stay) typically associated with acute hospitalization in these vulnerable individuals. These findings are particularly significant given the paucity of randomized controlled trials evaluating the impact of exercise intervention in preserving functional capacity of geriatric patients in the setting of acute hospitalization. While much more research is needed to facilitate future development of a consensus opinion in this regard, results from this study provide the rationale that implementation of an individualized multicomponent exercise program is feasible and safe and may attenuate functional decline in hospitalized older patients. Finally, the beneficial effects of in-hospital exercise intervention may extend to cognitive capacity, mood status, and QoL—domains that are essential to optimizing patient-centered care in the frailest elderly patients.
The study was well conceived with a number of strengths, including its randomized clinical trial design. In addition, the trial patients were advanced in age (35.1% were nonagenarians), which is particularly important because this is a vulnerable population that is frequently excluded from participation in trials of exercise interventions and because the evidence-base for physical activity guidelines is suboptimal. Moreover, the authors demonstrated that an individualized multicomponent exercise program could be successfully implemented in elderly patients in an acute setting via daily exercise sessions. This test of feasibility is significant in that clinical trials in exercise intervention in geriatrics are commonly performed in nonacute settings in the community, long-term care facilities, or subacute care. The major limitation in this study centers on the generalizability of its findings. It was noted that some patients were not assessed for changes from baseline to discharge on the Barthel Index (6.1%) and SPPB (2.3%) because of their poor condition. The exclusion of the most debilitated patients limits the application of the study’s key findings to the frailest elderly patients, who are most likely to require acute hospital care.
Applications for Clinical Pract
Functional decline is an exceedingly common adverse outcome associated with hospitalization in older patients. While more evidence is needed, early implementation of an individualized, multicomponent exercise regimen during hospitalization may help to prevent functional decline in vulnerable elderly patients.
—Fred Ko, MD, MS
1. Goldwater DS, Dharmarajan K, McEwan BS, Krumholz HM. Is posthospital syndrome a result of hospitalization-induced allostatic overload? J Hosp Med. 2018;13(5).doi:10.12788/jhm.2986.
2. Creditor MC. Hazards of hospitalization of the elderly. Ann Intern Med. 1993;118:219-223.
3. Minnick AF, Mion LC, Johnson ME, et al. Prevalence and variation of physical restraint use in acute care settings in the US. J Nurs Scholarsh. 2007;39:30-37.
4. Zisberg A, Shadmi E, Sinoff G et al. Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc. 2011;59:266-273.
5. Rubenstein LZ, et al. Effectiveness of a geriatric evaluation unit. A randomized clinical trial. N Engl J Med. 1984;311:1664-1670.
6. Landefeld CS, Palmer RM, Kresevic DM, et al. A randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients. N Engl J Med. 1995;332:1338-1344.
7. de Morton NA, Keating JL, Jeffs K. Exercise for acutely hospitalised older medical patients. Cochrane Database Syst Rev. 2007;CD005955.
Study Overview
Objective. To assess the effects of an individualized, multicomponent exercise intervention on the functional status of very elderly patients who were acutely hospitalized compared with those who received usual care.
Design. A single-center, single-blind randomized clinical trial comparing elderly (≥ 75 years old) hospitalized patients who received in-hospital exercise (ie, individualized low-intensity resistance, balance, and walking exercises) versus control (ie, usual care that included physical rehabilitation if needed) interventions. The exercise intervention was adapted from the multicomponent physical exercise program Vivifrail and was supervised and conducted by a fitness specialist in 2 daily (1 morning and 1 evening) sessions lasting 20 minutes for 5 to 7 consecutive days. The morning session consisted of supervised and individualized progressive resistance, balance, and walking exercises. The evening session consisted of functional unsupervised exercises including light weights, extension and flexion of knee and hip, and walking.
Setting and participants. The study was conducted in an acute care unit in a tertiary public hospital in Navarra, Spain, between 1 February 2015 and 30 August 2017. A total of 370 elderly patients undergoing acute care hospitalization were enrolled in the study and randomly assigned to receive in-hospital exercise or control intervention. Inclusion criteria were: age ≥ 75 years, Barthel Index score ≥ 60, and ambulatory with or without assistance.
Main outcome measures. The primary outcome was change in functional capacity from baseline (beginning of exercise or control intervention) to hospital discharge as assessed by the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary outcomes were changes in cognitive capacity (Mini-Mental State Examination [MMSE]) and mood status (Yesavage Geriatric Depression Scale [GDS]), quality of life (QoL; EuroQol-5D), handgrip strength (dominant hand), incident delirium (Confusion Assessment Method), length of stay (LOS), falls during hospitalization, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Intention-to-treat analysis was conducted.
Main results. Of the 370 patients included in the study’s analyses, 209 (56.5%) were women, mean age was 87.3 ± 4.9 years (range, 75-101 years; 130 [35.1%] nonagenarians). The median LOS was 8 days in both groups (interquartile range [IQR], 4 and 4 days, respectively). The median duration of the intervention was 5 days (IQR, 0 days), with 5 ± 1 morning and 4 ± 1 evening sessions in the exercise group. Adherence to the exercise intervention was high (95.8% for morning sessions; 83.4% for evening sessions), and no adverse effects were observed with the intervention.
The in-hospital exercise intervention program yielded significant benefits over usual care in functional outcomes in elderly patients. The exercise group had an increased change in measures of functional capacity compared to the usual care group (ie, Barthel Index, 6.9 points; 95% confidence interval [CI], 4.4-9.5; SPPB score, 2.2 points; 95% CI, 1.7-2.6). Furthermore, acute hospitalization led to an impairment in functional capacity from baseline to discharge in the Barthel Index (−5.0 points; 95% CI, −6.8 to −3.2) in the usual care group. In contrast, exercise intervention reversed this decline and improved functional outcomes as assessed by Barthel Index (1.9 points; 95% CI, 0.2-3.7) and SPPB score (2.4 points; 95% CI, 2.1-2.7).
The beneficial effects of the in-hospital exercise intervention extended to secondary end points indicative of cognitive capacity (MMSE, 1.8 points; 95% CI, 1.3-2.3), mood status (GDS, −2.0 points; 95% CI, −2.5 to −1.6), QoL (EuroQol-5D, 13.2 points; 95% CI, 8.2-18.2), and handgrip strength (2.3 kg; 95% CI, 1.8-2.8) compared to those who received usual care. In contrast, no differences were observed between groups that received exercise intervention and usual care in incident delirium, LOS, falls during hospitalization, transfer after discharge, and 3-month hospital readmission rate and mortality.
Conclusion. An individualized, multicomponent physical exercise program that includes low-intensity resistance, balance, and walking exercises performed during the course of hospitalization (average of 5 days) can reverse functional decline associated with acute hospitalization in very elderly patients. Furthermore, this in-hospital exercise intervention is safe and has a high adherence rate, and thus represents an opportunity to improve quality of care in this vulnerable population.
Commentary
Frail elderly patients are highly susceptible to adverse outcomes of acute hospitalization, including functional decline, disability, nursing home placement, rehospitalization, and mortality.1 Mobility limitation, a major hazard of hospitalization, has been associated with poorer functional recovery and increased vulnerability to these major adverse events after hospital discharge.2-4 Interdisciplinary care models delivered during hospitalization (eg, Geriatric Evaluation Unit, Acute Care for Elders) that emphasize functional independence and provide protocols for exercise and rehabilitation have demonstrated reduced hospital LOS, discharge to nursing home, and mortality, and improved functional status in elderly patients.5-7 Despite this evidence, significant gaps in knowledge exist in understanding whether early implementation of an individualized, multicomponent exercise training program can benefit the oldest old patients who are acutely hospitalized.
This study reported by Martinez-Velilla and colleagues provides an important and timely investigation in examining the effects of an individualized, multicomponent (ie, low-intensity resistance, balance, and walking) in-hospital exercise intervention on functional outcomes of hospitalized octogenarians and nonagenarians. The authors reported that such an intervention, administered 2 sessions per day for 5 to 7 consecutive days, can be safely implemented and reverse functional decline (ie, improvement in Barthel Index and SPPB score over course of hospital stay) typically associated with acute hospitalization in these vulnerable individuals. These findings are particularly significant given the paucity of randomized controlled trials evaluating the impact of exercise intervention in preserving functional capacity of geriatric patients in the setting of acute hospitalization. While much more research is needed to facilitate future development of a consensus opinion in this regard, results from this study provide the rationale that implementation of an individualized multicomponent exercise program is feasible and safe and may attenuate functional decline in hospitalized older patients. Finally, the beneficial effects of in-hospital exercise intervention may extend to cognitive capacity, mood status, and QoL—domains that are essential to optimizing patient-centered care in the frailest elderly patients.
The study was well conceived with a number of strengths, including its randomized clinical trial design. In addition, the trial patients were advanced in age (35.1% were nonagenarians), which is particularly important because this is a vulnerable population that is frequently excluded from participation in trials of exercise interventions and because the evidence-base for physical activity guidelines is suboptimal. Moreover, the authors demonstrated that an individualized multicomponent exercise program could be successfully implemented in elderly patients in an acute setting via daily exercise sessions. This test of feasibility is significant in that clinical trials in exercise intervention in geriatrics are commonly performed in nonacute settings in the community, long-term care facilities, or subacute care. The major limitation in this study centers on the generalizability of its findings. It was noted that some patients were not assessed for changes from baseline to discharge on the Barthel Index (6.1%) and SPPB (2.3%) because of their poor condition. The exclusion of the most debilitated patients limits the application of the study’s key findings to the frailest elderly patients, who are most likely to require acute hospital care.
Applications for Clinical Pract
Functional decline is an exceedingly common adverse outcome associated with hospitalization in older patients. While more evidence is needed, early implementation of an individualized, multicomponent exercise regimen during hospitalization may help to prevent functional decline in vulnerable elderly patients.
—Fred Ko, MD, MS
Study Overview
Objective. To assess the effects of an individualized, multicomponent exercise intervention on the functional status of very elderly patients who were acutely hospitalized compared with those who received usual care.
Design. A single-center, single-blind randomized clinical trial comparing elderly (≥ 75 years old) hospitalized patients who received in-hospital exercise (ie, individualized low-intensity resistance, balance, and walking exercises) versus control (ie, usual care that included physical rehabilitation if needed) interventions. The exercise intervention was adapted from the multicomponent physical exercise program Vivifrail and was supervised and conducted by a fitness specialist in 2 daily (1 morning and 1 evening) sessions lasting 20 minutes for 5 to 7 consecutive days. The morning session consisted of supervised and individualized progressive resistance, balance, and walking exercises. The evening session consisted of functional unsupervised exercises including light weights, extension and flexion of knee and hip, and walking.
