Physicians play an important role in improving quality improvement (QI) through clinical expertise and leadership.1, 2 The role of the physician leader is dynamic and complex, yet key competencies have been described in terms of personal commitment, professional credibility, QI behaviors and skills, and institutional linkages.3 Several characteristics have also been identified in hospitals successful in implementing QI, including shared goals for improvement, substantial administrative support, use of credible data feedback, and strong physician leadership.4 Cultivating physician leadership in hospital QI via development of these competencies is crucial for ongoing efforts in hospital QI activities.

The American Board of Internal Medicine (ABIM) developed web‐based assessment tools called Practice Improvement Modules (PIMs), as part of the maintenance of certification (MOC) program. Designed to facilitate physician involvement in QI, most PIMs target a single medical condition in the ambulatory practice,5 and involve a medical record audit performed by the physician, a patient survey, and a systems readiness survey. Physicians use the results of this data collection to perform a single test of change, and receive MOC credit when they report on the results of their intervention. Recognizing that QI activities may be different in hospital settings, the ABIM subsequently developed a Hospital‐based PIM (Hospital PIM) that allows physicians to use nationally‐approved hospital‐level performance data to complete the module. The Hospital PIM requires physicians to carry out a single test of change, and report any change in the perception of the environment supporting QI activities.

The ABIM has also begun work on potentially creating a focused pathway for hospitalists in the MOC program.6 Practice‐based learning and improvement (PBLI), systems‐based practice (SBP),7 and QI8 are core competencies of hospital medicine, and assessment of these competencies would be an important component of the new, focused MOC pathway. The Hospital PIM potentially provides an assessment methodology, thus it is important to understand the impact and value of this web‐based assessment tool.

The objective of this study is to explore the impact of the Hospital PIM on physicians participating in hospital‐based QI, including facilitators and barriers to a successful experience. We highlight several case studies to describe this impact, which can be defined as learning about QI, value‐added to practice, or an enhanced QI experience. We also describe 3 pathways suggesting how physician engagement, which is an emerging theme of our research, mediates the impact of the Hospital PIM.

Methods

A nonprobability purposive sample of physicians who completed the Hospital PIM (n = 21) as part of MOC by January 2007 was interviewed using semistructured telephone interviews. At the time of data collection, 771 physicians completed the Hospital PIM, and our sample strategically reflects equal proportions of those currently active on a QI team, as well as those who formed a QI team. Physicians were contacted via e‐mail and telephone to arrange an interview. None of the physicians contacted declined. All physicians were informed about the purpose of the study and provided consent for the ABIM to analyze and report data for purposes of understanding the feasibility of the PIM at improving practice. No physician personal identifiers were used in data analysis.

The interviews focused on four domains: reasons for choosing the module, assembly and role on any quality improvement teams, the value and satisfaction with the experience of completing the Hospital PIM, and prior experience with QI. Interviews were conducted by 1 trained member of the research team, and lasted approximately 30 minutes. Data collection was terminated when theoretical saturation was reached, or when no new data was revealed during the interviews. Interviews were audio‐recorded, and data were transcribed verbatim to facilitate analysis. Through an inductive and iterative approach, 3 members of the research team (including the interviewer) coded the data to identify themes that were consistently grounded in the data.9 These themes were subsequently discussed with a fourth researcher to maximize interrater reliability. Codes were then checked against existing literature to confirm linkages and enhance interpretation.

Results

The mean age of the participants (n = 21) was 42 years and 81% were male. Primary certificates were issued a mean of 13 years prior and completers came from a wide variety of disciplines, hospitals, and areas of expertise. Overall, the majority of physicians found the Hospital PIM to be a valuable experience (n = 17; 81%), which is similar to ABIM Hospital PIM surveillance data in which 75% of all completers said they would recommend the PIM to a colleague.

The impact and value of completing the PIM is illustrated in a variety of ways. For some, particularly those with extensive QI backgrounds, the PIM organized and broadened documentation of ongoing work. Several physicians described their utilization of the Hospital PIM as a byproduct of their hospital's existing cultural norms and interest in QI, and many Hospital PIM projects dovetailed with ongoing hospital QI activities. In these cases, even though the PIM did not stimulate new ideas, there was still value among physicians in receiving recognition for their ongoing QI activities and, perhaps more importantly, in learning by reflecting on their work.10

For others, the Hospital PIM was a catalyst to change. Similar to the role of a catalyst in a chemical reaction, our data suggest that the Hospital PIM facilitated QI by lowering the energy necessary for the process to occur. Many physicians reported the process stimulated new interest in QI, (eg, [The process] gave me some ideas about future QI projects that I plan to do, or described how the experience was an extra boost or stimulus to help change their ways.) These findings are consistent with recent findings on the use of PIMs in residency,11 which describes the Preventive Cardiology PIM as a catalyst to change.

Several physicians were surprised at how easy it was to begin and initiate a QI project, acknowledging the importance of leadership and teamwork (n = 7; 33%). In addition, many physicians highlighted reflective processes (n = 8; 38%) whereby the PIM led to an increased awareness of their clinical environment, or QI in general, including how QI can affect patient care and/or patient outcomes.

The most frequently reported facilitators to a successful PIM experience were familiarity/access to QI resources and staff, institutional support and culture of QI, and documentation of ongoing QI activities. The most frequently reported barrier (n = 9; 43%) was the time that it took to complete the module. Other barriers included a lack of institutional support or negative culture supporting QI activities, a lack of familiarity/access to QI resources and staff, and perceived irrelevance of QI activities to clinical practice.

Discussion

This study describes experiences for a small number of early‐completers of the Hospital PIM. For many, impact is described as an increased awareness of the hospital clinical environment, particularly an awareness of ongoing QI activities. For others, the primary impact was learning through an increased appreciation of the importance of QI activities and understanding of basic QI procedures (ie, interdisciplinary teamwork, enhanced communication, and documentation, buy‐in, using data). Still others described impact as an enhanced QI experience via reflection on current QI work or catalyzing change in their hospital environment. Further exploration of these findings will be important to determine the full impact of the PIM. An unanticipated finding, however, was the emerging theme of the role of physician engagement in mediating a successful experience with the Hospital PIM.

Prior research on physician engagement more generally demonstrates that increased physician engagement enhances interaction with nursing and other office staff,12 improves overall physician alignment,13 enhances QI,2 and may heighten physicians' willingness to participate in hospital administration and policy.14 Our data support these findings and further describe the importance of engagement in QI activities, whether it be through assembling and working in a team, helping analyze hospital systems, navigating existing institutional linkages, or simply becoming the creative initiative on a QI project. For completers of the Hospital PIM, engaging in any aspect of the QI process facilitates a successful PIM experience as documented by impact, and may stimulate physician leadership and hospital level change as well. Nonengaging physicians, in contrast, had a negative experience and documented little or no impact as a result of completing the PIM.

As our findings illustrate, engagement may not be a fixed construct, and may be acquired or generated through the QI process. In this context, physicians with varying levels of QI experience and expertise may learn and find value in completing the Hospital PIM, provided they become engaged with the process. Internal (ie, personal commitment, buy‐in, perceived relevance) and external (ie, hospital QI culture, access to QI team, access to data) factors may influence the degree of satisfaction and success with the Hospital PIM experience, thus maximizing facilitators and overcoming the barriers is also important for a positive outcome.

There are important limitations to this study. Most importantly, we acknowledge that the quality of the resources available between hospitals is highly variable. Therefore, our subjective assessment of whether or not someone was actively engaged is largely dependent on the quality of the available resources, and in a resource‐poor environment, this may not be a fair reflection of their engagement. We further recognize that coming to any broad or conclusive findings about the impact of the PIM is difficult given the qualitative nature of this study. However, our findings do suggest that the Hospital PIM may promote learning and value to completing physicians, especially those that engage in the QI process. Future studies should further explore the described impact and the relationship between engagement and QI.

To further enhance the Hospital PIM, consideration of prerequisite criteria for future completers, such as documentation of engagement, adequate access to hospital QI resources, and significant clinical work in the hospital setting, may be warranted. Additionally, consideration for alternative means of MOC credit may be warranted for physicians who demonstrate a proficiency in QI activities or who work in hospitals that efficiently participate in QI activities, such as a Health Maintenance Organization, for whom completion of the Hospital PIM may be redundant.

In conclusion, our findings suggest that the Hospital PIM is a useful component of MOC for appropriate groups of physicians despite the unique aspects of the Hospital PIM using hospital‐level outcomes data. Many physicians in our sample found it to be useful as a catalyst for learning about QI activities, which was facilitated through active engagement with the PIM QI process. While ongoing study is needed, it is anticipated that the findings from this study will help to inform the proposed pathway of focused practice in hospital medicine as part of MOC, particularly activities geared toward assessing competency in QI.

Physicians play an important role in improving quality improvement (QI) through clinical expertise and leadership.1, 2 The role of the physician leader is dynamic and complex, yet key competencies have been described in terms of personal commitment, professional credibility, QI behaviors and skills, and institutional linkages.3 Several characteristics have also been identified in hospitals successful in implementing QI, including shared goals for improvement, substantial administrative support, use of credible data feedback, and strong physician leadership.4 Cultivating physician leadership in hospital QI via development of these competencies is crucial for ongoing efforts in hospital QI activities.

The American Board of Internal Medicine (ABIM) developed web‐based assessment tools called Practice Improvement Modules (PIMs), as part of the maintenance of certification (MOC) program. Designed to facilitate physician involvement in QI, most PIMs target a single medical condition in the ambulatory practice,5 and involve a medical record audit performed by the physician, a patient survey, and a systems readiness survey. Physicians use the results of this data collection to perform a single test of change, and receive MOC credit when they report on the results of their intervention. Recognizing that QI activities may be different in hospital settings, the ABIM subsequently developed a Hospital‐based PIM (Hospital PIM) that allows physicians to use nationally‐approved hospital‐level performance data to complete the module. The Hospital PIM requires physicians to carry out a single test of change, and report any change in the perception of the environment supporting QI activities.

The ABIM has also begun work on potentially creating a focused pathway for hospitalists in the MOC program.6 Practice‐based learning and improvement (PBLI), systems‐based practice (SBP),7 and QI8 are core competencies of hospital medicine, and assessment of these competencies would be an important component of the new, focused MOC pathway. The Hospital PIM potentially provides an assessment methodology, thus it is important to understand the impact and value of this web‐based assessment tool.

The objective of this study is to explore the impact of the Hospital PIM on physicians participating in hospital‐based QI, including facilitators and barriers to a successful experience. We highlight several case studies to describe this impact, which can be defined as learning about QI, value‐added to practice, or an enhanced QI experience. We also describe 3 pathways suggesting how physician engagement, which is an emerging theme of our research, mediates the impact of the Hospital PIM.

Methods

A nonprobability purposive sample of physicians who completed the Hospital PIM (n = 21) as part of MOC by January 2007 was interviewed using semistructured telephone interviews. At the time of data collection, 771 physicians completed the Hospital PIM, and our sample strategically reflects equal proportions of those currently active on a QI team, as well as those who formed a QI team. Physicians were contacted via e‐mail and telephone to arrange an interview. None of the physicians contacted declined. All physicians were informed about the purpose of the study and provided consent for the ABIM to analyze and report data for purposes of understanding the feasibility of the PIM at improving practice. No physician personal identifiers were used in data analysis.

The interviews focused on four domains: reasons for choosing the module, assembly and role on any quality improvement teams, the value and satisfaction with the experience of completing the Hospital PIM, and prior experience with QI. Interviews were conducted by 1 trained member of the research team, and lasted approximately 30 minutes. Data collection was terminated when theoretical saturation was reached, or when no new data was revealed during the interviews. Interviews were audio‐recorded, and data were transcribed verbatim to facilitate analysis. Through an inductive and iterative approach, 3 members of the research team (including the interviewer) coded the data to identify themes that were consistently grounded in the data.9 These themes were subsequently discussed with a fourth researcher to maximize interrater reliability. Codes were then checked against existing literature to confirm linkages and enhance interpretation.

Results

The mean age of the participants (n = 21) was 42 years and 81% were male. Primary certificates were issued a mean of 13 years prior and completers came from a wide variety of disciplines, hospitals, and areas of expertise. Overall, the majority of physicians found the Hospital PIM to be a valuable experience (n = 17; 81%), which is similar to ABIM Hospital PIM surveillance data in which 75% of all completers said they would recommend the PIM to a colleague.

The impact and value of completing the PIM is illustrated in a variety of ways. For some, particularly those with extensive QI backgrounds, the PIM organized and broadened documentation of ongoing work. Several physicians described their utilization of the Hospital PIM as a byproduct of their hospital's existing cultural norms and interest in QI, and many Hospital PIM projects dovetailed with ongoing hospital QI activities. In these cases, even though the PIM did not stimulate new ideas, there was still value among physicians in receiving recognition for their ongoing QI activities and, perhaps more importantly, in learning by reflecting on their work.10

For others, the Hospital PIM was a catalyst to change. Similar to the role of a catalyst in a chemical reaction, our data suggest that the Hospital PIM facilitated QI by lowering the energy necessary for the process to occur. Many physicians reported the process stimulated new interest in QI, (eg, [The process] gave me some ideas about future QI projects that I plan to do, or described how the experience was an extra boost or stimulus to help change their ways.) These findings are consistent with recent findings on the use of PIMs in residency,11 which describes the Preventive Cardiology PIM as a catalyst to change.

Several physicians were surprised at how easy it was to begin and initiate a QI project, acknowledging the importance of leadership and teamwork (n = 7; 33%). In addition, many physicians highlighted reflective processes (n = 8; 38%) whereby the PIM led to an increased awareness of their clinical environment, or QI in general, including how QI can affect patient care and/or patient outcomes.

The most frequently reported facilitators to a successful PIM experience were familiarity/access to QI resources and staff, institutional support and culture of QI, and documentation of ongoing QI activities. The most frequently reported barrier (n = 9; 43%) was the time that it took to complete the module. Other barriers included a lack of institutional support or negative culture supporting QI activities, a lack of familiarity/access to QI resources and staff, and perceived irrelevance of QI activities to clinical practice.

Discussion

This study describes experiences for a small number of early‐completers of the Hospital PIM. For many, impact is described as an increased awareness of the hospital clinical environment, particularly an awareness of ongoing QI activities. For others, the primary impact was learning through an increased appreciation of the importance of QI activities and understanding of basic QI procedures (ie, interdisciplinary teamwork, enhanced communication, and documentation, buy‐in, using data). Still others described impact as an enhanced QI experience via reflection on current QI work or catalyzing change in their hospital environment. Further exploration of these findings will be important to determine the full impact of the PIM. An unanticipated finding, however, was the emerging theme of the role of physician engagement in mediating a successful experience with the Hospital PIM.

Prior research on physician engagement more generally demonstrates that increased physician engagement enhances interaction with nursing and other office staff,12 improves overall physician alignment,13 enhances QI,2 and may heighten physicians' willingness to participate in hospital administration and policy.14 Our data support these findings and further describe the importance of engagement in QI activities, whether it be through assembling and working in a team, helping analyze hospital systems, navigating existing institutional linkages, or simply becoming the creative initiative on a QI project. For completers of the Hospital PIM, engaging in any aspect of the QI process facilitates a successful PIM experience as documented by impact, and may stimulate physician leadership and hospital level change as well. Nonengaging physicians, in contrast, had a negative experience and documented little or no impact as a result of completing the PIM.

As our findings illustrate, engagement may not be a fixed construct, and may be acquired or generated through the QI process. In this context, physicians with varying levels of QI experience and expertise may learn and find value in completing the Hospital PIM, provided they become engaged with the process. Internal (ie, personal commitment, buy‐in, perceived relevance) and external (ie, hospital QI culture, access to QI team, access to data) factors may influence the degree of satisfaction and success with the Hospital PIM experience, thus maximizing facilitators and overcoming the barriers is also important for a positive outcome.

There are important limitations to this study. Most importantly, we acknowledge that the quality of the resources available between hospitals is highly variable. Therefore, our subjective assessment of whether or not someone was actively engaged is largely dependent on the quality of the available resources, and in a resource‐poor environment, this may not be a fair reflection of their engagement. We further recognize that coming to any broad or conclusive findings about the impact of the PIM is difficult given the qualitative nature of this study. However, our findings do suggest that the Hospital PIM may promote learning and value to completing physicians, especially those that engage in the QI process. Future studies should further explore the described impact and the relationship between engagement and QI.

To further enhance the Hospital PIM, consideration of prerequisite criteria for future completers, such as documentation of engagement, adequate access to hospital QI resources, and significant clinical work in the hospital setting, may be warranted. Additionally, consideration for alternative means of MOC credit may be warranted for physicians who demonstrate a proficiency in QI activities or who work in hospitals that efficiently participate in QI activities, such as a Health Maintenance Organization, for whom completion of the Hospital PIM may be redundant.

In conclusion, our findings suggest that the Hospital PIM is a useful component of MOC for appropriate groups of physicians despite the unique aspects of the Hospital PIM using hospital‐level outcomes data. Many physicians in our sample found it to be useful as a catalyst for learning about QI activities, which was facilitated through active engagement with the PIM QI process. While ongoing study is needed, it is anticipated that the findings from this study will help to inform the proposed pathway of focused practice in hospital medicine as part of MOC, particularly activities geared toward assessing competency in QI.

Physicians play an important role in improving quality improvement (QI) through clinical expertise and leadership.1, 2 The role of the physician leader is dynamic and complex, yet key competencies have been described in terms of personal commitment, professional credibility, QI behaviors and skills, and institutional linkages.3 Several characteristics have also been identified in hospitals successful in implementing QI, including shared goals for improvement, substantial administrative support, use of credible data feedback, and strong physician leadership.4 Cultivating physician leadership in hospital QI via development of these competencies is crucial for ongoing efforts in hospital QI activities.

The American Board of Internal Medicine (ABIM) developed web‐based assessment tools called Practice Improvement Modules (PIMs), as part of the maintenance of certification (MOC) program. Designed to facilitate physician involvement in QI, most PIMs target a single medical condition in the ambulatory practice,5 and involve a medical record audit performed by the physician, a patient survey, and a systems readiness survey. Physicians use the results of this data collection to perform a single test of change, and receive MOC credit when they report on the results of their intervention. Recognizing that QI activities may be different in hospital settings, the ABIM subsequently developed a Hospital‐based PIM (Hospital PIM) that allows physicians to use nationally‐approved hospital‐level performance data to complete the module. The Hospital PIM requires physicians to carry out a single test of change, and report any change in the perception of the environment supporting QI activities.

The ABIM has also begun work on potentially creating a focused pathway for hospitalists in the MOC program.6 Practice‐based learning and improvement (PBLI), systems‐based practice (SBP),7 and QI8 are core competencies of hospital medicine, and assessment of these competencies would be an important component of the new, focused MOC pathway. The Hospital PIM potentially provides an assessment methodology, thus it is important to understand the impact and value of this web‐based assessment tool.

The objective of this study is to explore the impact of the Hospital PIM on physicians participating in hospital‐based QI, including facilitators and barriers to a successful experience. We highlight several case studies to describe this impact, which can be defined as learning about QI, value‐added to practice, or an enhanced QI experience. We also describe 3 pathways suggesting how physician engagement, which is an emerging theme of our research, mediates the impact of the Hospital PIM.

Methods

A nonprobability purposive sample of physicians who completed the Hospital PIM (n = 21) as part of MOC by January 2007 was interviewed using semistructured telephone interviews. At the time of data collection, 771 physicians completed the Hospital PIM, and our sample strategically reflects equal proportions of those currently active on a QI team, as well as those who formed a QI team. Physicians were contacted via e‐mail and telephone to arrange an interview. None of the physicians contacted declined. All physicians were informed about the purpose of the study and provided consent for the ABIM to analyze and report data for purposes of understanding the feasibility of the PIM at improving practice. No physician personal identifiers were used in data analysis.

The interviews focused on four domains: reasons for choosing the module, assembly and role on any quality improvement teams, the value and satisfaction with the experience of completing the Hospital PIM, and prior experience with QI. Interviews were conducted by 1 trained member of the research team, and lasted approximately 30 minutes. Data collection was terminated when theoretical saturation was reached, or when no new data was revealed during the interviews. Interviews were audio‐recorded, and data were transcribed verbatim to facilitate analysis. Through an inductive and iterative approach, 3 members of the research team (including the interviewer) coded the data to identify themes that were consistently grounded in the data.9 These themes were subsequently discussed with a fourth researcher to maximize interrater reliability. Codes were then checked against existing literature to confirm linkages and enhance interpretation.

Results

The mean age of the participants (n = 21) was 42 years and 81% were male. Primary certificates were issued a mean of 13 years prior and completers came from a wide variety of disciplines, hospitals, and areas of expertise. Overall, the majority of physicians found the Hospital PIM to be a valuable experience (n = 17; 81%), which is similar to ABIM Hospital PIM surveillance data in which 75% of all completers said they would recommend the PIM to a colleague.

The impact and value of completing the PIM is illustrated in a variety of ways. For some, particularly those with extensive QI backgrounds, the PIM organized and broadened documentation of ongoing work. Several physicians described their utilization of the Hospital PIM as a byproduct of their hospital's existing cultural norms and interest in QI, and many Hospital PIM projects dovetailed with ongoing hospital QI activities. In these cases, even though the PIM did not stimulate new ideas, there was still value among physicians in receiving recognition for their ongoing QI activities and, perhaps more importantly, in learning by reflecting on their work.10

For others, the Hospital PIM was a catalyst to change. Similar to the role of a catalyst in a chemical reaction, our data suggest that the Hospital PIM facilitated QI by lowering the energy necessary for the process to occur. Many physicians reported the process stimulated new interest in QI, (eg, [The process] gave me some ideas about future QI projects that I plan to do, or described how the experience was an extra boost or stimulus to help change their ways.) These findings are consistent with recent findings on the use of PIMs in residency,11 which describes the Preventive Cardiology PIM as a catalyst to change.

Several physicians were surprised at how easy it was to begin and initiate a QI project, acknowledging the importance of leadership and teamwork (n = 7; 33%). In addition, many physicians highlighted reflective processes (n = 8; 38%) whereby the PIM led to an increased awareness of their clinical environment, or QI in general, including how QI can affect patient care and/or patient outcomes.

The most frequently reported facilitators to a successful PIM experience were familiarity/access to QI resources and staff, institutional support and culture of QI, and documentation of ongoing QI activities. The most frequently reported barrier (n = 9; 43%) was the time that it took to complete the module. Other barriers included a lack of institutional support or negative culture supporting QI activities, a lack of familiarity/access to QI resources and staff, and perceived irrelevance of QI activities to clinical practice.

Discussion

This study describes experiences for a small number of early‐completers of the Hospital PIM. For many, impact is described as an increased awareness of the hospital clinical environment, particularly an awareness of ongoing QI activities. For others, the primary impact was learning through an increased appreciation of the importance of QI activities and understanding of basic QI procedures (ie, interdisciplinary teamwork, enhanced communication, and documentation, buy‐in, using data). Still others described impact as an enhanced QI experience via reflection on current QI work or catalyzing change in their hospital environment. Further exploration of these findings will be important to determine the full impact of the PIM. An unanticipated finding, however, was the emerging theme of the role of physician engagement in mediating a successful experience with the Hospital PIM.

Prior research on physician engagement more generally demonstrates that increased physician engagement enhances interaction with nursing and other office staff,12 improves overall physician alignment,13 enhances QI,2 and may heighten physicians' willingness to participate in hospital administration and policy.14 Our data support these findings and further describe the importance of engagement in QI activities, whether it be through assembling and working in a team, helping analyze hospital systems, navigating existing institutional linkages, or simply becoming the creative initiative on a QI project. For completers of the Hospital PIM, engaging in any aspect of the QI process facilitates a successful PIM experience as documented by impact, and may stimulate physician leadership and hospital level change as well. Nonengaging physicians, in contrast, had a negative experience and documented little or no impact as a result of completing the PIM.