Setting and participants. The study was conducted in an acute care unit in a tertiary public hospital in Navarra, Spain, between 1 February 2015 and 30 August 2017. A total of 370 elderly patients undergoing acute care hospitalization were enrolled in the study and randomly assigned to receive in-hospital exercise or control intervention. Inclusion criteria were: age ≥ 75 years, Barthel Index score ≥ 60, and ambulatory with or without assistance.
Main outcome measures. The primary outcome was change in functional capacity from baseline (beginning of exercise or control intervention) to hospital discharge as assessed by the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary outcomes were changes in cognitive capacity (Mini-Mental State Examination [MMSE]) and mood status (Yesavage Geriatric Depression Scale [GDS]), quality of life (QoL; EuroQol-5D), handgrip strength (dominant hand), incident delirium (Confusion Assessment Method), length of stay (LOS), falls during hospitalization, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Intention-to-treat analysis was conducted.
Main results. Of the 370 patients included in the study’s analyses, 209 (56.5%) were women, mean age was 87.3 ± 4.9 years (range, 75-101 years; 130 [35.1%] nonagenarians). The median LOS was 8 days in both groups (interquartile range [IQR], 4 and 4 days, respectively). The median duration of the intervention was 5 days (IQR, 0 days), with 5 ± 1 morning and 4 ± 1 evening sessions in the exercise group. Adherence to the exercise intervention was high (95.8% for morning sessions; 83.4% for evening sessions), and no adverse effects were observed with the intervention.
The in-hospital exercise intervention program yielded significant benefits over usual care in functional outcomes in elderly patients. The exercise group had an increased change in measures of functional capacity compared to the usual care group (ie, Barthel Index, 6.9 points; 95% confidence interval [CI], 4.4-9.5; SPPB score, 2.2 points; 95% CI, 1.7-2.6). Furthermore, acute hospitalization led to an impairment in functional capacity from baseline to discharge in the Barthel Index (−5.0 points; 95% CI, −6.8 to −3.2) in the usual care group. In contrast, exercise intervention reversed this decline and improved functional outcomes as assessed by Barthel Index (1.9 points; 95% CI, 0.2-3.7) and SPPB score (2.4 points; 95% CI, 2.1-2.7).
The beneficial effects of the in-hospital exercise intervention extended to secondary end points indicative of cognitive capacity (MMSE, 1.8 points; 95% CI, 1.3-2.3), mood status (GDS, −2.0 points; 95% CI, −2.5 to −1.6), QoL (EuroQol-5D, 13.2 points; 95% CI, 8.2-18.2), and handgrip strength (2.3 kg; 95% CI, 1.8-2.8) compared to those who received usual care. In contrast, no differences were observed between groups that received exercise intervention and usual care in incident delirium, LOS, falls during hospitalization, transfer after discharge, and 3-month hospital readmission rate and mortality.
Conclusion. An individualized, multicomponent physical exercise program that includes low-intensity resistance, balance, and walking exercises performed during the course of hospitalization (average of 5 days) can reverse functional decline associated with acute hospitalization in very elderly patients. Furthermore, this in-hospital exercise intervention is safe and has a high adherence rate, and thus represents an opportunity to improve quality of care in this vulnerable population.
Commentary
Frail elderly patients are highly susceptible to adverse outcomes of acute hospitalization, including functional decline, disability, nursing home placement, rehospitalization, and mortality.1 Mobility limitation, a major hazard of hospitalization, has been associated with poorer functional recovery and increased vulnerability to these major adverse events after hospital discharge.2-4 Interdisciplinary care models delivered during hospitalization (eg, Geriatric Evaluation Unit, Acute Care for Elders) that emphasize functional independence and provide protocols for exercise and rehabilitation have demonstrated reduced hospital LOS, discharge to nursing home, and mortality, and improved functional status in elderly patients.5-7 Despite this evidence, significant gaps in knowledge exist in understanding whether early implementation of an individualized, multicomponent exercise training program can benefit the oldest old patients who are acutely hospitalized.
This study reported by Martinez-Velilla and colleagues provides an important and timely investigation in examining the effects of an individualized, multicomponent (ie, low-intensity resistance, balance, and walking) in-hospital exercise intervention on functional outcomes of hospitalized octogenarians and nonagenarians. The authors reported that such an intervention, administered 2 sessions per day for 5 to 7 consecutive days, can be safely implemented and reverse functional decline (ie, improvement in Barthel Index and SPPB score over course of hospital stay) typically associated with acute hospitalization in these vulnerable individuals. These findings are particularly significant given the paucity of randomized controlled trials evaluating the impact of exercise intervention in preserving functional capacity of geriatric patients in the setting of acute hospitalization. While much more research is needed to facilitate future development of a consensus opinion in this regard, results from this study provide the rationale that implementation of an individualized multicomponent exercise program is feasible and safe and may attenuate functional decline in hospitalized older patients. Finally, the beneficial effects of in-hospital exercise intervention may extend to cognitive capacity, mood status, and QoL—domains that are essential to optimizing patient-centered care in the frailest elderly patients.
The study was well conceived with a number of strengths, including its randomized clinical trial design. In addition, the trial patients were advanced in age (35.1% were nonagenarians), which is particularly important because this is a vulnerable population that is frequently excluded from participation in trials of exercise interventions and because the evidence-base for physical activity guidelines is suboptimal. Moreover, the authors demonstrated that an individualized multicomponent exercise program could be successfully implemented in elderly patients in an acute setting via daily exercise sessions. This test of feasibility is significant in that clinical trials in exercise intervention in geriatrics are commonly performed in nonacute settings in the community, long-term care facilities, or subacute care. The major limitation in this study centers on the generalizability of its findings. It was noted that some patients were not assessed for changes from baseline to discharge on the Barthel Index (6.1%) and SPPB (2.3%) because of their poor condition. The exclusion of the most debilitated patients limits the application of the study’s key findings to the frailest elderly patients, who are most likely to require acute hospital care.
Applications for Clinical Pract
Functional decline is an exceedingly common adverse outcome associated with hospitalization in older patients. While more evidence is needed, early implementation of an individualized, multicomponent exercise regimen during hospitalization may help to prevent functional decline in vulnerable elderly patients.
—Fred Ko, MD, MS
1. Goldwater DS, Dharmarajan K, McEwan BS, Krumholz HM. Is posthospital syndrome a result of hospitalization-induced allostatic overload? J Hosp Med. 2018;13(5).doi:10.12788/jhm.2986.
2. Creditor MC. Hazards of hospitalization of the elderly. Ann Intern Med. 1993;118:219-223.
3. Minnick AF, Mion LC, Johnson ME, et al. Prevalence and variation of physical restraint use in acute care settings in the US. J Nurs Scholarsh. 2007;39:30-37.
4. Zisberg A, Shadmi E, Sinoff G et al. Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc. 2011;59:266-273.
5. Rubenstein LZ, et al. Effectiveness of a geriatric evaluation unit. A randomized clinical trial. N Engl J Med. 1984;311:1664-1670.
6. Landefeld CS, Palmer RM, Kresevic DM, et al. A randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients. N Engl J Med. 1995;332:1338-1344.
7. de Morton NA, Keating JL, Jeffs K. Exercise for acutely hospitalised older medical patients. Cochrane Database Syst Rev. 2007;CD005955.
1. Goldwater DS, Dharmarajan K, McEwan BS, Krumholz HM. Is posthospital syndrome a result of hospitalization-induced allostatic overload? J Hosp Med. 2018;13(5).doi:10.12788/jhm.2986.
2. Creditor MC. Hazards of hospitalization of the elderly. Ann Intern Med. 1993;118:219-223.
3. Minnick AF, Mion LC, Johnson ME, et al. Prevalence and variation of physical restraint use in acute care settings in the US. J Nurs Scholarsh. 2007;39:30-37.
4. Zisberg A, Shadmi E, Sinoff G et al. Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc. 2011;59:266-273.
5. Rubenstein LZ, et al. Effectiveness of a geriatric evaluation unit. A randomized clinical trial. N Engl J Med. 1984;311:1664-1670.
6. Landefeld CS, Palmer RM, Kresevic DM, et al. A randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients. N Engl J Med. 1995;332:1338-1344.
7. de Morton NA, Keating JL, Jeffs K. Exercise for acutely hospitalised older medical patients. Cochrane Database Syst Rev. 2007;CD005955.
Hip Fracture in Nursing Home Residents with Advanced Dementia: An Opportunity for Palliative Care
Study Overview
Objective. To compare clinical outcomes (mortality, pain, physical restraint use, pressure ulcer, antipsychotic drug use) in long-term care nursing home (NH) residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management.
Design. A retrospective cohort study utilizing nationwide Medicare (Parts A, B, D and hospice) claims data linked with Centers for Medicare & Medicaid Services Minimum Data Set (MDS version 2.0) assessments.
Setting and participants. Long-stay NH residents older than 65 years with advanced dementia (defined as being assigned to Cognitive Performance Scale category 5 or 6 and a diagnosis of dementia or Alzheimer disease) and without a do not hospitalize (DNH) directive before hip fracture were identified by using MDS assessments completed from January 1, 2008 to December 31, 2013. Medicare (Part A – inpatient, or Part B – outpatient) claims data was then used to identify those residents who experienced a hip fracture within 2 years of the full MDS assessment using the International Classification of Diseases, Ninth Revision diagnostic codes. Procedure codes were used to determine whether a resident who experienced hip fracture underwent surgical repair.
Main outcome measures. The main outcome measure was all-cause mortality after hip fracture ascertained by the Medicare Enrollment File through 2013. The secondary outcome measures were documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status in NH residents who survived 6 months after hip fracture. These outcome measures were captured from the first MDS assessment completed between 120 and 240 days following the fracture or Medicare Part D claims. Documented pain was determined using a validated MDS 2.0 nursing assessment pain instrument within 7 days preceding MDS assessment. Physical restraint use was defined by the use of trunk, limb, or chair restraint within 7 days prior to MDS assessment. Pressure ulcer was defined as any stage 2 to 4 pressure ulcer. Antipsychotic drug use of any medication subclass was determined using Medicare Part D claims data and affirmative if drug was administered 180 days after hip fracture. Ambulatory status between 120 and 240 days following the fracture was determined in a subset of NH residents who were ambulatory before the hip fracture. The utilization of comfort-focused care after hip fracture was determined in NH residents who had a Medicare hospice claim or a new DNH directive in the 180 days after hip fracture.
The differences in survival among NH residents with advanced dementia and hip fracture were described by Kaplan-Meier curves. The association between surgical repair and survival was determined using multivariable Cox proportional hazards for all NH residents and stratified by pre-fracture ambulatory status. In those who survived 6 months after hip fracture, the associations between surgical repair and outcomes including documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status were determined using multivariable logistic regression models. Adjustment for differences in characteristics before hip fracture was performed using inverse probability of treatment weighting (IPTW) models.
Main results. 3083 long-stay NH residents with advanced dementia and hip fracture were included in the study. The cohort’s mean age was 84.2 ± 7.1 years, 79.2% were female (n = 2441), and 28.5% were ambulatory before hip fracture (n = 879). Of these NH residents, 84.8% (n = 2615) underwent surgical repair and 15.2% (n = 468) received nonsurgical management. At 6 months after hip fracture, mortality was 31.5% in the surgical group compared to 53.8% in the nonsurgical group. The greatest mortality difference between groups occurred in the first 30 days after hip fracture (11.5% in surgical group versus 30.6% in nonsurgical group). Surgical repair was associated with a decreased risk of death (Cox proportional hazard ratio) in the unadjusted (hazard ratio [HR], 0.55 [95% confidence interval {CI}, 0.49-0.61), multivariable adjusted (adjusted HR, 0.56 [95% CI, 0.49-0.63]), and IPTW (adjusted HR, 0.88 [95% CI, 0.79-0.98]) models. Similarly, surgically treated NH residents were less likely to die than those managed non-surgically when mortality was stratified by pre-fracture ambulatory status.
Among NH residents who survived 6 months after hip fracture, those who underwent surgical repair compared with those who received nonsurgical management had less documented pain (29.0% versus 30.9%), fewer pressure ulcers (11.2% versus 19.0%), greater physical restraint use (13.0% versus 11.1%), and greater antipsychotic drug use (29.5% versus 20.4%). In the adjusted IPTW models, surgical repair was associated with less pain (adjusted HR, 0.78 [95% CI, 0.61-0.99]) and fewer pressure ulcers (adjusted HR, 0.64 [95% CI, 0.47-0.86]).
Overall, 21.5% of NH residents utilized comfort-focused care within 6 months after hip fracture, with a mean time to utilization of hospice care of 56 ± 49 days. In those who were managed surgically, 19.3% utilized hospice care, as compared with 33.8% in those who did not receive surgical intervention. In NH residents who survived 6 months after hip fracture, only 1.1% in both groups acquired a DNH directive.
Conclusion. In older long-stay NH residents with advanced dementia and hip fracture, surgical repair was associated with lower all-cause mortality, less documented pain, and fewer pressure ulcers compared to nonsurgical management. However, adverse clinical outcomes such as pain, physical restraint use, pressure ulcers, and antipsychotic drug use were common regardless of treatment modality. The high incidence of these adverse outcomes and hazardous interventions, coupled with low utilization of comfort-focused care and DNH directive, highlight an opportunity to improve the quality of care in this vulnerable population.
Commentary
Hip fracture is very common in NH residents, with an overall incident rate of 2.3 per 100 person years and is associated with a high mortality rate of 36.2% by 6 months after fracture.1,2 Moreover, Neuman and colleagues have recently reported that among NH residents who have some degree of functional independence in locomotion prior to hip fracture, 54% either die or develop new total dependence in locomotion within 6 months of fracture and that severe cognitive impairment is a risk factor highly associated with these adverse outcomes.3 Despite this emerging knowledge, surgical repair of hip fracture remains the mainstay treatment in many NH residents in the hope of alleviating pain and improving mobility, and palliative care is considered only when patients are imminently dying or have deteriorated past the point of meaningful recovery. In cases of NH residents with advanced dementia whose life expectancy is limited and whose care goals may favor maintaining comfort, the health care proxies are frequently challenged with a difficult choice of either pursuing or foregoing surgical management—a complex medical decision to be made in the absence of sufficient evidence in this uniquely frail patient population.
The study reported by Berry and colleagues provides an important and timely investigation in examining associations of adverse clinical outcomes (mortality, pain, pressure ulcer) and hazardous interventions (physical restraint and antipsychotic drug use) in long-stay NH residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management. The authors reported a 6-month mortality rate of 31.5% in NH residents who underwent surgical repair, an event rate similar to that reported by Neuman and colleagues. While surgical repair after hip fracture was associated with a decreased risk of death compared to nonsurgical management, high incidences of pain (29.0% to 30.9%) and pressure ulcers (11.2% to 19.0%), and frequent physical restraint use (11.1% to 13.0%) and antipsychotic drug use (20.4% to 29.5%) were noted in NH residents who survived 6 months after fracture regardless of treatment modality. These findings are consistent with the high rate of post-hip fracture functional disability previously reported by Neuman and colleagues, and highlight the trajectory of decline, frequent distressing symptoms, and prevalent use of pharmacologic and nonpharmacologic restraints in long-stay NH residents after hip fracture. Taken together, the low utilization of comfort-focused care (21.5%) and DNH directive (1.1%) in NH residents who survived 6 months suggest a missed opportunity to integrate palliative care in a patient population that stands to benefit from this intervention.
This study is the first to report the associations between hip fracture surgery and a reduction in adverse outcomes such as pain and pressure ulcer that commonly affect vulnerable NH residents with advanced dementia. This study was well designed and leveraged strengths of Medicare claims data linked with MDS assessments to capture outcome measures including pain, pressure ulcer, and restraint use that would otherwise be difficult to ascertain. However, as in all retrospective cohort design, there were limitations in this study. For instance, secondary outcomes were determined from a single time point (ie, first MDS assessment completed between 120 to 240 days following hip fracture) and thus data capture may be incomplete. Additionally, other conditions important to complex decision making in the care of frail older adults including postoperative complications (eg, delirium, infections, cardiac complications) and in-hospital mortality were not examined. Despite these limitations, this study has enhanced our understanding of the clinical course of long-term care NH residents with advanced dementia who endured hip fracture.
Applications for Clinical Practice
Patients’ goals of care should guide medical decision making in the management of hip fracture in NH residents with advanced dementia. The increased survival benefit of surgical repair of hip fracture in this patient population should be considered in the medical decision-making process if life-prolongation is preferred. However, palliative and hospice care need to be an important facet of discussion given the high rates of mortality, pain, pressure ulcer, and restraint use in this vulnerable subset of older adults.
—Fred Ko, MD, MS
1. Berry SD, Lee Y, Zullo AR, et al. Incidence of hip fracture in U.S. nursing homes. J Gerontol A Biol Sci Med Sci. 2016;71:1230-1234.
2. Neuman MD, Silber JH, Magaziner JS, et al. Survival and functional outcomes after hip fracture among nursing home residents. JAMA Intern Med. 2014;174:1273-1280.
3. Berry SD, Rothbaum RR, Kiel DP, et al. Association of clinical outcomes with surgical repair of hip fractures vs nonsurgical management in nursing home residents with advanced dementia. JAMA Intern Med. 2018;178:774-780.
Study Overview
Objective. To compare clinical outcomes (mortality, pain, physical restraint use, pressure ulcer, antipsychotic drug use) in long-term care nursing home (NH) residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management.
Design. A retrospective cohort study utilizing nationwide Medicare (Parts A, B, D and hospice) claims data linked with Centers for Medicare & Medicaid Services Minimum Data Set (MDS version 2.0) assessments.
Setting and participants. Long-stay NH residents older than 65 years with advanced dementia (defined as being assigned to Cognitive Performance Scale category 5 or 6 and a diagnosis of dementia or Alzheimer disease) and without a do not hospitalize (DNH) directive before hip fracture were identified by using MDS assessments completed from January 1, 2008 to December 31, 2013. Medicare (Part A – inpatient, or Part B – outpatient) claims data was then used to identify those residents who experienced a hip fracture within 2 years of the full MDS assessment using the International Classification of Diseases, Ninth Revision diagnostic codes. Procedure codes were used to determine whether a resident who experienced hip fracture underwent surgical repair.
Main outcome measures. The main outcome measure was all-cause mortality after hip fracture ascertained by the Medicare Enrollment File through 2013. The secondary outcome measures were documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status in NH residents who survived 6 months after hip fracture. These outcome measures were captured from the first MDS assessment completed between 120 and 240 days following the fracture or Medicare Part D claims. Documented pain was determined using a validated MDS 2.0 nursing assessment pain instrument within 7 days preceding MDS assessment. Physical restraint use was defined by the use of trunk, limb, or chair restraint within 7 days prior to MDS assessment. Pressure ulcer was defined as any stage 2 to 4 pressure ulcer. Antipsychotic drug use of any medication subclass was determined using Medicare Part D claims data and affirmative if drug was administered 180 days after hip fracture. Ambulatory status between 120 and 240 days following the fracture was determined in a subset of NH residents who were ambulatory before the hip fracture. The utilization of comfort-focused care after hip fracture was determined in NH residents who had a Medicare hospice claim or a new DNH directive in the 180 days after hip fracture.
The differences in survival among NH residents with advanced dementia and hip fracture were described by Kaplan-Meier curves. The association between surgical repair and survival was determined using multivariable Cox proportional hazards for all NH residents and stratified by pre-fracture ambulatory status. In those who survived 6 months after hip fracture, the associations between surgical repair and outcomes including documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status were determined using multivariable logistic regression models. Adjustment for differences in characteristics before hip fracture was performed using inverse probability of treatment weighting (IPTW) models.