As our findings illustrate, engagement may not be a fixed construct, and may be acquired or generated through the QI process. In this context, physicians with varying levels of QI experience and expertise may learn and find value in completing the Hospital PIM, provided they become engaged with the process. Internal (ie, personal commitment, buy‐in, perceived relevance) and external (ie, hospital QI culture, access to QI team, access to data) factors may influence the degree of satisfaction and success with the Hospital PIM experience, thus maximizing facilitators and overcoming the barriers is also important for a positive outcome.

There are important limitations to this study. Most importantly, we acknowledge that the quality of the resources available between hospitals is highly variable. Therefore, our subjective assessment of whether or not someone was actively engaged is largely dependent on the quality of the available resources, and in a resource‐poor environment, this may not be a fair reflection of their engagement. We further recognize that coming to any broad or conclusive findings about the impact of the PIM is difficult given the qualitative nature of this study. However, our findings do suggest that the Hospital PIM may promote learning and value to completing physicians, especially those that engage in the QI process. Future studies should further explore the described impact and the relationship between engagement and QI.

To further enhance the Hospital PIM, consideration of prerequisite criteria for future completers, such as documentation of engagement, adequate access to hospital QI resources, and significant clinical work in the hospital setting, may be warranted. Additionally, consideration for alternative means of MOC credit may be warranted for physicians who demonstrate a proficiency in QI activities or who work in hospitals that efficiently participate in QI activities, such as a Health Maintenance Organization, for whom completion of the Hospital PIM may be redundant.

In conclusion, our findings suggest that the Hospital PIM is a useful component of MOC for appropriate groups of physicians despite the unique aspects of the Hospital PIM using hospital‐level outcomes data. Many physicians in our sample found it to be useful as a catalyst for learning about QI activities, which was facilitated through active engagement with the PIM QI process. While ongoing study is needed, it is anticipated that the findings from this study will help to inform the proposed pathway of focused practice in hospital medicine as part of MOC, particularly activities geared toward assessing competency in QI.

In recent years, medical educators have recognized the importance of the inclusion of patient‐centered care in the medical school curriculum.1 There is an increased awareness of the importance of patient involvement in medical decision‐making, as well as a realization that patient‐centered care positively affects patient satisfaction and outcomes measures.2 The Institute of Medicine, in its 2001 report Crossing the Quality Chasm: A New Health System for the 21st Century, included patient‐centered care as one of the areas for the development of quality measures, defining it as providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.3 Several organizations, such as the Institute for Healthcare Improvement,4 have initiatives related to achieving the goals of patient‐centered care. While not a new phenomenon, patient‐centered care is permeating many areas of the healthcare delivery system.5 The recognition of patient‐centered care as both a desirable and measurable outcome of the healthcare enterprise has also renewed interest in the field of medical humanities as a valid tool for the advancement of patient‐centered initiatives and goals.

The Basis for Patient‐centered Care

Stewart et al.,6 in their book Patient‐Centered Medicine: Transforming the Clinical Method, identify 6 essential components of the patient‐centered clinical method: exploration of the disease and illness experience; understanding of the whole person; finding common ground; incorporating prevention and health promotion; enhancing the patient‐doctor relationship; and being realistic. These recommendations seek to improve the patient‐physician relationship by empowering the patient to be an active participant in his/her own health care.

The American Academy of Pediatrics recently released a policy statement7 outlining the benefits of family‐centered care in patient‐family outcomes, as well as in staff satisfaction. The statement also highlights the importance of bedside rounding by the attending physician and the healthcare team. Bedside rounding involves the patient in management discussions and decision making, while allowing for the unfiltered exchange of information. Nurses, therapists, and ancillary staff involved in the care of the patient also participate in the presentation. After the presentation, goals for the hospitalization are established, and the patient and family are asked for permission to implement the plan of care. Educational discussions regarding the patient's diagnosis usually take place outside the room, unless the patient's physical exam warrants a bedside teaching moment. Regardless of the format, patient‐involvement in the decision process is the central objective.

The Basis for the Medical Humanities

At the same time, there is renewed interest in the inclusion of the humanities in medicine. There is a perceived gap between the technological emphasis of the current medical school curriculum and the human values integral to the patient‐physician relationship.8 Namely, there is a growing concern that medical technology has suffused medical education with a sort of trade mentality in which doctors are trained in the latest scientific medical breakthroughs without the proper contextualization of the patient as the center of the healthcare enterprise.9 The National Endowment for the Humanities, the Association of American Medical Colleges, the Accreditation Council on Graduate Medical Education, and the Society for Health and Human Values have all called for increased emphasis of the humanities in medical education.10

What are the medical humanities? There is no clear‐cut definition. Felice Aull11 correlates the term with various so‐called liberal arts disciplines and their application to medical education and practice. She develops the notion that the medical humanities contribute to medical education in areas pertinent to patient‐centered care: insight into the human condition, development of observational and analytical skills, development of empathy and self‐reflection, and intercultural understanding.

In general, the medical humanities provide broad educational perspectives, and allow learners to develop skills critical to the development of a humane approach to patients.12 The paradigm relies on the assumption that exposure to the humanities in medical schoolin the form of formal lectures dealing with topics such as philosophy and literature, or through the role‐modeling interactions of teaching physicians and their perceived empathy to their patientswill allow the students to become more humane, and therefore, better doctors.13 The medical humanities seek to equip doctors with the critical thinking incumbent to the conversation about human values in a scientific field, and to explore questions of value and purpose critical in the medical setting.14

Shared Values

What are the values associated with the medical humanities that make them ideal for the teaching of patient‐centered care? Lester Friedman15 delineates 2 domains pertaining to the intrinsic values of the medical humanities. He identifies an affective domain, corresponding to a loose interpretation of the traditional affective perspective identified in the patient‐physician relationship; and a cognitive domain, a refocusing of medicine to its so‐called traditional professional roots, contrasted with the trade mentality of some in the profession today. Donnie Self16 identifies 2 currents of thought regarding the medical humanities: the affective approach, related to the development of compassion, sensitivity, empathy between the patients and their care providers; and the cognitive approach, which pertains to the development of logical and critical thinking required by medical education. These correspond to the integral attributes of patient‐centered care: incorporating the patients' ideas and affective responses to their illness; and establishing common ground and goals agreed upon by both patient and physician.17

The medical humanities are used to address such patient‐centered issues as end‐of‐life care in children,18 the physician‐patient narrative interaction,19 and the patients' role in their own health care.20 Medical humanities courses are also used in the training of cultural competence.21 Of course, the best‐known contribution of the medical humanities to patient‐centered care is the continuing importance of bioethics programs and their interrelation with other humanities fields.22

One of the goals of patient‐centered care is the elimination of perceived barriers of communication between patient and healthcare providers, in order to create a partnership aimed at improving healthcare outcomes.2 Since one of the fundamental aspects of medical training is learning the language of medicine,23 enhancing the communication skills of future physicians is part of the educational goals pursued by medical humanities programs.24 Language and its applicationsfor example, courses on medical interviewing or narrative medicineserve as the link between patient care and the medical humanities. Effective communication with patients is a measurable predictor of patient satisfaction, patient outcomes, and occurrences of malpractice litigation.17 For example, a study examining communication behaviors between physicians and the occurrence of malpractice claims25 found that doctors who were not sued spent more time with patients, educating patients about what to expect, and asking patients their understanding and opinion of the situation. Another study26 demonstrated that a patient‐focused approach improved the management of asthma, decreasing emergency room visits and hospitalizations. Therefore, it is not surprising that the Institute of Medicine's Committee on Behavioral and Social Sciences in Medical School Curricula identified basic and complex communications skills as priorities for inclusion in the medical curriculum.27

Doubts About the Process

There are doubts as to whether the medical humanities can really instill humanistic qualities in doctors. There are also questions about the physician‐centric focus of the medical humanities.28 This physician‐centric attitude runs counter to the intent of the medical humanities. Edmund Pellegrino and David Thomasma29 define the patient‐physician interaction as a human relationship where 1 person in need of healing seeks out another who professes to heal, or to assist in healing. The act of medicine ties these 2 persons together. While acknowledging the basic imbalance of the physician‐patient relationship, Pellegrino and Thomasma29 strive to close the gap by establishing medicine as a relation of mutual consent to effect individualized well‐being by working in, with, and through the body. The individualized exercise of well‐being, framed in, with, and through the body of the patient is similar to the description used by Stewart et al.6 of the patient as the unit of analysis delineating patient‐centered care, as it incorporates the interactive components proposed for a successful patient‐centered interaction.

There is also confusion between the teaching of humanities in medical schoolfor example, courses in history of medicine, narrative medicine, and medicine and the artsand the attempt to train humanistic physicians.30 Although an examination of humanities texts is certainly useful, the focus of the teaching of the medical humanities should evolve beyond a simple lucubration based on liberal studies, to a focused interaction between patient and physician, and a recentralization of the patient as the focus of that relationship.31

Conclusions

There is general agreement that a humane doctor is a better doctor. There is less agreement on how to measure the impact of a humanities education, as a qualitative assessment of satisfactory health care.19, 22, 25 There has been great growth in the teaching of medical humanities in medical schools. Most of the focus has been on the inclusion of humanities textssuch as literary, philosophical, and historical documentsas tools to establish a correlation between the arts and medicine, in hopes that the clarification of such association will provide medical students a broad‐based assessment, a so‐called world‐view, from which they can become introspective and humanistic when faced with their patients.³² Although this is a desirable goal, the driving force behind the medical humanities should shift to a quantifiable, evidence‐based assessment of its goals. A tool to achieve this verification is through the process of patient‐centered care. There is evidence to suggest patient‐centered care improves satisfaction and outcomes measures. It also refocuses care on the patient, which is the same goal of the medical humanities. By focusing on the patient, instead of the physician, the medical humanities will gain verification and validation within the academic healthcare environment.

In recent years, medical educators have recognized the importance of the inclusion of patient‐centered care in the medical school curriculum.1 There is an increased awareness of the importance of patient involvement in medical decision‐making, as well as a realization that patient‐centered care positively affects patient satisfaction and outcomes measures.2 The Institute of Medicine, in its 2001 report Crossing the Quality Chasm: A New Health System for the 21st Century, included patient‐centered care as one of the areas for the development of quality measures, defining it as providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.3 Several organizations, such as the Institute for Healthcare Improvement,4 have initiatives related to achieving the goals of patient‐centered care. While not a new phenomenon, patient‐centered care is permeating many areas of the healthcare delivery system.5 The recognition of patient‐centered care as both a desirable and measurable outcome of the healthcare enterprise has also renewed interest in the field of medical humanities as a valid tool for the advancement of patient‐centered initiatives and goals.

The Basis for Patient‐centered Care

Stewart et al.,6 in their book Patient‐Centered Medicine: Transforming the Clinical Method, identify 6 essential components of the patient‐centered clinical method: exploration of the disease and illness experience; understanding of the whole person; finding common ground; incorporating prevention and health promotion; enhancing the patient‐doctor relationship; and being realistic. These recommendations seek to improve the patient‐physician relationship by empowering the patient to be an active participant in his/her own health care.

The American Academy of Pediatrics recently released a policy statement7 outlining the benefits of family‐centered care in patient‐family outcomes, as well as in staff satisfaction. The statement also highlights the importance of bedside rounding by the attending physician and the healthcare team. Bedside rounding involves the patient in management discussions and decision making, while allowing for the unfiltered exchange of information. Nurses, therapists, and ancillary staff involved in the care of the patient also participate in the presentation. After the presentation, goals for the hospitalization are established, and the patient and family are asked for permission to implement the plan of care. Educational discussions regarding the patient's diagnosis usually take place outside the room, unless the patient's physical exam warrants a bedside teaching moment. Regardless of the format, patient‐involvement in the decision process is the central objective.