Main results. 3083 long-stay NH residents with advanced dementia and hip fracture were included in the study. The cohort’s mean age was 84.2 ± 7.1 years, 79.2% were female (n = 2441), and 28.5% were ambulatory before hip fracture (n = 879). Of these NH residents, 84.8% (n = 2615) underwent surgical repair and 15.2% (n = 468) received nonsurgical management. At 6 months after hip fracture, mortality was 31.5% in the surgical group compared to 53.8% in the nonsurgical group. The greatest mortality difference between groups occurred in the first 30 days after hip fracture (11.5% in surgical group versus 30.6% in nonsurgical group). Surgical repair was associated with a decreased risk of death (Cox proportional hazard ratio) in the unadjusted (hazard ratio [HR], 0.55 [95% confidence interval {CI}, 0.49-0.61), multivariable adjusted (adjusted HR, 0.56 [95% CI, 0.49-0.63]), and IPTW (adjusted HR, 0.88 [95% CI, 0.79-0.98]) models. Similarly, surgically treated NH residents were less likely to die than those managed non-surgically when mortality was stratified by pre-fracture ambulatory status.
Among NH residents who survived 6 months after hip fracture, those who underwent surgical repair compared with those who received nonsurgical management had less documented pain (29.0% versus 30.9%), fewer pressure ulcers (11.2% versus 19.0%), greater physical restraint use (13.0% versus 11.1%), and greater antipsychotic drug use (29.5% versus 20.4%). In the adjusted IPTW models, surgical repair was associated with less pain (adjusted HR, 0.78 [95% CI, 0.61-0.99]) and fewer pressure ulcers (adjusted HR, 0.64 [95% CI, 0.47-0.86]).
Overall, 21.5% of NH residents utilized comfort-focused care within 6 months after hip fracture, with a mean time to utilization of hospice care of 56 ± 49 days. In those who were managed surgically, 19.3% utilized hospice care, as compared with 33.8% in those who did not receive surgical intervention. In NH residents who survived 6 months after hip fracture, only 1.1% in both groups acquired a DNH directive.
Conclusion. In older long-stay NH residents with advanced dementia and hip fracture, surgical repair was associated with lower all-cause mortality, less documented pain, and fewer pressure ulcers compared to nonsurgical management. However, adverse clinical outcomes such as pain, physical restraint use, pressure ulcers, and antipsychotic drug use were common regardless of treatment modality. The high incidence of these adverse outcomes and hazardous interventions, coupled with low utilization of comfort-focused care and DNH directive, highlight an opportunity to improve the quality of care in this vulnerable population.
Commentary
Hip fracture is very common in NH residents, with an overall incident rate of 2.3 per 100 person years and is associated with a high mortality rate of 36.2% by 6 months after fracture.1,2 Moreover, Neuman and colleagues have recently reported that among NH residents who have some degree of functional independence in locomotion prior to hip fracture, 54% either die or develop new total dependence in locomotion within 6 months of fracture and that severe cognitive impairment is a risk factor highly associated with these adverse outcomes.3 Despite this emerging knowledge, surgical repair of hip fracture remains the mainstay treatment in many NH residents in the hope of alleviating pain and improving mobility, and palliative care is considered only when patients are imminently dying or have deteriorated past the point of meaningful recovery. In cases of NH residents with advanced dementia whose life expectancy is limited and whose care goals may favor maintaining comfort, the health care proxies are frequently challenged with a difficult choice of either pursuing or foregoing surgical management—a complex medical decision to be made in the absence of sufficient evidence in this uniquely frail patient population.
The study reported by Berry and colleagues provides an important and timely investigation in examining associations of adverse clinical outcomes (mortality, pain, pressure ulcer) and hazardous interventions (physical restraint and antipsychotic drug use) in long-stay NH residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management. The authors reported a 6-month mortality rate of 31.5% in NH residents who underwent surgical repair, an event rate similar to that reported by Neuman and colleagues. While surgical repair after hip fracture was associated with a decreased risk of death compared to nonsurgical management, high incidences of pain (29.0% to 30.9%) and pressure ulcers (11.2% to 19.0%), and frequent physical restraint use (11.1% to 13.0%) and antipsychotic drug use (20.4% to 29.5%) were noted in NH residents who survived 6 months after fracture regardless of treatment modality. These findings are consistent with the high rate of post-hip fracture functional disability previously reported by Neuman and colleagues, and highlight the trajectory of decline, frequent distressing symptoms, and prevalent use of pharmacologic and nonpharmacologic restraints in long-stay NH residents after hip fracture. Taken together, the low utilization of comfort-focused care (21.5%) and DNH directive (1.1%) in NH residents who survived 6 months suggest a missed opportunity to integrate palliative care in a patient population that stands to benefit from this intervention.
This study is the first to report the associations between hip fracture surgery and a reduction in adverse outcomes such as pain and pressure ulcer that commonly affect vulnerable NH residents with advanced dementia. This study was well designed and leveraged strengths of Medicare claims data linked with MDS assessments to capture outcome measures including pain, pressure ulcer, and restraint use that would otherwise be difficult to ascertain. However, as in all retrospective cohort design, there were limitations in this study. For instance, secondary outcomes were determined from a single time point (ie, first MDS assessment completed between 120 to 240 days following hip fracture) and thus data capture may be incomplete. Additionally, other conditions important to complex decision making in the care of frail older adults including postoperative complications (eg, delirium, infections, cardiac complications) and in-hospital mortality were not examined. Despite these limitations, this study has enhanced our understanding of the clinical course of long-term care NH residents with advanced dementia who endured hip fracture.
Applications for Clinical Practice
Patients’ goals of care should guide medical decision making in the management of hip fracture in NH residents with advanced dementia. The increased survival benefit of surgical repair of hip fracture in this patient population should be considered in the medical decision-making process if life-prolongation is preferred. However, palliative and hospice care need to be an important facet of discussion given the high rates of mortality, pain, pressure ulcer, and restraint use in this vulnerable subset of older adults.
—Fred Ko, MD, MS
Study Overview
Objective. To compare clinical outcomes (mortality, pain, physical restraint use, pressure ulcer, antipsychotic drug use) in long-term care nursing home (NH) residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management.
Design. A retrospective cohort study utilizing nationwide Medicare (Parts A, B, D and hospice) claims data linked with Centers for Medicare & Medicaid Services Minimum Data Set (MDS version 2.0) assessments.
Setting and participants. Long-stay NH residents older than 65 years with advanced dementia (defined as being assigned to Cognitive Performance Scale category 5 or 6 and a diagnosis of dementia or Alzheimer disease) and without a do not hospitalize (DNH) directive before hip fracture were identified by using MDS assessments completed from January 1, 2008 to December 31, 2013. Medicare (Part A – inpatient, or Part B – outpatient) claims data was then used to identify those residents who experienced a hip fracture within 2 years of the full MDS assessment using the International Classification of Diseases, Ninth Revision diagnostic codes. Procedure codes were used to determine whether a resident who experienced hip fracture underwent surgical repair.
Main outcome measures. The main outcome measure was all-cause mortality after hip fracture ascertained by the Medicare Enrollment File through 2013. The secondary outcome measures were documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status in NH residents who survived 6 months after hip fracture. These outcome measures were captured from the first MDS assessment completed between 120 and 240 days following the fracture or Medicare Part D claims. Documented pain was determined using a validated MDS 2.0 nursing assessment pain instrument within 7 days preceding MDS assessment. Physical restraint use was defined by the use of trunk, limb, or chair restraint within 7 days prior to MDS assessment. Pressure ulcer was defined as any stage 2 to 4 pressure ulcer. Antipsychotic drug use of any medication subclass was determined using Medicare Part D claims data and affirmative if drug was administered 180 days after hip fracture. Ambulatory status between 120 and 240 days following the fracture was determined in a subset of NH residents who were ambulatory before the hip fracture. The utilization of comfort-focused care after hip fracture was determined in NH residents who had a Medicare hospice claim or a new DNH directive in the 180 days after hip fracture.
The differences in survival among NH residents with advanced dementia and hip fracture were described by Kaplan-Meier curves. The association between surgical repair and survival was determined using multivariable Cox proportional hazards for all NH residents and stratified by pre-fracture ambulatory status. In those who survived 6 months after hip fracture, the associations between surgical repair and outcomes including documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status were determined using multivariable logistic regression models. Adjustment for differences in characteristics before hip fracture was performed using inverse probability of treatment weighting (IPTW) models.
Main results. 3083 long-stay NH residents with advanced dementia and hip fracture were included in the study. The cohort’s mean age was 84.2 ± 7.1 years, 79.2% were female (n = 2441), and 28.5% were ambulatory before hip fracture (n = 879). Of these NH residents, 84.8% (n = 2615) underwent surgical repair and 15.2% (n = 468) received nonsurgical management. At 6 months after hip fracture, mortality was 31.5% in the surgical group compared to 53.8% in the nonsurgical group. The greatest mortality difference between groups occurred in the first 30 days after hip fracture (11.5% in surgical group versus 30.6% in nonsurgical group). Surgical repair was associated with a decreased risk of death (Cox proportional hazard ratio) in the unadjusted (hazard ratio [HR], 0.55 [95% confidence interval {CI}, 0.49-0.61), multivariable adjusted (adjusted HR, 0.56 [95% CI, 0.49-0.63]), and IPTW (adjusted HR, 0.88 [95% CI, 0.79-0.98]) models. Similarly, surgically treated NH residents were less likely to die than those managed non-surgically when mortality was stratified by pre-fracture ambulatory status.
Among NH residents who survived 6 months after hip fracture, those who underwent surgical repair compared with those who received nonsurgical management had less documented pain (29.0% versus 30.9%), fewer pressure ulcers (11.2% versus 19.0%), greater physical restraint use (13.0% versus 11.1%), and greater antipsychotic drug use (29.5% versus 20.4%). In the adjusted IPTW models, surgical repair was associated with less pain (adjusted HR, 0.78 [95% CI, 0.61-0.99]) and fewer pressure ulcers (adjusted HR, 0.64 [95% CI, 0.47-0.86]).
Overall, 21.5% of NH residents utilized comfort-focused care within 6 months after hip fracture, with a mean time to utilization of hospice care of 56 ± 49 days. In those who were managed surgically, 19.3% utilized hospice care, as compared with 33.8% in those who did not receive surgical intervention. In NH residents who survived 6 months after hip fracture, only 1.1% in both groups acquired a DNH directive.
Conclusion. In older long-stay NH residents with advanced dementia and hip fracture, surgical repair was associated with lower all-cause mortality, less documented pain, and fewer pressure ulcers compared to nonsurgical management. However, adverse clinical outcomes such as pain, physical restraint use, pressure ulcers, and antipsychotic drug use were common regardless of treatment modality. The high incidence of these adverse outcomes and hazardous interventions, coupled with low utilization of comfort-focused care and DNH directive, highlight an opportunity to improve the quality of care in this vulnerable population.
Commentary
Hip fracture is very common in NH residents, with an overall incident rate of 2.3 per 100 person years and is associated with a high mortality rate of 36.2% by 6 months after fracture.1,2 Moreover, Neuman and colleagues have recently reported that among NH residents who have some degree of functional independence in locomotion prior to hip fracture, 54% either die or develop new total dependence in locomotion within 6 months of fracture and that severe cognitive impairment is a risk factor highly associated with these adverse outcomes.3 Despite this emerging knowledge, surgical repair of hip fracture remains the mainstay treatment in many NH residents in the hope of alleviating pain and improving mobility, and palliative care is considered only when patients are imminently dying or have deteriorated past the point of meaningful recovery. In cases of NH residents with advanced dementia whose life expectancy is limited and whose care goals may favor maintaining comfort, the health care proxies are frequently challenged with a difficult choice of either pursuing or foregoing surgical management—a complex medical decision to be made in the absence of sufficient evidence in this uniquely frail patient population.
The study reported by Berry and colleagues provides an important and timely investigation in examining associations of adverse clinical outcomes (mortality, pain, pressure ulcer) and hazardous interventions (physical restraint and antipsychotic drug use) in long-stay NH residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management. The authors reported a 6-month mortality rate of 31.5% in NH residents who underwent surgical repair, an event rate similar to that reported by Neuman and colleagues. While surgical repair after hip fracture was associated with a decreased risk of death compared to nonsurgical management, high incidences of pain (29.0% to 30.9%) and pressure ulcers (11.2% to 19.0%), and frequent physical restraint use (11.1% to 13.0%) and antipsychotic drug use (20.4% to 29.5%) were noted in NH residents who survived 6 months after fracture regardless of treatment modality. These findings are consistent with the high rate of post-hip fracture functional disability previously reported by Neuman and colleagues, and highlight the trajectory of decline, frequent distressing symptoms, and prevalent use of pharmacologic and nonpharmacologic restraints in long-stay NH residents after hip fracture. Taken together, the low utilization of comfort-focused care (21.5%) and DNH directive (1.1%) in NH residents who survived 6 months suggest a missed opportunity to integrate palliative care in a patient population that stands to benefit from this intervention.
This study is the first to report the associations between hip fracture surgery and a reduction in adverse outcomes such as pain and pressure ulcer that commonly affect vulnerable NH residents with advanced dementia. This study was well designed and leveraged strengths of Medicare claims data linked with MDS assessments to capture outcome measures including pain, pressure ulcer, and restraint use that would otherwise be difficult to ascertain. However, as in all retrospective cohort design, there were limitations in this study. For instance, secondary outcomes were determined from a single time point (ie, first MDS assessment completed between 120 to 240 days following hip fracture) and thus data capture may be incomplete. Additionally, other conditions important to complex decision making in the care of frail older adults including postoperative complications (eg, delirium, infections, cardiac complications) and in-hospital mortality were not examined. Despite these limitations, this study has enhanced our understanding of the clinical course of long-term care NH residents with advanced dementia who endured hip fracture.
Applications for Clinical Practice
Patients’ goals of care should guide medical decision making in the management of hip fracture in NH residents with advanced dementia. The increased survival benefit of surgical repair of hip fracture in this patient population should be considered in the medical decision-making process if life-prolongation is preferred. However, palliative and hospice care need to be an important facet of discussion given the high rates of mortality, pain, pressure ulcer, and restraint use in this vulnerable subset of older adults.
—Fred Ko, MD, MS
1. Berry SD, Lee Y, Zullo AR, et al. Incidence of hip fracture in U.S. nursing homes. J Gerontol A Biol Sci Med Sci. 2016;71:1230-1234.
2. Neuman MD, Silber JH, Magaziner JS, et al. Survival and functional outcomes after hip fracture among nursing home residents. JAMA Intern Med. 2014;174:1273-1280.
3. Berry SD, Rothbaum RR, Kiel DP, et al. Association of clinical outcomes with surgical repair of hip fractures vs nonsurgical management in nursing home residents with advanced dementia. JAMA Intern Med. 2018;178:774-780.
1. Berry SD, Lee Y, Zullo AR, et al. Incidence of hip fracture in U.S. nursing homes. J Gerontol A Biol Sci Med Sci. 2016;71:1230-1234.
2. Neuman MD, Silber JH, Magaziner JS, et al. Survival and functional outcomes after hip fracture among nursing home residents. JAMA Intern Med. 2014;174:1273-1280.
3. Berry SD, Rothbaum RR, Kiel DP, et al. Association of clinical outcomes with surgical repair of hip fractures vs nonsurgical management in nursing home residents with advanced dementia. JAMA Intern Med. 2018;178:774-780.
How Should Physicians Assess and Manage Pressure Ulcers in the Hospitalized Patient?
The Case
An 85-year-old woman with stroke, functional quadriplegia, and diabetes mellitus presents with altered mental status. She is febrile (38.5°C) with leukocytosis (14,400 cells/mm3) and has a 5 cm x 4 cm x 2 cm Stage III malodorous sacral ulcer without surrounding erythema, tunneling, or pain. The ulcer base is partially covered by green slough. How should this pressure ulcer be evaluated and treated?
Overview
Pressure ulcers in vulnerable populations, such as the elderly and those with limited mobility, are exceedingly common. In the acute-care setting, the incidence of pressure ulcers ranges from 0.4% to 38%, with 2.5 million cases treated annually at an estimated cost of $11 billion per year.1,2 Moreover, as of Oct. 1, 2008, the Centers for Medicare & Medicaid Services (CMS) guideline states that hospitals will no longer receive additional payment when a hospitalized patient develops Stage III or IV pressure ulcers that are not present on admission.
A pressure ulcer is a localized injury to skin and underlying soft tissue over a bony prominence due to sustained external pressure.3 Prolonged pressure on these weight-bearing areas leads to reduced blood flow, ischemia, cell death, and necrosis of local tissues.4 Risk factors for developing pressure ulcers include increased external pressure, shear, friction, moisture, poor perfusion, immobility, incontinence, malnutrition, and impaired mental status.4 Inadequately treated pressure ulcers can lead to pain, tunneling, fistula formation, disfigurement, infection, prolonged hospitalization, lower quality of life, and increased mortality.4
Because of the significant morbidities and high costs associated with the care of pressure ulcers in acute care, hospitalists must be familiar with the assessment and treatment of pressure ulcers in vulnerable patients.
Review of the Data
The management of pressure ulcers in the hospitalized patient starts with a comprehensive assessment of the patient’s medical comorbidities, risk factors, and wound-staging. Considerations must be given to differentiate an infected pressure ulcer from a noninfected ulcer. These evaluations then guide the appropriate treatments of pressure ulcers, including the prevention of progression or formation of new ulcers, debridement, application of wound dressing, and antibiotic use.
Assessing pressure ulcer stage. The National Pressure Ulcer Advisory Panel (NPUAP) Classification System is the most commonly used staging tool. It describes four stages of pressure ulcers (see Table 1).3 A Stage 1 pressure ulcer is characterized by intact skin with nonblanchable erythema and may be discolored, painful, soft, firm, and warmer or cooler compared to adjacent area. A Stage II pressure ulcer presents with partial thickness skin loss with a shallow red-pink wound bed without slough, or as an intact or ruptured serum-filled blister. Stage II pressure ulcers do not include skin tears, tape burns, macerations, or excoriations. A Stage III pressure ulcer has full thickness skin loss with or without visible subcutaneous fat. Bone, tendon, or muscle are not exposed or directly palpable. Slough may be present but it does not obscure the depth of ulcer. Deep ulcers can develop in anatomical regions with high adiposity, such as the pelvic girdle. A Stage IV pressure ulcer has full thickness tissue loss with exposed and palpable bone, tendon, or muscle. Slough, eschar, undermining, and tunneling may be present. The depth of a Stage IV ulcer varies depending on anatomical location and adiposity. Stage IV ulcers also create a nidus for osteomyelitis.
NPUAP describes two additional categories of pressure ulcers: unstageable and deep tissue injury.3 An unstageable ulcer has full thickness skin or tissue loss of unknown depth because the wound base is completely obscured by slough or eschar. The ulcer can only be accurately categorized as Stage III or IV after sufficient slough or eschar is removed to identify wound depth. Lastly, suspected deep tissue injury describes a localized area of discolored intact skin (purple or maroon) or blood-filled blister due to damage of underlying tissue from pressure or shear.
Diagnosing infected pressure ulcers. Pressure ulcer infection delays wound healing and increases risks for sepsis, cellulitis, osteomyelitis, and death.5,6 Clinical evidence of soft tissue involvement, such as erythema, warmth, tenderness, foul odor, or purulent discharge, and systemic inflammatory response (fever, tachycardia, or leukocytosis) are suggestive of a wound infection.3,5 However, these clinical signs may be absent and thus make the distinction between chronic wound and infected pressure ulcer difficult.7 Delayed healing with friable granulation tissue and increased pain in a treated wound may be the only signs of a pressure ulcer infection.3,5,7
Routine laboratory tests (i.e. white blood cell count, C-reactive protein, and erythrocyte sedimentation rate) are neither sensitive nor specific in diagnosing wound infection. Moreover, because pressure ulcers are typically colonized with ≥105 organisms/mL of normal skin flora and bacteria from adjacent gastrointestinal or urogenital environments, swab cultures identify colonizing organisms and are not recommended as a diagnostic test for pressure ulcer microbiologic evaluation.5,6 If microbiological data are needed to guide antibiotic use, cultures of blood, bone, or deep tissue biopsied from a surgically debrided wound should be used.5 Importantly, a higher index of suspicion should be maintained for infection of Stage III or IV pressure ulcers because they are more commonly infected than Stage I or II ulcers.3
Prevention. The prevention of wound progression is essential in treating acute, chronic, or infected pressure ulcers. Although management guidelines are limited by few high-quality, randomized controlled trials, NPUAP recommends a number of prevention strategies targeting risk factors that contribute to pressure ulcer development.2,3,8
For all bed-bound and chair-bound persons with impaired ability to self-reposition, risk assessment for pressure ulcer should be done on admission and repeated every 24 hours. The presence of such risk factors as immobility, shear, friction, moisture, incontinence, and malnutrition should be used to guide preventive treatments. Pressure relief on an ulcer can be achieved by repositioning the immobile patient at one- to two-hour intervals. Pressure-redistributing support surfaces (static, overlays, or dynamic) reduce tissue pressure and decrease overall incidence of pressure ulcers. Due to a lack of relative efficacy data, the selection of a support surface should be determined by the patient’s individual needs in order to reduce pressure and shear.3 For instance, dynamic support is an appropriate surface for an immobile patient with multiple or nonhealing ulcers. Shearing force and friction can be reduced by limiting head-of-bed elevation to <30° and using such transfer aids as bed linens while repositioning patients. The use of pillows, foam wedges, or other devices should be used to eliminate direct contact of bony prominences or reduce pressure on heels.8
Skin care should be optimized to limit excessive dryness or moisture. This includes using moisturizers for dry skin, particularly for the sacrum, and implementing bowel and bladder programs and absorbent underpads in patients with bowel or bladder incontinence.2 Given that patients with pressure ulcers are in a catabolic state, those who are nutritionally compromised may benefit from nutritional supplementation.3 Lastly, appropriate use of local and systemic pain regimen for painful pressure ulcers can improve patient cooperation in repositioning, dressing change, and quality of life.