The Basis for the Medical Humanities

At the same time, there is renewed interest in the inclusion of the humanities in medicine. There is a perceived gap between the technological emphasis of the current medical school curriculum and the human values integral to the patient‐physician relationship.8 Namely, there is a growing concern that medical technology has suffused medical education with a sort of trade mentality in which doctors are trained in the latest scientific medical breakthroughs without the proper contextualization of the patient as the center of the healthcare enterprise.9 The National Endowment for the Humanities, the Association of American Medical Colleges, the Accreditation Council on Graduate Medical Education, and the Society for Health and Human Values have all called for increased emphasis of the humanities in medical education.10

What are the medical humanities? There is no clear‐cut definition. Felice Aull11 correlates the term with various so‐called liberal arts disciplines and their application to medical education and practice. She develops the notion that the medical humanities contribute to medical education in areas pertinent to patient‐centered care: insight into the human condition, development of observational and analytical skills, development of empathy and self‐reflection, and intercultural understanding.

In general, the medical humanities provide broad educational perspectives, and allow learners to develop skills critical to the development of a humane approach to patients.12 The paradigm relies on the assumption that exposure to the humanities in medical schoolin the form of formal lectures dealing with topics such as philosophy and literature, or through the role‐modeling interactions of teaching physicians and their perceived empathy to their patientswill allow the students to become more humane, and therefore, better doctors.13 The medical humanities seek to equip doctors with the critical thinking incumbent to the conversation about human values in a scientific field, and to explore questions of value and purpose critical in the medical setting.14

Shared Values

What are the values associated with the medical humanities that make them ideal for the teaching of patient‐centered care? Lester Friedman15 delineates 2 domains pertaining to the intrinsic values of the medical humanities. He identifies an affective domain, corresponding to a loose interpretation of the traditional affective perspective identified in the patient‐physician relationship; and a cognitive domain, a refocusing of medicine to its so‐called traditional professional roots, contrasted with the trade mentality of some in the profession today. Donnie Self16 identifies 2 currents of thought regarding the medical humanities: the affective approach, related to the development of compassion, sensitivity, empathy between the patients and their care providers; and the cognitive approach, which pertains to the development of logical and critical thinking required by medical education. These correspond to the integral attributes of patient‐centered care: incorporating the patients' ideas and affective responses to their illness; and establishing common ground and goals agreed upon by both patient and physician.17

The medical humanities are used to address such patient‐centered issues as end‐of‐life care in children,18 the physician‐patient narrative interaction,19 and the patients' role in their own health care.20 Medical humanities courses are also used in the training of cultural competence.21 Of course, the best‐known contribution of the medical humanities to patient‐centered care is the continuing importance of bioethics programs and their interrelation with other humanities fields.22

One of the goals of patient‐centered care is the elimination of perceived barriers of communication between patient and healthcare providers, in order to create a partnership aimed at improving healthcare outcomes.2 Since one of the fundamental aspects of medical training is learning the language of medicine,23 enhancing the communication skills of future physicians is part of the educational goals pursued by medical humanities programs.24 Language and its applicationsfor example, courses on medical interviewing or narrative medicineserve as the link between patient care and the medical humanities. Effective communication with patients is a measurable predictor of patient satisfaction, patient outcomes, and occurrences of malpractice litigation.17 For example, a study examining communication behaviors between physicians and the occurrence of malpractice claims25 found that doctors who were not sued spent more time with patients, educating patients about what to expect, and asking patients their understanding and opinion of the situation. Another study26 demonstrated that a patient‐focused approach improved the management of asthma, decreasing emergency room visits and hospitalizations. Therefore, it is not surprising that the Institute of Medicine's Committee on Behavioral and Social Sciences in Medical School Curricula identified basic and complex communications skills as priorities for inclusion in the medical curriculum.27

Doubts About the Process

There are doubts as to whether the medical humanities can really instill humanistic qualities in doctors. There are also questions about the physician‐centric focus of the medical humanities.28 This physician‐centric attitude runs counter to the intent of the medical humanities. Edmund Pellegrino and David Thomasma29 define the patient‐physician interaction as a human relationship where 1 person in need of healing seeks out another who professes to heal, or to assist in healing. The act of medicine ties these 2 persons together. While acknowledging the basic imbalance of the physician‐patient relationship, Pellegrino and Thomasma29 strive to close the gap by establishing medicine as a relation of mutual consent to effect individualized well‐being by working in, with, and through the body. The individualized exercise of well‐being, framed in, with, and through the body of the patient is similar to the description used by Stewart et al.6 of the patient as the unit of analysis delineating patient‐centered care, as it incorporates the interactive components proposed for a successful patient‐centered interaction.

There is also confusion between the teaching of humanities in medical schoolfor example, courses in history of medicine, narrative medicine, and medicine and the artsand the attempt to train humanistic physicians.30 Although an examination of humanities texts is certainly useful, the focus of the teaching of the medical humanities should evolve beyond a simple lucubration based on liberal studies, to a focused interaction between patient and physician, and a recentralization of the patient as the focus of that relationship.31

Conclusions

There is general agreement that a humane doctor is a better doctor. There is less agreement on how to measure the impact of a humanities education, as a qualitative assessment of satisfactory health care.19, 22, 25 There has been great growth in the teaching of medical humanities in medical schools. Most of the focus has been on the inclusion of humanities textssuch as literary, philosophical, and historical documentsas tools to establish a correlation between the arts and medicine, in hopes that the clarification of such association will provide medical students a broad‐based assessment, a so‐called world‐view, from which they can become introspective and humanistic when faced with their patients.³² Although this is a desirable goal, the driving force behind the medical humanities should shift to a quantifiable, evidence‐based assessment of its goals. A tool to achieve this verification is through the process of patient‐centered care. There is evidence to suggest patient‐centered care improves satisfaction and outcomes measures. It also refocuses care on the patient, which is the same goal of the medical humanities. By focusing on the patient, instead of the physician, the medical humanities will gain verification and validation within the academic healthcare environment.

In recent years, medical educators have recognized the importance of the inclusion of patient‐centered care in the medical school curriculum.1 There is an increased awareness of the importance of patient involvement in medical decision‐making, as well as a realization that patient‐centered care positively affects patient satisfaction and outcomes measures.2 The Institute of Medicine, in its 2001 report Crossing the Quality Chasm: A New Health System for the 21st Century, included patient‐centered care as one of the areas for the development of quality measures, defining it as providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.3 Several organizations, such as the Institute for Healthcare Improvement,4 have initiatives related to achieving the goals of patient‐centered care. While not a new phenomenon, patient‐centered care is permeating many areas of the healthcare delivery system.5 The recognition of patient‐centered care as both a desirable and measurable outcome of the healthcare enterprise has also renewed interest in the field of medical humanities as a valid tool for the advancement of patient‐centered initiatives and goals.

The Basis for Patient‐centered Care

Stewart et al.,6 in their book Patient‐Centered Medicine: Transforming the Clinical Method, identify 6 essential components of the patient‐centered clinical method: exploration of the disease and illness experience; understanding of the whole person; finding common ground; incorporating prevention and health promotion; enhancing the patient‐doctor relationship; and being realistic. These recommendations seek to improve the patient‐physician relationship by empowering the patient to be an active participant in his/her own health care.

The American Academy of Pediatrics recently released a policy statement7 outlining the benefits of family‐centered care in patient‐family outcomes, as well as in staff satisfaction. The statement also highlights the importance of bedside rounding by the attending physician and the healthcare team. Bedside rounding involves the patient in management discussions and decision making, while allowing for the unfiltered exchange of information. Nurses, therapists, and ancillary staff involved in the care of the patient also participate in the presentation. After the presentation, goals for the hospitalization are established, and the patient and family are asked for permission to implement the plan of care. Educational discussions regarding the patient's diagnosis usually take place outside the room, unless the patient's physical exam warrants a bedside teaching moment. Regardless of the format, patient‐involvement in the decision process is the central objective.

The Basis for the Medical Humanities

At the same time, there is renewed interest in the inclusion of the humanities in medicine. There is a perceived gap between the technological emphasis of the current medical school curriculum and the human values integral to the patient‐physician relationship.8 Namely, there is a growing concern that medical technology has suffused medical education with a sort of trade mentality in which doctors are trained in the latest scientific medical breakthroughs without the proper contextualization of the patient as the center of the healthcare enterprise.9 The National Endowment for the Humanities, the Association of American Medical Colleges, the Accreditation Council on Graduate Medical Education, and the Society for Health and Human Values have all called for increased emphasis of the humanities in medical education.10

What are the medical humanities? There is no clear‐cut definition. Felice Aull11 correlates the term with various so‐called liberal arts disciplines and their application to medical education and practice. She develops the notion that the medical humanities contribute to medical education in areas pertinent to patient‐centered care: insight into the human condition, development of observational and analytical skills, development of empathy and self‐reflection, and intercultural understanding.

In general, the medical humanities provide broad educational perspectives, and allow learners to develop skills critical to the development of a humane approach to patients.12 The paradigm relies on the assumption that exposure to the humanities in medical schoolin the form of formal lectures dealing with topics such as philosophy and literature, or through the role‐modeling interactions of teaching physicians and their perceived empathy to their patientswill allow the students to become more humane, and therefore, better doctors.13 The medical humanities seek to equip doctors with the critical thinking incumbent to the conversation about human values in a scientific field, and to explore questions of value and purpose critical in the medical setting.14

Shared Values

What are the values associated with the medical humanities that make them ideal for the teaching of patient‐centered care? Lester Friedman15 delineates 2 domains pertaining to the intrinsic values of the medical humanities. He identifies an affective domain, corresponding to a loose interpretation of the traditional affective perspective identified in the patient‐physician relationship; and a cognitive domain, a refocusing of medicine to its so‐called traditional professional roots, contrasted with the trade mentality of some in the profession today. Donnie Self16 identifies 2 currents of thought regarding the medical humanities: the affective approach, related to the development of compassion, sensitivity, empathy between the patients and their care providers; and the cognitive approach, which pertains to the development of logical and critical thinking required by medical education. These correspond to the integral attributes of patient‐centered care: incorporating the patients' ideas and affective responses to their illness; and establishing common ground and goals agreed upon by both patient and physician.17

The medical humanities are used to address such patient‐centered issues as end‐of‐life care in children,18 the physician‐patient narrative interaction,19 and the patients' role in their own health care.20 Medical humanities courses are also used in the training of cultural competence.21 Of course, the best‐known contribution of the medical humanities to patient‐centered care is the continuing importance of bioethics programs and their interrelation with other humanities fields.22

One of the goals of patient‐centered care is the elimination of perceived barriers of communication between patient and healthcare providers, in order to create a partnership aimed at improving healthcare outcomes.2 Since one of the fundamental aspects of medical training is learning the language of medicine,23 enhancing the communication skills of future physicians is part of the educational goals pursued by medical humanities programs.24 Language and its applicationsfor example, courses on medical interviewing or narrative medicineserve as the link between patient care and the medical humanities. Effective communication with patients is a measurable predictor of patient satisfaction, patient outcomes, and occurrences of malpractice litigation.17 For example, a study examining communication behaviors between physicians and the occurrence of malpractice claims25 found that doctors who were not sued spent more time with patients, educating patients about what to expect, and asking patients their understanding and opinion of the situation. Another study26 demonstrated that a patient‐focused approach improved the management of asthma, decreasing emergency room visits and hospitalizations. Therefore, it is not surprising that the Institute of Medicine's Committee on Behavioral and Social Sciences in Medical School Curricula identified basic and complex communications skills as priorities for inclusion in the medical curriculum.27

Doubts About the Process

There are doubts as to whether the medical humanities can really instill humanistic qualities in doctors. There are also questions about the physician‐centric focus of the medical humanities.28 This physician‐centric attitude runs counter to the intent of the medical humanities. Edmund Pellegrino and David Thomasma29 define the patient‐physician interaction as a human relationship where 1 person in need of healing seeks out another who professes to heal, or to assist in healing. The act of medicine ties these 2 persons together. While acknowledging the basic imbalance of the physician‐patient relationship, Pellegrino and Thomasma29 strive to close the gap by establishing medicine as a relation of mutual consent to effect individualized well‐being by working in, with, and through the body. The individualized exercise of well‐being, framed in, with, and through the body of the patient is similar to the description used by Stewart et al.6 of the patient as the unit of analysis delineating patient‐centered care, as it incorporates the interactive components proposed for a successful patient‐centered interaction.