Debridement. Wound debridement removes necrotic tissue often present in infected or chronic pressure ulcers, reduces risk for further infection, and promotes granulation tissue formation and wound healing. Debridement, however, is not indicated for ulcers of an ischemic limb or dry eschar of the heel, due to propensity for complications.3,4 The five common debridement methods are sharp, mechanical, autolytic, enzymatic, and biosurgical. The debridement method of choice is determined by clinician preference and availability.4
Sharp debridement results in rapid removal of large amounts of nonviable necrotic tissues and eschar using sharp instruments and, therefore, is indicated if wound infection or sepsis is present. Mechanical debridement by wet-to-dry dressing or whirlpool nonselectively removes granulation tissue and, thus, should be used cautiously. Autolytic debridement uses occlusive dressings (i.e. hydrocolloid or hydrogel) to maintain a moist wound environment in order to optimize the body’s inherent ability to selectively self-digest necrotic tissues. Enzymatic debridement with concentrated topical proteolytic enzymes (i.e. collagenase) digests necrotic tissues and achieves faster debridement than autolysis while being less invasive than surgical intervention. Biosurgery utilizes maggots (i.e. Lucilia sericata) that produce enzymes to effectively debride necrotic tissues.
Wound care and dressing. Pressure ulcers should be cleansed with each dressing change using such physiologic solutions as normal saline. Cleansing with antimicrobial solutions for ulcers with large necrotic debris or infection needs to be thoughtfully administered due to the potential impairment on wound healing.4 Wound dressing should maintain a moist wound environment to allow epithelialization and limit excessive exudates in order to prevent maceration. Although there are many categories of moisture retentive dressings, their comparative effectiveness remain unclear.4 Table 2 summarizes characteristics of common wound dressings and their applications.
Antibiotic use. Topical antibiotics are appropriate for Stage III or IV ulcers with signs of local infection, including periwound erythema and friable granulation tissue.4 The Agency for Health Care Policy and Research recommends a two-week trial of a topical antibiotic, such as silver sulfadiazine, for pressure ulcers that fail to heal after two to four weeks of optimal care.6 Systemic antibiotics should be used for patients who demonstrate evidence of systemic infection including sepsis, osteomyelitis, or cellulitis with associated fever and leukocytosis. The choice of systemic antibiotics should be based on cultures from blood, bone, or deep tissue biopsied from a surgically debrided wound.4,6
Back to the Case
The patient was hospitalized for altered mental status. She was at high risk for the progression of her sacral ulcer and the development of new pressure ulcers due to immobility, incontinence, malnutrition, and impaired mental status. The sacral wound was a chronic, Stage III pressure ulcer without evidence of local tissue infection. However, the presence of leukocytosis and fever were suggestive of an underlying infection. Her urine analysis was consistent with a urinary tract infection.
Trimethoprim/sulfamethoxazole was administered with subsequent resolution of leukocytosis, fever, and delirium. The sacral ulcer was cleansed with normal saline and covered with hydrocolloid dressing every 72 hours in order to maintain a moist wound environment and facilitate autolysis. Preventive interventions guided by her risk factors for pressure ulcer were implemented. Interventions included:
- Daily skin and wound assessment;
- Pressure relief with repositioning every two hours;
- Use of a dynamic support surface;
- Head-of-bed elevation of no more than <30° to reduce shear and friction;
- Use of transfer aids;
- Use of devices to eliminate direct contact of bony prominences;
- Optimizing skin care with moisturizers for dry skin and frequent changing of absorbent under pads for incontinence; and
- Consulting nutrition service to optimize nutritional intake.
Bottom Line
Assessments of pressure ulcer stage, wound infection, and risk factors guide targeted therapeutic interventions that facilitate wound healing and prevent new pressure ulcer formation.
Dr. Prager is a fellow in the Brookdale Department of Geriatrics and Palliative Medicine at Mount Sinai School of Medicine in New York City. Dr. Ko is a hospitalist and an assistant professor in the Brookdale Department of Geriatrics and Palliative Medicine at Mount Sinai.
References
- Pressure ulcers in America: prevalence, incidence, and implications for the future. An executive summary of the National Pressure Ulcer Advisory Panel monograph. Adv Skin Wound Care. 2001;14(4):208-215.
- Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: a systematic review. JAMA. 2006;296(8):974-984.
- European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel. Treatment of Pressure Ulcers: Quick Reference Guide. Washington, D.C.: National Pressure Ulcer Advisory Panel; 2009.
- Bates-Jensen BM. Chapter 58. Pressure Ulcers. In: Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, Asthana S, eds. Hazzard’s Geriatric Medicine and Gerontology. 6th ed. New York: McGraw-Hill; 2009.
- Livesley NJ, Chow AW. Infected pressure ulcers in elderly individuals. Clin Infect Dis. 2002;35(11):1390-1396.
- Agency for Health Care Policy and Research (AHCPR). Treatment of Pressure Ulcers. Clinical Practice Guideline Number 15. U.S. Department of Health and Human Services. 1994.
- Reddy M, Gill SS, Wu W, Kalkar SR, Rochon PA. Does this patient have an infection of a chronic wound? JAMA. 2012;307(6):605-611.
- National Pressure Ulcer Advisory Panel. Pressure Ulcer Prevention Points. National Pressure Ulcer Advisory Panel website. Available at: http://www.npuap.org/resources/educational-and-clinical-resources/pressure-ulcer-prevention-points/. Accessed Aug. 1, 2012.
- Reuben DB, Herr KA, Pacala JT, et al. Skin Ulcers. In: Geriatrics At Your Fingertips. 12th ed. New York: The American Geriatrics Society; 2010.
The Case
An 85-year-old woman with stroke, functional quadriplegia, and diabetes mellitus presents with altered mental status. She is febrile (38.5°C) with leukocytosis (14,400 cells/mm3) and has a 5 cm x 4 cm x 2 cm Stage III malodorous sacral ulcer without surrounding erythema, tunneling, or pain. The ulcer base is partially covered by green slough. How should this pressure ulcer be evaluated and treated?
Overview
Pressure ulcers in vulnerable populations, such as the elderly and those with limited mobility, are exceedingly common. In the acute-care setting, the incidence of pressure ulcers ranges from 0.4% to 38%, with 2.5 million cases treated annually at an estimated cost of $11 billion per year.1,2 Moreover, as of Oct. 1, 2008, the Centers for Medicare & Medicaid Services (CMS) guideline states that hospitals will no longer receive additional payment when a hospitalized patient develops Stage III or IV pressure ulcers that are not present on admission.
A pressure ulcer is a localized injury to skin and underlying soft tissue over a bony prominence due to sustained external pressure.3 Prolonged pressure on these weight-bearing areas leads to reduced blood flow, ischemia, cell death, and necrosis of local tissues.4 Risk factors for developing pressure ulcers include increased external pressure, shear, friction, moisture, poor perfusion, immobility, incontinence, malnutrition, and impaired mental status.4 Inadequately treated pressure ulcers can lead to pain, tunneling, fistula formation, disfigurement, infection, prolonged hospitalization, lower quality of life, and increased mortality.4
Because of the significant morbidities and high costs associated with the care of pressure ulcers in acute care, hospitalists must be familiar with the assessment and treatment of pressure ulcers in vulnerable patients.
Review of the Data
The management of pressure ulcers in the hospitalized patient starts with a comprehensive assessment of the patient’s medical comorbidities, risk factors, and wound-staging. Considerations must be given to differentiate an infected pressure ulcer from a noninfected ulcer. These evaluations then guide the appropriate treatments of pressure ulcers, including the prevention of progression or formation of new ulcers, debridement, application of wound dressing, and antibiotic use.
Assessing pressure ulcer stage. The National Pressure Ulcer Advisory Panel (NPUAP) Classification System is the most commonly used staging tool. It describes four stages of pressure ulcers (see Table 1).3 A Stage 1 pressure ulcer is characterized by intact skin with nonblanchable erythema and may be discolored, painful, soft, firm, and warmer or cooler compared to adjacent area. A Stage II pressure ulcer presents with partial thickness skin loss with a shallow red-pink wound bed without slough, or as an intact or ruptured serum-filled blister. Stage II pressure ulcers do not include skin tears, tape burns, macerations, or excoriations. A Stage III pressure ulcer has full thickness skin loss with or without visible subcutaneous fat. Bone, tendon, or muscle are not exposed or directly palpable. Slough may be present but it does not obscure the depth of ulcer. Deep ulcers can develop in anatomical regions with high adiposity, such as the pelvic girdle. A Stage IV pressure ulcer has full thickness tissue loss with exposed and palpable bone, tendon, or muscle. Slough, eschar, undermining, and tunneling may be present. The depth of a Stage IV ulcer varies depending on anatomical location and adiposity. Stage IV ulcers also create a nidus for osteomyelitis.
NPUAP describes two additional categories of pressure ulcers: unstageable and deep tissue injury.3 An unstageable ulcer has full thickness skin or tissue loss of unknown depth because the wound base is completely obscured by slough or eschar. The ulcer can only be accurately categorized as Stage III or IV after sufficient slough or eschar is removed to identify wound depth. Lastly, suspected deep tissue injury describes a localized area of discolored intact skin (purple or maroon) or blood-filled blister due to damage of underlying tissue from pressure or shear.
Diagnosing infected pressure ulcers. Pressure ulcer infection delays wound healing and increases risks for sepsis, cellulitis, osteomyelitis, and death.5,6 Clinical evidence of soft tissue involvement, such as erythema, warmth, tenderness, foul odor, or purulent discharge, and systemic inflammatory response (fever, tachycardia, or leukocytosis) are suggestive of a wound infection.3,5 However, these clinical signs may be absent and thus make the distinction between chronic wound and infected pressure ulcer difficult.7 Delayed healing with friable granulation tissue and increased pain in a treated wound may be the only signs of a pressure ulcer infection.3,5,7
Routine laboratory tests (i.e. white blood cell count, C-reactive protein, and erythrocyte sedimentation rate) are neither sensitive nor specific in diagnosing wound infection. Moreover, because pressure ulcers are typically colonized with ≥105 organisms/mL of normal skin flora and bacteria from adjacent gastrointestinal or urogenital environments, swab cultures identify colonizing organisms and are not recommended as a diagnostic test for pressure ulcer microbiologic evaluation.5,6 If microbiological data are needed to guide antibiotic use, cultures of blood, bone, or deep tissue biopsied from a surgically debrided wound should be used.5 Importantly, a higher index of suspicion should be maintained for infection of Stage III or IV pressure ulcers because they are more commonly infected than Stage I or II ulcers.3
Prevention. The prevention of wound progression is essential in treating acute, chronic, or infected pressure ulcers. Although management guidelines are limited by few high-quality, randomized controlled trials, NPUAP recommends a number of prevention strategies targeting risk factors that contribute to pressure ulcer development.2,3,8
For all bed-bound and chair-bound persons with impaired ability to self-reposition, risk assessment for pressure ulcer should be done on admission and repeated every 24 hours. The presence of such risk factors as immobility, shear, friction, moisture, incontinence, and malnutrition should be used to guide preventive treatments. Pressure relief on an ulcer can be achieved by repositioning the immobile patient at one- to two-hour intervals. Pressure-redistributing support surfaces (static, overlays, or dynamic) reduce tissue pressure and decrease overall incidence of pressure ulcers. Due to a lack of relative efficacy data, the selection of a support surface should be determined by the patient’s individual needs in order to reduce pressure and shear.3 For instance, dynamic support is an appropriate surface for an immobile patient with multiple or nonhealing ulcers. Shearing force and friction can be reduced by limiting head-of-bed elevation to <30° and using such transfer aids as bed linens while repositioning patients. The use of pillows, foam wedges, or other devices should be used to eliminate direct contact of bony prominences or reduce pressure on heels.8
Skin care should be optimized to limit excessive dryness or moisture. This includes using moisturizers for dry skin, particularly for the sacrum, and implementing bowel and bladder programs and absorbent underpads in patients with bowel or bladder incontinence.2 Given that patients with pressure ulcers are in a catabolic state, those who are nutritionally compromised may benefit from nutritional supplementation.3 Lastly, appropriate use of local and systemic pain regimen for painful pressure ulcers can improve patient cooperation in repositioning, dressing change, and quality of life.
Debridement. Wound debridement removes necrotic tissue often present in infected or chronic pressure ulcers, reduces risk for further infection, and promotes granulation tissue formation and wound healing. Debridement, however, is not indicated for ulcers of an ischemic limb or dry eschar of the heel, due to propensity for complications.3,4 The five common debridement methods are sharp, mechanical, autolytic, enzymatic, and biosurgical. The debridement method of choice is determined by clinician preference and availability.4
Sharp debridement results in rapid removal of large amounts of nonviable necrotic tissues and eschar using sharp instruments and, therefore, is indicated if wound infection or sepsis is present. Mechanical debridement by wet-to-dry dressing or whirlpool nonselectively removes granulation tissue and, thus, should be used cautiously. Autolytic debridement uses occlusive dressings (i.e. hydrocolloid or hydrogel) to maintain a moist wound environment in order to optimize the body’s inherent ability to selectively self-digest necrotic tissues. Enzymatic debridement with concentrated topical proteolytic enzymes (i.e. collagenase) digests necrotic tissues and achieves faster debridement than autolysis while being less invasive than surgical intervention. Biosurgery utilizes maggots (i.e. Lucilia sericata) that produce enzymes to effectively debride necrotic tissues.
Wound care and dressing. Pressure ulcers should be cleansed with each dressing change using such physiologic solutions as normal saline. Cleansing with antimicrobial solutions for ulcers with large necrotic debris or infection needs to be thoughtfully administered due to the potential impairment on wound healing.4 Wound dressing should maintain a moist wound environment to allow epithelialization and limit excessive exudates in order to prevent maceration. Although there are many categories of moisture retentive dressings, their comparative effectiveness remain unclear.4 Table 2 summarizes characteristics of common wound dressings and their applications.
Antibiotic use. Topical antibiotics are appropriate for Stage III or IV ulcers with signs of local infection, including periwound erythema and friable granulation tissue.4 The Agency for Health Care Policy and Research recommends a two-week trial of a topical antibiotic, such as silver sulfadiazine, for pressure ulcers that fail to heal after two to four weeks of optimal care.6 Systemic antibiotics should be used for patients who demonstrate evidence of systemic infection including sepsis, osteomyelitis, or cellulitis with associated fever and leukocytosis. The choice of systemic antibiotics should be based on cultures from blood, bone, or deep tissue biopsied from a surgically debrided wound.4,6
Back to the Case
The patient was hospitalized for altered mental status. She was at high risk for the progression of her sacral ulcer and the development of new pressure ulcers due to immobility, incontinence, malnutrition, and impaired mental status. The sacral wound was a chronic, Stage III pressure ulcer without evidence of local tissue infection. However, the presence of leukocytosis and fever were suggestive of an underlying infection. Her urine analysis was consistent with a urinary tract infection.
Trimethoprim/sulfamethoxazole was administered with subsequent resolution of leukocytosis, fever, and delirium. The sacral ulcer was cleansed with normal saline and covered with hydrocolloid dressing every 72 hours in order to maintain a moist wound environment and facilitate autolysis. Preventive interventions guided by her risk factors for pressure ulcer were implemented. Interventions included:
- Daily skin and wound assessment;
- Pressure relief with repositioning every two hours;
- Use of a dynamic support surface;
- Head-of-bed elevation of no more than <30° to reduce shear and friction;
- Use of transfer aids;
- Use of devices to eliminate direct contact of bony prominences;
- Optimizing skin care with moisturizers for dry skin and frequent changing of absorbent under pads for incontinence; and
- Consulting nutrition service to optimize nutritional intake.
Bottom Line
Assessments of pressure ulcer stage, wound infection, and risk factors guide targeted therapeutic interventions that facilitate wound healing and prevent new pressure ulcer formation.
Dr. Prager is a fellow in the Brookdale Department of Geriatrics and Palliative Medicine at Mount Sinai School of Medicine in New York City. Dr. Ko is a hospitalist and an assistant professor in the Brookdale Department of Geriatrics and Palliative Medicine at Mount Sinai.
References
- Pressure ulcers in America: prevalence, incidence, and implications for the future. An executive summary of the National Pressure Ulcer Advisory Panel monograph. Adv Skin Wound Care. 2001;14(4):208-215.
- Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: a systematic review. JAMA. 2006;296(8):974-984.
- European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel. Treatment of Pressure Ulcers: Quick Reference Guide. Washington, D.C.: National Pressure Ulcer Advisory Panel; 2009.
- Bates-Jensen BM. Chapter 58. Pressure Ulcers. In: Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, Asthana S, eds. Hazzard’s Geriatric Medicine and Gerontology. 6th ed. New York: McGraw-Hill; 2009.
- Livesley NJ, Chow AW. Infected pressure ulcers in elderly individuals. Clin Infect Dis. 2002;35(11):1390-1396.
- Agency for Health Care Policy and Research (AHCPR). Treatment of Pressure Ulcers. Clinical Practice Guideline Number 15. U.S. Department of Health and Human Services. 1994.
- Reddy M, Gill SS, Wu W, Kalkar SR, Rochon PA. Does this patient have an infection of a chronic wound? JAMA. 2012;307(6):605-611.
- National Pressure Ulcer Advisory Panel. Pressure Ulcer Prevention Points. National Pressure Ulcer Advisory Panel website. Available at: http://www.npuap.org/resources/educational-and-clinical-resources/pressure-ulcer-prevention-points/. Accessed Aug. 1, 2012.
- Reuben DB, Herr KA, Pacala JT, et al. Skin Ulcers. In: Geriatrics At Your Fingertips. 12th ed. New York: The American Geriatrics Society; 2010.
The Case
An 85-year-old woman with stroke, functional quadriplegia, and diabetes mellitus presents with altered mental status. She is febrile (38.5°C) with leukocytosis (14,400 cells/mm3) and has a 5 cm x 4 cm x 2 cm Stage III malodorous sacral ulcer without surrounding erythema, tunneling, or pain. The ulcer base is partially covered by green slough. How should this pressure ulcer be evaluated and treated?
Overview
Pressure ulcers in vulnerable populations, such as the elderly and those with limited mobility, are exceedingly common. In the acute-care setting, the incidence of pressure ulcers ranges from 0.4% to 38%, with 2.5 million cases treated annually at an estimated cost of $11 billion per year.1,2 Moreover, as of Oct. 1, 2008, the Centers for Medicare & Medicaid Services (CMS) guideline states that hospitals will no longer receive additional payment when a hospitalized patient develops Stage III or IV pressure ulcers that are not present on admission.
A pressure ulcer is a localized injury to skin and underlying soft tissue over a bony prominence due to sustained external pressure.3 Prolonged pressure on these weight-bearing areas leads to reduced blood flow, ischemia, cell death, and necrosis of local tissues.4 Risk factors for developing pressure ulcers include increased external pressure, shear, friction, moisture, poor perfusion, immobility, incontinence, malnutrition, and impaired mental status.4 Inadequately treated pressure ulcers can lead to pain, tunneling, fistula formation, disfigurement, infection, prolonged hospitalization, lower quality of life, and increased mortality.4
Because of the significant morbidities and high costs associated with the care of pressure ulcers in acute care, hospitalists must be familiar with the assessment and treatment of pressure ulcers in vulnerable patients.
Review of the Data
The management of pressure ulcers in the hospitalized patient starts with a comprehensive assessment of the patient’s medical comorbidities, risk factors, and wound-staging. Considerations must be given to differentiate an infected pressure ulcer from a noninfected ulcer. These evaluations then guide the appropriate treatments of pressure ulcers, including the prevention of progression or formation of new ulcers, debridement, application of wound dressing, and antibiotic use.