There is also confusion between the teaching of humanities in medical schoolfor example, courses in history of medicine, narrative medicine, and medicine and the artsand the attempt to train humanistic physicians.30 Although an examination of humanities texts is certainly useful, the focus of the teaching of the medical humanities should evolve beyond a simple lucubration based on liberal studies, to a focused interaction between patient and physician, and a recentralization of the patient as the focus of that relationship.31

Conclusions

There is general agreement that a humane doctor is a better doctor. There is less agreement on how to measure the impact of a humanities education, as a qualitative assessment of satisfactory health care.19, 22, 25 There has been great growth in the teaching of medical humanities in medical schools. Most of the focus has been on the inclusion of humanities textssuch as literary, philosophical, and historical documentsas tools to establish a correlation between the arts and medicine, in hopes that the clarification of such association will provide medical students a broad‐based assessment, a so‐called world‐view, from which they can become introspective and humanistic when faced with their patients.³² Although this is a desirable goal, the driving force behind the medical humanities should shift to a quantifiable, evidence‐based assessment of its goals. A tool to achieve this verification is through the process of patient‐centered care. There is evidence to suggest patient‐centered care improves satisfaction and outcomes measures. It also refocuses care on the patient, which is the same goal of the medical humanities. By focusing on the patient, instead of the physician, the medical humanities will gain verification and validation within the academic healthcare environment.

Since contrast nephropathy (CN) was recognized more than 50 years ago,1 there have been continuous efforts to chemically modify radiocontrast agents to be less nephrotoxic. Although radiocontrast media have indeed become safer, which reduces the likelihood of CN per procedure, the indications for radiocontrast administration have dramatically increased, since over 80 million doses are delivered in the world annually.2, 3 Furthermore, the number of patients with CN risks, which are mainly chronic renal insufficiency (CRI) and diabetes (Table 1), has also grown. Currently, more than 26 million people are estimated to have CRI in the United States4 and 200 million people have diabetes worldwide.5 The combination of increased radiocontrast administration frequency and greater prevalence of at‐risk patients is likely to result in continued increases in CN events.

The incidence of CN varies between studies, depending on risk factors of the cohort and definition of CN, but figures have been reported to be as high as 50% in studies enriched with CRI and diabetic patients. However, a very recent study disputes such high incidence rates by demonstrating that patients receiving no radiocontrast media had a similar frequency of serum creatinine increases compared to a comparable group of historical CN patients.6 This study emphasizes that conventional definitions of CN, eg, 25% increase in serum creatinine above baseline, may be too conservative.

A retrospective study of 7586 patients showed 22% in‐hospital mortality in patients who developed CN vs. 1.4% in those who did not, after adjusting for comorbidities. One‐ and 5‐year mortality rates were also higher in the CN group (12.1% vs. 3.7% and 44.6% vs. 14.5%, respectively).7 Another study of 1826 patients, who underwent coronary artery intervention procedures, showed that 14.4% developed CN and 0.8% required hemodialysis. Mortality was 1.1% in patients who did not develop CN, 7.1% in those with CN, and 35.7% in the hemodialysis‐treated CN group.8 Moreover, studies by several other groups also support the position that CN is associated with increased in‐hospital and long‐term mortality.911 Although radiocontrast administration may not be a causal risk factor for mortality, since at‐risk patients have a number of comorbidities, radiocontrast media should nevertheless at least be viewed as an important marker of acute kidney injury and death risk.

Despite the enhanced morbidity and mortality associated with CN, there are no strict guidelines for prevention of CN. Part of the reason is that the literature is controversial regarding most prevention strategies. Several interventions are commonly proposed to help prevent CN, including discriminate selection of the type of radiocontrast, N‐acetylcysteine, volume expansion with saline and/or NaHCO₃, and prophylactic hemofiltration. The major purpose of this review is to discuss these different approaches to CN prevention, with the ultimate goal of offering discrete recommendations.

The basis of this semisystematic review was a literature search using the PubMed database (www.ncbi.nlm.nih.gov/sites/entrez) to identify studies published in English language journals between January 1966 and July 2008 comparing regimens for prophylaxis of CN. Search terms included contrast, radiocontrast, radioiodinated AND nephropathy, nephrotoxicity, renal failure, kidney injury AND N‐acetylcysteine, Mucomyst, sodium bicarbonate, NaHCO₃, hemofiltration, continuous venovenous hemofiltration (CVVH), theophylline, statin, ascorbic acid, dopamine, fenoldopam, adenosine, and endothelin. The total number of articles that met the search criteria exceeded 3000 and over 200 in high profile biomedical journals were scrutinized in detail. The articles cited in this review were independently considered by 2 authors (B.G.A. and J.R.S.) to have the greatest impact.

We report on prophylactic maneuvers that are either commonly considered by nephrology consultants or contain sufficient data to warrant a meta‐analysis study. Studies involving statins, ascorbic acid, dopamine analogs, endothelin antagonists, and theophylline were not addressed in this review due to insufficient, inconclusive, or predominantly negative data. Clinical characteristics and pathogenesis of CN, which include vasoconstriction, ischemia, production of oxygen free radicals, tubular cell apoptosis, and intratubular obstruction, are also not discussed in detail, but have recently been reviewed.12

Risk Associated with Different Types of Radiocontrast Media

There are 3 generations of radiocontrast media: hyperosmolar (14001800 mosm/kg), low osmolar (500850 mosm/kg) and isoosmolar (290 mosm/kg). Note that the low osmolar agents have lower osmolarity relative to the hyperosmolar agents, but are still hyperosmolar compared to serum. Multiple studies have compared effects of radiocontrast with different osmolarities.

The Iohexol Cooperative Study was a double‐blind, randomized, controlled trial (RCT) that randomized 1196 patients to Iohexol (low osmolarity) or diatrizoate (hyperosmolar). Definition of CN was a rise in serum creatinine by >1 mg/dL within 48 to 72 hours after the radiocontrast exposure. Results were in favor of the iohexol group (3% developed CN vs. 7% in the diatrizoate group; P = 0.002). Subgroup analysis of patients with CRI and CRI plus diabetes also revealed less CN in the iohexol vs. diatrizoate groups (7% vs. 16% and 12% vs. 27%, respectively).13

An earlier non‐RCT of 303 patients undergoing femoral angiography compared iohexol/emoxaglate (both are low osmolar) to diatrizoate (hyperosmolar). Six different CN definitions were used. Each comprised a combination of different magnitudes of rise of serum creatinine over various periods of time. Overall, the incidence of CN was 7% in the low osmolar group vs. 26% in the hyperosmolar group (P = 0.001). In subgroup analysis of patients with CRI, and of patients with diabetes, less CN was again observed with low osmolar agents (10% vs. 41%, P = 0.017, in the CRI group; and 10% vs. 31%, P = 0.012, in the diabetes group). Analysis of subjects with baseline serum creatinine <1.5 mg/dL showed no differences between the 2 groups, emphasizing that prior CRI is an important CN risk factor.14

The RECOVER study was a double‐blind RCT of 300 patients undergoing coronary angiography, who were randomized to iodixanol (isoosmolar) or ioxaglate (low osmolarity). CN was defined as a rise in serum creatinine by >25% or 0.5 mg/dL at 24 and 48 hours. CN incidence was 7.9% in the iodixanol group vs. 17% in the ioxaglate group (P = 0.021). Subgroup analyses of patients stratified by severe CRI, diabetes, and contrast volume also favored iodixanol.15 In a similarly designed, double‐blind RCT involving 129 patients with diabetes and CRI randomized to iodixanol or iohexol, CN developed in 3% of iodixanol group vs. 26% in the iohexol group (P = 0.002).16 These results were further supported by a very recent double‐blind RCT comparing iodixanol to iopromide (low osmolar) in 117 patients with baseline serum creatinine 1.5 mg/dL undergoing CT scans. The incidence of serum creatinine increases of 0.5 mg/dL or 25% above baseline or glomerular filtration rate (GFR) reduction of 5 mL/minute was significantly lower in the iodixanol group (P = 0.04, 0.01, and 0.04 respectively).17

In contrast to these reports, 2 double‐blind RCTs showed no differences in CN incidence between iodixanol and low osmolar agents. One study compared iodixanol to iopromide in 64 patients undergoing intravenous pyelography (IVP),18 and the other included 16 nondiabetic patients with CRI and compared iodixanol to iohexol.19 However, because of the small sample sizes, it is likely that neither study is adequately powered to detect differences in outcome between the 2 types of radiocontrast media.

Given the importance of the issue and conflicting results from individual studies, a meta‐analysis of 16 double‐blind RCTs was performed.20 This study included 2727 patients undergoing angiography, compared iodixanol (isoosmolar) to a variety of low osmolar agents, and demonstrated that iodixanol was less nephrotoxic compared to the low osmolarity agents in CRI patients (2.8% vs. 8.4%; P = 0.001) and in patients with CRI plus diabetes (3.5% vs. 15.5%; P = 0.003). Independent predictors of CN were CRI, CRI plus diabetes, and the use of low‐osmolarity media, whereas diabetes, age, and radiocontrast volume were not statistically significant independent predictors.20

Taken together, we conclude that isoosmolar media represents the lowest risk for CN. An additional benefit is that isoosmolar media, on the basis of diminished osmotic load, is less likely to precipitate extracellular fluid volume overload, which is particularly germane for patients with CRI, who have diminished capacity to excrete solute loads. Therefore, we recommend using isoosmolar media, particularly in patients at high risk for CN, such as those with CRI, especially due to diabetic nephropathy.

Oral N‐Acetylcysteine

Based primarily upon in vitro evidence, N‐acetylcysteine (NAC) may theoretically prevent CN by direct antioxidant and vasodilatory effects. However, in vivo, NAC is rapidly metabolized and inactivated by the liver. Therefore, it has been postulated that the mechanism of action may be indirect, and the cysteine metabolite of NAC may stimulate glutathione synthesis, which then inhibits cellular oxidation.21

The first clinical trial to address the prophylactic role of NAC in CN was an RCT of 83 patients with CRI (mean serum creatinine [Cr] = 2.4) undergoing CT scans, who were randomized to NAC plus 0.45% NaCl vs. placebo and 0.9% NaCl.22 The NAC dose was 600 mg orally twice daily for 2 doses before and 2 doses after the procedure. Intravenous fluids were started 12 hours before and stopped 12 hours after the procedure and infused at a rate of 1 ml/kg/hour. CN definition was rise in serum creatinine by >0.5 mg/dL at 48 hours. The results were statistically significant, with a relative risk of CN = 0.1 (95%CI, 0.020.9) in subjects treated with NAC.

There have been many subsequent reports that have evaluated NAC in small numbers of patients with mild to moderate CRI. In general, results from these trials have been inconsistent, which has led to several meta‐analyses to delineate NAC efficacy in CN prevention. The most recent and largest meta‐analysis included 26 NAC RCTs, and revealed a statistically significant benefit from NAC (relative risk [RR] = 0.62; 95%CI, 0.440.88).23 Twelve other meta‐analyses, which incorporated fewer studies, have been published,2435 and 7 of the 12 reported a benefit from NAC.25, 27, 29, 30, 32, 34, 35

Although meta‐analysis is considered the most accepted strategy to define conclusions from multiple trials, conflicting results between NAC meta‐analyses highlight the possibility that this approach may still not provide resolution to clinical questions, especially when inclusion criteria differ between meta‐analyses. Therefore, as discussed by Bagshaw et al.,36 meta‐analyses are not always a panacea, and should be avoided if the trials to be included exhibit significant statistical or clinical heterogeneity, as is the case with studies involving NAC prophylaxis of CN. Finally, because meta‐analyses require pooling of data from published studies, which tend to be positive, the possibility of publication bias exists.

In summary, conclusions from trials to assess efficacy of oral NAC in the prevention of CN have been inconsistent, though there has been a general trend toward benefit. Factors contributing to inconsistent results include variable definitions of CN, degree of CRI and diabetes in the cohort, amount and type of contrast used, NAC dosing and intravenous hydration protocols. As a result, a large multicenter RCT would certainly be helpful. However, the size of such trial might be cost‐prohibitive, and unlikely to be underwritten by the pharmaceutical industry because the patent for NAC has expired.36

Intravenous NAC

In addition to the vast literature on oral NAC for CN prophylaxis, there are now studies that have also evaluated efficacy of intravenous NAC. In one of the largest double‐blind RCTs,37 487 patients (mean baseline serum creatinine = 1.6 mg/dL) were randomized to NAC 500 mg intravenously vs. placebo before cardiac catheterization. Both groups received the same hydration protocols. The study was stopped when an interim analysis determined that there was no advantage to NAC (CN incidence, which was defined as a decrease in creatinine clearance by >5 mL/minute at days 1 to 8 postprocedure, was 23.3% vs. 20.7% in the placebo group).

The RAPPID study examined higher intravenous NAC doses in 80 patients undergoing cardiac catheterization.38 Subjects in this study were randomized to either NAC (150 mg/kg in 500 mL 0.9% NaCl before procedure and then 50 mg/kg in 500 mL 0.9% NaCl over 4 hours after procedure) or 0.9% NaCl 12 hours before and 12 hours after procedure. Despite the relatively small study size, intravenous NAC demonstrated a significant benefit in the prevention of CN (RR = 0.28; P = 0.045) defined as rise in serum creatinine by >25% at 2 or 4 days postexposure. Hypersensitivity‐like reactions were observed in 14.5% of patients receiving intravenous NAC, but symptoms were easily recognized and managed.38

A recent study of 354 patients undergoing primary angioplasty evaluated the combination of intravenous and oral NAC in different doses.39 Patients were randomized to 3 groups: (1) NAC 600 mg intravenously once before procedure and then 600 mg orally twice daily for 48 hours; (2) NAC 1200 mg intravenously once before procedure and then 1200 mg orally twice daily for 48 hours; or (3) placebo. The primary outcome was increase in Cr by >25% and secondary outcomes were in‐hospital death and a composite score that included death and need for renal replacement therapy. Results were significantly in favor of the 1200‐mg NAC regimen across all outcomes (P = <0.001, 0.02, and 0.002, respectively). It should be emphasized that this study was restricted to patients undergoing primary angioplasty, which is an emergent procedure. As a result, implementation of this protocol would necessarily require rapid administration of intravenous NAC prior to the procedure, which might even require maintenance of NAC stocks within the catheterization laboratory.

Because there is a trend toward benefit from oral NAC and the benefit from intravenous NAC in trials from limited settings, and both NAC formulations are inexpensive and safe, we recommend that NAC should be included in CN prophylaxis protocols.

Extracellular Fluid Volume Expansion

Since publication of work by Solomon et al.,40 which demonstrated a benefit of intravenous hydration with 0.45% NaCl in the prevention of CN in a group of CKD patients, it has been considered standard practice to prescribe intravenous fluid regimens for CN prophylaxis in high‐risk subjects. In the largest study to test the effect of different hydration protocols for CN prevention, Mueller et al.41 randomized 1620 patients with normal baseline serum creatinine to intravenous 0.9 % NaCl vs. 0.45% NaCl. The definition of CN was rise in serum creatinine by >0.5 mg/dL at 48 hours and the incidence was 0.7% for the 0.9% NaCl group and 2% for the 0.45% NaCl group (P = 0.04).

More recently, several trials have examined the relative efficacy of intravenous NaCl vs. NaHCO₃ for CN prophylaxis. In the first NaHCO₃ RCT, Merten et al.42 compared 0.9% NaHCO₃ to 0.9% NaCl infusion in a population with a mean serum creatinine of 1.8 mg/dL. Both groups received 3 mL/kg intravenous bolus over 1 hour before the radiographic procedure followed by 1 mL/kg/hour for 6 hours. Urine pH was measured to confirm alkalinization of urine in the NaHCO₃‐treated patients and the primary end point was increase in serum creatinine by >25% within 48 hours. The study was terminated early (after enrollment of 119 patients) when the interim analysis showed CN incidence was 1.7% in the NaHCO₃ group vs. 13.6% in the NaCl group (P = 0.02).

These results were corroborated in the recent REMEDIAL trial,43 which enrolled 326 patients with serum creatinine >2 mg/dL, who were randomized to 1 of 3 arms. One group received intravenous saline (0.9% NaCl for 12 hours before and 12 hours after the procedure) and oral NAC; a second group received intravenous NaHCO₃ (3 mL/kg intravenous bolus over 1 hour before the radiographic procedure followed by 1 mL/kg/hour for 6 hours) and oral NAC; and a third group received intravenous 0.9% NaCl plus oral NAC and ascorbic acid. Patients had similar baseline characteristics and the primary end point was an increase in serum creatinine by >25% within 48 hours. The best results were observed in the NaHCO₃ plus NAC group; 1.9% developed CN in this group vs. 9.9% in the NaCl plus NAC group vs. 10.3% in the NaCl plus NAC plus ascorbic acid group (P = 0.019). Three additional prospective but smaller studies also showed the superiority of NaHCO₃.4446

In contrast to studies supporting a role for prophylactic NaHCO₃, a recent RCT showed no superiority of NaHCO₃ infusion regimens.47 In this trial, 352 patients undergoing coronary angiography were randomized to receive either NaHCO₃ or 0.9% NaCl. Both solutions were administered at rates of 3 mL/kg for 1 hour before the procedure and 1.5 mL/kg/hour for 4 hours postprocedure. The primary endpoint (>25% decrease in estimated GFR during the first 4 days after contrast exposure) was met in 13.3% of NaHCO₃ group vs. 14.6% of the 0.9% NaCl group (P = 0.82). Moreover, there were no differences in the rates of secondary outcomes, which included death, dialysis, and cardiovascular and cerebrovascular events.

Results from a very recent retrospective cohort study of 7977 patients demonstrated that NaHCO₃ infusion was associated with increased risk of CN compared to no treatment (odds ratio [OR] = 3.1; P < 0.001), whereas NAC alone or in combination with NaHCO₃ was associated with no significant difference in the incidence of CN.48 However, multiple weaknesses associated with the retrospective study design, such as inclusion of few patients at high CN risk, and acceptance of serum creatinine values within 7 days before and after the contrast procedure, which likely captures causes of acute kidney injury other than CN, preclude abandonment of NaHCO₃ prophylaxis for CN solely on the basis of this study.

In an effort to resolve the conflicting NaHCO₃ prophylaxis literature, a meta‐analysis was recently conducted.49 This study encompassed 1307 patients enrolled in 7 RCTs that examined outcomes for NaHCO₃ vs. saline prevention of CN. The main finding was a significant benefit of NaHCO₃ for protection against CN (RR = 0.37; P = 0.005). No benefit of NaHCO₃ infusion could be shown for postprocedure renal replacement therapy or death.

Therefore, based upon the results of multiple prospective trials, the recent meta‐analysis, the relative safety of NaHCO₃ infusion with appropriate monitoring, and a plausible biological mechanism whereby bicarbonate may have antioxidant properties and scavenge oxygen‐derived free radicals, which have been implicated in CN pathogenesis,50 we advocate a prophylactic regimen employing NaHCO₃ for patients at high risk for CN.

Renal Replacement Therapies

Two studies have been conducted by the same group (Marenzi et al.51, 52) to examine efficacy of continuous hemofiltration (CVVH) in preventing CN (hemofiltration clears solute by convection, and involves administration of a HCO‐rich replacement solution, whereas hemodialysis clears solute by both diffusion and convection, and there is routinely no replacement fluid). In the first study,51 114 patients with baseline serum creatinine greater than 2 mg/dL undergoing coronary angiography were randomized to hemofiltration vs. 0.9% NaCl infusion. Isovolemic hemofiltration was implemented for 4 to 6 hours before and 18 to 24 hours after the radiographic procedure. The primary endpoint was increase in creatinine by >25% within 72 hours. CN incidence was 5% in the hemofiltration group vs. 50% in the 0.9% NaCl group (P < 0.001). The secondary outcomes including in‐hospital mortality, 1‐year mortality and temporary renal replacement were also superior in the hemofiltration group. In the second study, the same investigators compared 2 different hemofiltration protocols, using the same definition of CN.52 Patients with baseline creatinine clearance <30 mL/minute (n = 92) were randomized to 0.9% NaCl infusion, postprocedure isovolemic hemofiltration only, or preprocedure plus postprocedure hemofiltration (same protocol as previous study). The incidence of CN was significantly lower in the preprocedure plus postprocedure hemofiltration group (3% vs. 26% in the postprocedure hemofiltration group vs. 40% in the 0.9% NaCl without hemofiltration group; P = 0.0001). The preprocedure plus postprocedure hemofiltration group also had reductions in in‐hospital mortality and temporary renal replacement therapy rates.

Although the mechanism of hemofiltration prevention of CN is unknown, it is certainly not enhanced clearance of contrast material, inasmuch as hemofiltration was discontinued during the angiography procedure in all protocols, and radiocontrast was therefore not cleared by hemofiltration until the process was reinstituted. Furthermore, the second study indicates that the major benefit was derived from the preprocedure hemofiltration component. Contributing factors might be control of extracellular pH and redox potential with bicarbonate replacement fluid during hemofiltration. Important confounding issues to consider are that patients receiving hemofiltration were in controlled, monitored settings and thus received more intensive care than the hydration group, and that serum creatinine, the major outcome parameter, is cleared by hemofiltration. Before hemofiltration can be recommended as routine prophylactic therapy for CN, the data will need to be corroborated by other groups, preferably involving larger numbers of study subjects and including cost‐benefit analyses.

Multiple small studies have examined the possibility that dialysis immediately following radiocontrast exposure could prevent CN, presumably by accelerating radiocontrast clearance. Most of these reports were negative, including a well‐designed meta‐analysis of RCTs, which showed no benefit of hemodialysis.53 Of note, one report suggested that hemodialysis might be potentially harmful.54 The single prospective trial that showed benefit from prophylactic hemodialysis analyzed 82 patients with advanced CRI (baseline creatinine clearance 13 mL/minute) referred for coronary angiography55 These subjects were randomly assigned to intravenous 0.9% NaCl and hemodialysis vs. intravenous 0.9% NaCl alone. Subsequent renal replacement therapy was required in 35% of control patients and in only 2% in the prophylactic dialysis group. One potential limitation of this study is that the investigators were more cognizant of volume status in the hemodialysis group to avoid fluid shifts and volume depletion during dialysis, while the control group appeared to experience no comparable intravascular volume management. Moreover, this study was conducted in patients with extremely advanced renal insufficiency, and therefore does not reflect the vast majority of patients at risk for CN.

Conclusions

CN is associated with increased morbidity and mortality, and efforts to minimize CN are therefore warranted. However, the overwhelming majority of CN trials were designed to investigate the effects of prophylaxis strategies on surrogate endpoints for estimates of GFR. Therefore, conclusions regarding the effect of these regimens on definitive outcomes, such as death and vascular events, cannot be drawn. On balance, there is evidence that oral and intravenous NAC, as well as extracellular volume expansion with intravenous NaHCO₃ are effective measures to prevent CN, whereas the data for renal replacement therapies are more equivocal. We emphasize though, that the literature on this topic is vast, and includes a large number of conflicting studies, including multiple meta‐analyses. As a result, we refrain from being too dogmatic about the best approach, and therefore cautiously offer the following recommendations for prevention of CN.

The first step is to identify high‐risk patients, who are most likely to benefit from prophylaxis (Table 1). Although risk stratification was not the focus of this review, Mehran et al.56 have developed a scoring system to quantitatively predict CN risk, with weighted parameters including CRI, diabetes, radiocontrast volume, age, hypotension, congestive heart failure, treatment with an intraaortic balloon pump, and anemia. For low‐risk patients, hydration with saline is probably adequate. For high‐risk patients, it would be prudent to initially consider whether sufficient information could be obtained from an alternative, noncontrasted radiologic procedure. If not, it would behoove the prescribing physician to then treat modifiable risk factors, as well as to discontinue potentially nephrotoxic medications.