Assessing pressure ulcer stage. The National Pressure Ulcer Advisory Panel (NPUAP) Classification System is the most commonly used staging tool. It describes four stages of pressure ulcers (see Table 1).3 A Stage 1 pressure ulcer is characterized by intact skin with nonblanchable erythema and may be discolored, painful, soft, firm, and warmer or cooler compared to adjacent area. A Stage II pressure ulcer presents with partial thickness skin loss with a shallow red-pink wound bed without slough, or as an intact or ruptured serum-filled blister. Stage II pressure ulcers do not include skin tears, tape burns, macerations, or excoriations. A Stage III pressure ulcer has full thickness skin loss with or without visible subcutaneous fat. Bone, tendon, or muscle are not exposed or directly palpable. Slough may be present but it does not obscure the depth of ulcer. Deep ulcers can develop in anatomical regions with high adiposity, such as the pelvic girdle. A Stage IV pressure ulcer has full thickness tissue loss with exposed and palpable bone, tendon, or muscle. Slough, eschar, undermining, and tunneling may be present. The depth of a Stage IV ulcer varies depending on anatomical location and adiposity. Stage IV ulcers also create a nidus for osteomyelitis.
NPUAP describes two additional categories of pressure ulcers: unstageable and deep tissue injury.3 An unstageable ulcer has full thickness skin or tissue loss of unknown depth because the wound base is completely obscured by slough or eschar. The ulcer can only be accurately categorized as Stage III or IV after sufficient slough or eschar is removed to identify wound depth. Lastly, suspected deep tissue injury describes a localized area of discolored intact skin (purple or maroon) or blood-filled blister due to damage of underlying tissue from pressure or shear.
Diagnosing infected pressure ulcers. Pressure ulcer infection delays wound healing and increases risks for sepsis, cellulitis, osteomyelitis, and death.5,6 Clinical evidence of soft tissue involvement, such as erythema, warmth, tenderness, foul odor, or purulent discharge, and systemic inflammatory response (fever, tachycardia, or leukocytosis) are suggestive of a wound infection.3,5 However, these clinical signs may be absent and thus make the distinction between chronic wound and infected pressure ulcer difficult.7 Delayed healing with friable granulation tissue and increased pain in a treated wound may be the only signs of a pressure ulcer infection.3,5,7
Routine laboratory tests (i.e. white blood cell count, C-reactive protein, and erythrocyte sedimentation rate) are neither sensitive nor specific in diagnosing wound infection. Moreover, because pressure ulcers are typically colonized with ≥105 organisms/mL of normal skin flora and bacteria from adjacent gastrointestinal or urogenital environments, swab cultures identify colonizing organisms and are not recommended as a diagnostic test for pressure ulcer microbiologic evaluation.5,6 If microbiological data are needed to guide antibiotic use, cultures of blood, bone, or deep tissue biopsied from a surgically debrided wound should be used.5 Importantly, a higher index of suspicion should be maintained for infection of Stage III or IV pressure ulcers because they are more commonly infected than Stage I or II ulcers.3
Prevention. The prevention of wound progression is essential in treating acute, chronic, or infected pressure ulcers. Although management guidelines are limited by few high-quality, randomized controlled trials, NPUAP recommends a number of prevention strategies targeting risk factors that contribute to pressure ulcer development.2,3,8
For all bed-bound and chair-bound persons with impaired ability to self-reposition, risk assessment for pressure ulcer should be done on admission and repeated every 24 hours. The presence of such risk factors as immobility, shear, friction, moisture, incontinence, and malnutrition should be used to guide preventive treatments. Pressure relief on an ulcer can be achieved by repositioning the immobile patient at one- to two-hour intervals. Pressure-redistributing support surfaces (static, overlays, or dynamic) reduce tissue pressure and decrease overall incidence of pressure ulcers. Due to a lack of relative efficacy data, the selection of a support surface should be determined by the patient’s individual needs in order to reduce pressure and shear.3 For instance, dynamic support is an appropriate surface for an immobile patient with multiple or nonhealing ulcers. Shearing force and friction can be reduced by limiting head-of-bed elevation to <30° and using such transfer aids as bed linens while repositioning patients. The use of pillows, foam wedges, or other devices should be used to eliminate direct contact of bony prominences or reduce pressure on heels.8
Skin care should be optimized to limit excessive dryness or moisture. This includes using moisturizers for dry skin, particularly for the sacrum, and implementing bowel and bladder programs and absorbent underpads in patients with bowel or bladder incontinence.2 Given that patients with pressure ulcers are in a catabolic state, those who are nutritionally compromised may benefit from nutritional supplementation.3 Lastly, appropriate use of local and systemic pain regimen for painful pressure ulcers can improve patient cooperation in repositioning, dressing change, and quality of life.
Debridement. Wound debridement removes necrotic tissue often present in infected or chronic pressure ulcers, reduces risk for further infection, and promotes granulation tissue formation and wound healing. Debridement, however, is not indicated for ulcers of an ischemic limb or dry eschar of the heel, due to propensity for complications.3,4 The five common debridement methods are sharp, mechanical, autolytic, enzymatic, and biosurgical. The debridement method of choice is determined by clinician preference and availability.4
Sharp debridement results in rapid removal of large amounts of nonviable necrotic tissues and eschar using sharp instruments and, therefore, is indicated if wound infection or sepsis is present. Mechanical debridement by wet-to-dry dressing or whirlpool nonselectively removes granulation tissue and, thus, should be used cautiously. Autolytic debridement uses occlusive dressings (i.e. hydrocolloid or hydrogel) to maintain a moist wound environment in order to optimize the body’s inherent ability to selectively self-digest necrotic tissues. Enzymatic debridement with concentrated topical proteolytic enzymes (i.e. collagenase) digests necrotic tissues and achieves faster debridement than autolysis while being less invasive than surgical intervention. Biosurgery utilizes maggots (i.e. Lucilia sericata) that produce enzymes to effectively debride necrotic tissues.
Wound care and dressing. Pressure ulcers should be cleansed with each dressing change using such physiologic solutions as normal saline. Cleansing with antimicrobial solutions for ulcers with large necrotic debris or infection needs to be thoughtfully administered due to the potential impairment on wound healing.4 Wound dressing should maintain a moist wound environment to allow epithelialization and limit excessive exudates in order to prevent maceration. Although there are many categories of moisture retentive dressings, their comparative effectiveness remain unclear.4 Table 2 summarizes characteristics of common wound dressings and their applications.
Antibiotic use. Topical antibiotics are appropriate for Stage III or IV ulcers with signs of local infection, including periwound erythema and friable granulation tissue.4 The Agency for Health Care Policy and Research recommends a two-week trial of a topical antibiotic, such as silver sulfadiazine, for pressure ulcers that fail to heal after two to four weeks of optimal care.6 Systemic antibiotics should be used for patients who demonstrate evidence of systemic infection including sepsis, osteomyelitis, or cellulitis with associated fever and leukocytosis. The choice of systemic antibiotics should be based on cultures from blood, bone, or deep tissue biopsied from a surgically debrided wound.4,6
Back to the Case
The patient was hospitalized for altered mental status. She was at high risk for the progression of her sacral ulcer and the development of new pressure ulcers due to immobility, incontinence, malnutrition, and impaired mental status. The sacral wound was a chronic, Stage III pressure ulcer without evidence of local tissue infection. However, the presence of leukocytosis and fever were suggestive of an underlying infection. Her urine analysis was consistent with a urinary tract infection.
Trimethoprim/sulfamethoxazole was administered with subsequent resolution of leukocytosis, fever, and delirium. The sacral ulcer was cleansed with normal saline and covered with hydrocolloid dressing every 72 hours in order to maintain a moist wound environment and facilitate autolysis. Preventive interventions guided by her risk factors for pressure ulcer were implemented. Interventions included:
- Daily skin and wound assessment;
- Pressure relief with repositioning every two hours;
- Use of a dynamic support surface;
- Head-of-bed elevation of no more than <30° to reduce shear and friction;
- Use of transfer aids;
- Use of devices to eliminate direct contact of bony prominences;
- Optimizing skin care with moisturizers for dry skin and frequent changing of absorbent under pads for incontinence; and
- Consulting nutrition service to optimize nutritional intake.
Bottom Line
Assessments of pressure ulcer stage, wound infection, and risk factors guide targeted therapeutic interventions that facilitate wound healing and prevent new pressure ulcer formation.
Dr. Prager is a fellow in the Brookdale Department of Geriatrics and Palliative Medicine at Mount Sinai School of Medicine in New York City. Dr. Ko is a hospitalist and an assistant professor in the Brookdale Department of Geriatrics and Palliative Medicine at Mount Sinai.
References
- Pressure ulcers in America: prevalence, incidence, and implications for the future. An executive summary of the National Pressure Ulcer Advisory Panel monograph. Adv Skin Wound Care. 2001;14(4):208-215.
- Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: a systematic review. JAMA. 2006;296(8):974-984.
- European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel. Treatment of Pressure Ulcers: Quick Reference Guide. Washington, D.C.: National Pressure Ulcer Advisory Panel; 2009.
- Bates-Jensen BM. Chapter 58. Pressure Ulcers. In: Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, Asthana S, eds. Hazzard’s Geriatric Medicine and Gerontology. 6th ed. New York: McGraw-Hill; 2009.
- Livesley NJ, Chow AW. Infected pressure ulcers in elderly individuals. Clin Infect Dis. 2002;35(11):1390-1396.
- Agency for Health Care Policy and Research (AHCPR). Treatment of Pressure Ulcers. Clinical Practice Guideline Number 15. U.S. Department of Health and Human Services. 1994.
- Reddy M, Gill SS, Wu W, Kalkar SR, Rochon PA. Does this patient have an infection of a chronic wound? JAMA. 2012;307(6):605-611.
- National Pressure Ulcer Advisory Panel. Pressure Ulcer Prevention Points. National Pressure Ulcer Advisory Panel website. Available at: http://www.npuap.org/resources/educational-and-clinical-resources/pressure-ulcer-prevention-points/. Accessed Aug. 1, 2012.
- Reuben DB, Herr KA, Pacala JT, et al. Skin Ulcers. In: Geriatrics At Your Fingertips. 12th ed. New York: The American Geriatrics Society; 2010.