In high‐risk patients undergoing radiocontrast procedures, we recommend using NAC and volume expansion with NaHCO₃ (Table 2). Although the evidence for this combined approach is limited,43 we believe it is biologically consistent, since the rationale for both strategies is primarily modification of redox state and inhibition of oxygen free radical generation. Because NAC formulations are generally effective, safe and inexpensive ($0.04 for 600 mg oral NAC and $24 for 1200 mg intravenous NAC at our hospital), we recommend the protocol used by Marenzi et al.,39 NAC 1200 mg intravenously once before procedure and then 1200 mg orally twice daily for 48 hours, as prophylaxis for all contrast procedures in high‐risk patients. However, we recognize that this regimen would require formal evaluation in procedures other than emergent coronary artery angioplasty before it could be enthusiastically endorsed. Therefore, if intravenous NAC is not available and/or the procedure is not emergent, NAC 6001200 mg orally twice a day, 2 doses before and 2 doses after the procedure would be a rational alternative. For the NaHCO₃ infusion, we recommend 3 mL/kg for 1 hour before the procedure, followed by 1 mL/kg/hour for 6 hours after.

Hemofiltration is labor‐intensive, expensive, and not readily available in all hospitals that renders it difficult to endorse as a definitive or routine CN prophylaxis modality. However, if a patient is already undergoing acute dialysis with catheter vascular access, it would be reasonable to consider CVVH 6 hours before and for 24 hours after the procedure (Table 2).

For high‐risk patients, we recommend minimizing the radiocontrast dose (reviewed in Ref.57). Although the dose has not consistently been identified as a risk factor (Table 1), we envision no harm in reducing the dose, particularly if adequate information can be obtained by other means, eg, coronary angiogram accompanied by an echocardiogram, rather than a ventriculogram. We would also consider the use of isoosmolar media in high‐risk patients, since the data are relatively compelling.20 Low doses of isoosmolar media should be particularly beneficial to patients with preexisting hypertension or congestive heart failure, for which the osmotic load and excess extracellular volume expansion might be deleterious. However, because isoosmolar media is expensive, a detailed cost‐benefit analysis would be required before definitive recommendations could be made, especially for patients at lower risk for CN. Finally, because of the complex literature, as well as budgetary issues, we encourage communication between the physician ordering the contrast study and the operator (radiologist or cardiologist) concerning the type of procedure and contrast media to be used.

Since contrast nephropathy (CN) was recognized more than 50 years ago,1 there have been continuous efforts to chemically modify radiocontrast agents to be less nephrotoxic. Although radiocontrast media have indeed become safer, which reduces the likelihood of CN per procedure, the indications for radiocontrast administration have dramatically increased, since over 80 million doses are delivered in the world annually.2, 3 Furthermore, the number of patients with CN risks, which are mainly chronic renal insufficiency (CRI) and diabetes (Table 1), has also grown. Currently, more than 26 million people are estimated to have CRI in the United States4 and 200 million people have diabetes worldwide.5 The combination of increased radiocontrast administration frequency and greater prevalence of at‐risk patients is likely to result in continued increases in CN events.

The incidence of CN varies between studies, depending on risk factors of the cohort and definition of CN, but figures have been reported to be as high as 50% in studies enriched with CRI and diabetic patients. However, a very recent study disputes such high incidence rates by demonstrating that patients receiving no radiocontrast media had a similar frequency of serum creatinine increases compared to a comparable group of historical CN patients.6 This study emphasizes that conventional definitions of CN, eg, 25% increase in serum creatinine above baseline, may be too conservative.

A retrospective study of 7586 patients showed 22% in‐hospital mortality in patients who developed CN vs. 1.4% in those who did not, after adjusting for comorbidities. One‐ and 5‐year mortality rates were also higher in the CN group (12.1% vs. 3.7% and 44.6% vs. 14.5%, respectively).7 Another study of 1826 patients, who underwent coronary artery intervention procedures, showed that 14.4% developed CN and 0.8% required hemodialysis. Mortality was 1.1% in patients who did not develop CN, 7.1% in those with CN, and 35.7% in the hemodialysis‐treated CN group.8 Moreover, studies by several other groups also support the position that CN is associated with increased in‐hospital and long‐term mortality.911 Although radiocontrast administration may not be a causal risk factor for mortality, since at‐risk patients have a number of comorbidities, radiocontrast media should nevertheless at least be viewed as an important marker of acute kidney injury and death risk.

Despite the enhanced morbidity and mortality associated with CN, there are no strict guidelines for prevention of CN. Part of the reason is that the literature is controversial regarding most prevention strategies. Several interventions are commonly proposed to help prevent CN, including discriminate selection of the type of radiocontrast, N‐acetylcysteine, volume expansion with saline and/or NaHCO₃, and prophylactic hemofiltration. The major purpose of this review is to discuss these different approaches to CN prevention, with the ultimate goal of offering discrete recommendations.

The basis of this semisystematic review was a literature search using the PubMed database (www.ncbi.nlm.nih.gov/sites/entrez) to identify studies published in English language journals between January 1966 and July 2008 comparing regimens for prophylaxis of CN. Search terms included contrast, radiocontrast, radioiodinated AND nephropathy, nephrotoxicity, renal failure, kidney injury AND N‐acetylcysteine, Mucomyst, sodium bicarbonate, NaHCO₃, hemofiltration, continuous venovenous hemofiltration (CVVH), theophylline, statin, ascorbic acid, dopamine, fenoldopam, adenosine, and endothelin. The total number of articles that met the search criteria exceeded 3000 and over 200 in high profile biomedical journals were scrutinized in detail. The articles cited in this review were independently considered by 2 authors (B.G.A. and J.R.S.) to have the greatest impact.

We report on prophylactic maneuvers that are either commonly considered by nephrology consultants or contain sufficient data to warrant a meta‐analysis study. Studies involving statins, ascorbic acid, dopamine analogs, endothelin antagonists, and theophylline were not addressed in this review due to insufficient, inconclusive, or predominantly negative data. Clinical characteristics and pathogenesis of CN, which include vasoconstriction, ischemia, production of oxygen free radicals, tubular cell apoptosis, and intratubular obstruction, are also not discussed in detail, but have recently been reviewed.12

Risk Associated with Different Types of Radiocontrast Media

There are 3 generations of radiocontrast media: hyperosmolar (14001800 mosm/kg), low osmolar (500850 mosm/kg) and isoosmolar (290 mosm/kg). Note that the low osmolar agents have lower osmolarity relative to the hyperosmolar agents, but are still hyperosmolar compared to serum. Multiple studies have compared effects of radiocontrast with different osmolarities.

The Iohexol Cooperative Study was a double‐blind, randomized, controlled trial (RCT) that randomized 1196 patients to Iohexol (low osmolarity) or diatrizoate (hyperosmolar). Definition of CN was a rise in serum creatinine by >1 mg/dL within 48 to 72 hours after the radiocontrast exposure. Results were in favor of the iohexol group (3% developed CN vs. 7% in the diatrizoate group; P = 0.002). Subgroup analysis of patients with CRI and CRI plus diabetes also revealed less CN in the iohexol vs. diatrizoate groups (7% vs. 16% and 12% vs. 27%, respectively).13

An earlier non‐RCT of 303 patients undergoing femoral angiography compared iohexol/emoxaglate (both are low osmolar) to diatrizoate (hyperosmolar). Six different CN definitions were used. Each comprised a combination of different magnitudes of rise of serum creatinine over various periods of time. Overall, the incidence of CN was 7% in the low osmolar group vs. 26% in the hyperosmolar group (P = 0.001). In subgroup analysis of patients with CRI, and of patients with diabetes, less CN was again observed with low osmolar agents (10% vs. 41%, P = 0.017, in the CRI group; and 10% vs. 31%, P = 0.012, in the diabetes group). Analysis of subjects with baseline serum creatinine <1.5 mg/dL showed no differences between the 2 groups, emphasizing that prior CRI is an important CN risk factor.14

The RECOVER study was a double‐blind RCT of 300 patients undergoing coronary angiography, who were randomized to iodixanol (isoosmolar) or ioxaglate (low osmolarity). CN was defined as a rise in serum creatinine by >25% or 0.5 mg/dL at 24 and 48 hours. CN incidence was 7.9% in the iodixanol group vs. 17% in the ioxaglate group (P = 0.021). Subgroup analyses of patients stratified by severe CRI, diabetes, and contrast volume also favored iodixanol.15 In a similarly designed, double‐blind RCT involving 129 patients with diabetes and CRI randomized to iodixanol or iohexol, CN developed in 3% of iodixanol group vs. 26% in the iohexol group (P = 0.002).16 These results were further supported by a very recent double‐blind RCT comparing iodixanol to iopromide (low osmolar) in 117 patients with baseline serum creatinine 1.5 mg/dL undergoing CT scans. The incidence of serum creatinine increases of 0.5 mg/dL or 25% above baseline or glomerular filtration rate (GFR) reduction of 5 mL/minute was significantly lower in the iodixanol group (P = 0.04, 0.01, and 0.04 respectively).17

In contrast to these reports, 2 double‐blind RCTs showed no differences in CN incidence between iodixanol and low osmolar agents. One study compared iodixanol to iopromide in 64 patients undergoing intravenous pyelography (IVP),18 and the other included 16 nondiabetic patients with CRI and compared iodixanol to iohexol.19 However, because of the small sample sizes, it is likely that neither study is adequately powered to detect differences in outcome between the 2 types of radiocontrast media.

Given the importance of the issue and conflicting results from individual studies, a meta‐analysis of 16 double‐blind RCTs was performed.20 This study included 2727 patients undergoing angiography, compared iodixanol (isoosmolar) to a variety of low osmolar agents, and demonstrated that iodixanol was less nephrotoxic compared to the low osmolarity agents in CRI patients (2.8% vs. 8.4%; P = 0.001) and in patients with CRI plus diabetes (3.5% vs. 15.5%; P = 0.003). Independent predictors of CN were CRI, CRI plus diabetes, and the use of low‐osmolarity media, whereas diabetes, age, and radiocontrast volume were not statistically significant independent predictors.20

Taken together, we conclude that isoosmolar media represents the lowest risk for CN. An additional benefit is that isoosmolar media, on the basis of diminished osmotic load, is less likely to precipitate extracellular fluid volume overload, which is particularly germane for patients with CRI, who have diminished capacity to excrete solute loads. Therefore, we recommend using isoosmolar media, particularly in patients at high risk for CN, such as those with CRI, especially due to diabetic nephropathy.

Oral N‐Acetylcysteine

Based primarily upon in vitro evidence, N‐acetylcysteine (NAC) may theoretically prevent CN by direct antioxidant and vasodilatory effects. However, in vivo, NAC is rapidly metabolized and inactivated by the liver. Therefore, it has been postulated that the mechanism of action may be indirect, and the cysteine metabolite of NAC may stimulate glutathione synthesis, which then inhibits cellular oxidation.21

The first clinical trial to address the prophylactic role of NAC in CN was an RCT of 83 patients with CRI (mean serum creatinine [Cr] = 2.4) undergoing CT scans, who were randomized to NAC plus 0.45% NaCl vs. placebo and 0.9% NaCl.22 The NAC dose was 600 mg orally twice daily for 2 doses before and 2 doses after the procedure. Intravenous fluids were started 12 hours before and stopped 12 hours after the procedure and infused at a rate of 1 ml/kg/hour. CN definition was rise in serum creatinine by >0.5 mg/dL at 48 hours. The results were statistically significant, with a relative risk of CN = 0.1 (95%CI, 0.020.9) in subjects treated with NAC.

There have been many subsequent reports that have evaluated NAC in small numbers of patients with mild to moderate CRI. In general, results from these trials have been inconsistent, which has led to several meta‐analyses to delineate NAC efficacy in CN prevention. The most recent and largest meta‐analysis included 26 NAC RCTs, and revealed a statistically significant benefit from NAC (relative risk [RR] = 0.62; 95%CI, 0.440.88).23 Twelve other meta‐analyses, which incorporated fewer studies, have been published,2435 and 7 of the 12 reported a benefit from NAC.25, 27, 29, 30, 32, 34, 35

Although meta‐analysis is considered the most accepted strategy to define conclusions from multiple trials, conflicting results between NAC meta‐analyses highlight the possibility that this approach may still not provide resolution to clinical questions, especially when inclusion criteria differ between meta‐analyses. Therefore, as discussed by Bagshaw et al.,36 meta‐analyses are not always a panacea, and should be avoided if the trials to be included exhibit significant statistical or clinical heterogeneity, as is the case with studies involving NAC prophylaxis of CN. Finally, because meta‐analyses require pooling of data from published studies, which tend to be positive, the possibility of publication bias exists.

In summary, conclusions from trials to assess efficacy of oral NAC in the prevention of CN have been inconsistent, though there has been a general trend toward benefit. Factors contributing to inconsistent results include variable definitions of CN, degree of CRI and diabetes in the cohort, amount and type of contrast used, NAC dosing and intravenous hydration protocols. As a result, a large multicenter RCT would certainly be helpful. However, the size of such trial might be cost‐prohibitive, and unlikely to be underwritten by the pharmaceutical industry because the patent for NAC has expired.36

Intravenous NAC

In addition to the vast literature on oral NAC for CN prophylaxis, there are now studies that have also evaluated efficacy of intravenous NAC. In one of the largest double‐blind RCTs,37 487 patients (mean baseline serum creatinine = 1.6 mg/dL) were randomized to NAC 500 mg intravenously vs. placebo before cardiac catheterization. Both groups received the same hydration protocols. The study was stopped when an interim analysis determined that there was no advantage to NAC (CN incidence, which was defined as a decrease in creatinine clearance by >5 mL/minute at days 1 to 8 postprocedure, was 23.3% vs. 20.7% in the placebo group).

The RAPPID study examined higher intravenous NAC doses in 80 patients undergoing cardiac catheterization.38 Subjects in this study were randomized to either NAC (150 mg/kg in 500 mL 0.9% NaCl before procedure and then 50 mg/kg in 500 mL 0.9% NaCl over 4 hours after procedure) or 0.9% NaCl 12 hours before and 12 hours after procedure. Despite the relatively small study size, intravenous NAC demonstrated a significant benefit in the prevention of CN (RR = 0.28; P = 0.045) defined as rise in serum creatinine by >25% at 2 or 4 days postexposure. Hypersensitivity‐like reactions were observed in 14.5% of patients receiving intravenous NAC, but symptoms were easily recognized and managed.38

A recent study of 354 patients undergoing primary angioplasty evaluated the combination of intravenous and oral NAC in different doses.39 Patients were randomized to 3 groups: (1) NAC 600 mg intravenously once before procedure and then 600 mg orally twice daily for 48 hours; (2) NAC 1200 mg intravenously once before procedure and then 1200 mg orally twice daily for 48 hours; or (3) placebo. The primary outcome was increase in Cr by >25% and secondary outcomes were in‐hospital death and a composite score that included death and need for renal replacement therapy. Results were significantly in favor of the 1200‐mg NAC regimen across all outcomes (P = <0.001, 0.02, and 0.002, respectively). It should be emphasized that this study was restricted to patients undergoing primary angioplasty, which is an emergent procedure. As a result, implementation of this protocol would necessarily require rapid administration of intravenous NAC prior to the procedure, which might even require maintenance of NAC stocks within the catheterization laboratory.

Because there is a trend toward benefit from oral NAC and the benefit from intravenous NAC in trials from limited settings, and both NAC formulations are inexpensive and safe, we recommend that NAC should be included in CN prophylaxis protocols.

Extracellular Fluid Volume Expansion

Since publication of work by Solomon et al.,40 which demonstrated a benefit of intravenous hydration with 0.45% NaCl in the prevention of CN in a group of CKD patients, it has been considered standard practice to prescribe intravenous fluid regimens for CN prophylaxis in high‐risk subjects. In the largest study to test the effect of different hydration protocols for CN prevention, Mueller et al.41 randomized 1620 patients with normal baseline serum creatinine to intravenous 0.9 % NaCl vs. 0.45% NaCl. The definition of CN was rise in serum creatinine by >0.5 mg/dL at 48 hours and the incidence was 0.7% for the 0.9% NaCl group and 2% for the 0.45% NaCl group (P = 0.04).

More recently, several trials have examined the relative efficacy of intravenous NaCl vs. NaHCO₃ for CN prophylaxis. In the first NaHCO₃ RCT, Merten et al.42 compared 0.9% NaHCO₃ to 0.9% NaCl infusion in a population with a mean serum creatinine of 1.8 mg/dL. Both groups received 3 mL/kg intravenous bolus over 1 hour before the radiographic procedure followed by 1 mL/kg/hour for 6 hours. Urine pH was measured to confirm alkalinization of urine in the NaHCO₃‐treated patients and the primary end point was increase in serum creatinine by >25% within 48 hours. The study was terminated early (after enrollment of 119 patients) when the interim analysis showed CN incidence was 1.7% in the NaHCO₃ group vs. 13.6% in the NaCl group (P = 0.02).

These results were corroborated in the recent REMEDIAL trial,43 which enrolled 326 patients with serum creatinine >2 mg/dL, who were randomized to 1 of 3 arms. One group received intravenous saline (0.9% NaCl for 12 hours before and 12 hours after the procedure) and oral NAC; a second group received intravenous NaHCO₃ (3 mL/kg intravenous bolus over 1 hour before the radiographic procedure followed by 1 mL/kg/hour for 6 hours) and oral NAC; and a third group received intravenous 0.9% NaCl plus oral NAC and ascorbic acid. Patients had similar baseline characteristics and the primary end point was an increase in serum creatinine by >25% within 48 hours. The best results were observed in the NaHCO₃ plus NAC group; 1.9% developed CN in this group vs. 9.9% in the NaCl plus NAC group vs. 10.3% in the NaCl plus NAC plus ascorbic acid group (P = 0.019). Three additional prospective but smaller studies also showed the superiority of NaHCO₃.4446

In contrast to studies supporting a role for prophylactic NaHCO₃, a recent RCT showed no superiority of NaHCO₃ infusion regimens.47 In this trial, 352 patients undergoing coronary angiography were randomized to receive either NaHCO₃ or 0.9% NaCl. Both solutions were administered at rates of 3 mL/kg for 1 hour before the procedure and 1.5 mL/kg/hour for 4 hours postprocedure. The primary endpoint (>25% decrease in estimated GFR during the first 4 days after contrast exposure) was met in 13.3% of NaHCO₃ group vs. 14.6% of the 0.9% NaCl group (P = 0.82). Moreover, there were no differences in the rates of secondary outcomes, which included death, dialysis, and cardiovascular and cerebrovascular events.

Results from a very recent retrospective cohort study of 7977 patients demonstrated that NaHCO₃ infusion was associated with increased risk of CN compared to no treatment (odds ratio [OR] = 3.1; P < 0.001), whereas NAC alone or in combination with NaHCO₃ was associated with no significant difference in the incidence of CN.48 However, multiple weaknesses associated with the retrospective study design, such as inclusion of few patients at high CN risk, and acceptance of serum creatinine values within 7 days before and after the contrast procedure, which likely captures causes of acute kidney injury other than CN, preclude abandonment of NaHCO₃ prophylaxis for CN solely on the basis of this study.

In an effort to resolve the conflicting NaHCO₃ prophylaxis literature, a meta‐analysis was recently conducted.49 This study encompassed 1307 patients enrolled in 7 RCTs that examined outcomes for NaHCO₃ vs. saline prevention of CN. The main finding was a significant benefit of NaHCO₃ for protection against CN (RR = 0.37; P = 0.005). No benefit of NaHCO₃ infusion could be shown for postprocedure renal replacement therapy or death.

Therefore, based upon the results of multiple prospective trials, the recent meta‐analysis, the relative safety of NaHCO₃ infusion with appropriate monitoring, and a plausible biological mechanism whereby bicarbonate may have antioxidant properties and scavenge oxygen‐derived free radicals, which have been implicated in CN pathogenesis,50 we advocate a prophylactic regimen employing NaHCO₃ for patients at high risk for CN.

Renal Replacement Therapies

Two studies have been conducted by the same group (Marenzi et al.51, 52) to examine efficacy of continuous hemofiltration (CVVH) in preventing CN (hemofiltration clears solute by convection, and involves administration of a HCO‐rich replacement solution, whereas hemodialysis clears solute by both diffusion and convection, and there is routinely no replacement fluid). In the first study,51 114 patients with baseline serum creatinine greater than 2 mg/dL undergoing coronary angiography were randomized to hemofiltration vs. 0.9% NaCl infusion. Isovolemic hemofiltration was implemented for 4 to 6 hours before and 18 to 24 hours after the radiographic procedure. The primary endpoint was increase in creatinine by >25% within 72 hours. CN incidence was 5% in the hemofiltration group vs. 50% in the 0.9% NaCl group (P < 0.001). The secondary outcomes including in‐hospital mortality, 1‐year mortality and temporary renal replacement were also superior in the hemofiltration group. In the second study, the same investigators compared 2 different hemofiltration protocols, using the same definition of CN.52 Patients with baseline creatinine clearance <30 mL/minute (n = 92) were randomized to 0.9% NaCl infusion, postprocedure isovolemic hemofiltration only, or preprocedure plus postprocedure hemofiltration (same protocol as previous study). The incidence of CN was significantly lower in the preprocedure plus postprocedure hemofiltration group (3% vs. 26% in the postprocedure hemofiltration group vs. 40% in the 0.9% NaCl without hemofiltration group; P = 0.0001). The preprocedure plus postprocedure hemofiltration group also had reductions in in‐hospital mortality and temporary renal replacement therapy rates.

Although the mechanism of hemofiltration prevention of CN is unknown, it is certainly not enhanced clearance of contrast material, inasmuch as hemofiltration was discontinued during the angiography procedure in all protocols, and radiocontrast was therefore not cleared by hemofiltration until the process was reinstituted. Furthermore, the second study indicates that the major benefit was derived from the preprocedure hemofiltration component. Contributing factors might be control of extracellular pH and redox potential with bicarbonate replacement fluid during hemofiltration. Important confounding issues to consider are that patients receiving hemofiltration were in controlled, monitored settings and thus received more intensive care than the hydration group, and that serum creatinine, the major outcome parameter, is cleared by hemofiltration. Before hemofiltration can be recommended as routine prophylactic therapy for CN, the data will need to be corroborated by other groups, preferably involving larger numbers of study subjects and including cost‐benefit analyses.

Multiple small studies have examined the possibility that dialysis immediately following radiocontrast exposure could prevent CN, presumably by accelerating radiocontrast clearance. Most of these reports were negative, including a well‐designed meta‐analysis of RCTs, which showed no benefit of hemodialysis.53 Of note, one report suggested that hemodialysis might be potentially harmful.54 The single prospective trial that showed benefit from prophylactic hemodialysis analyzed 82 patients with advanced CRI (baseline creatinine clearance 13 mL/minute) referred for coronary angiography55 These subjects were randomly assigned to intravenous 0.9% NaCl and hemodialysis vs. intravenous 0.9% NaCl alone. Subsequent renal replacement therapy was required in 35% of control patients and in only 2% in the prophylactic dialysis group. One potential limitation of this study is that the investigators were more cognizant of volume status in the hemodialysis group to avoid fluid shifts and volume depletion during dialysis, while the control group appeared to experience no comparable intravascular volume management. Moreover, this study was conducted in patients with extremely advanced renal insufficiency, and therefore does not reflect the vast majority of patients at risk for CN.

Conclusions

CN is associated with increased morbidity and mortality, and efforts to minimize CN are therefore warranted. However, the overwhelming majority of CN trials were designed to investigate the effects of prophylaxis strategies on surrogate endpoints for estimates of GFR. Therefore, conclusions regarding the effect of these regimens on definitive outcomes, such as death and vascular events, cannot be drawn. On balance, there is evidence that oral and intravenous NAC, as well as extracellular volume expansion with intravenous NaHCO₃ are effective measures to prevent CN, whereas the data for renal replacement therapies are more equivocal. We emphasize though, that the literature on this topic is vast, and includes a large number of conflicting studies, including multiple meta‐analyses. As a result, we refrain from being too dogmatic about the best approach, and therefore cautiously offer the following recommendations for prevention of CN.

The first step is to identify high‐risk patients, who are most likely to benefit from prophylaxis (Table 1). Although risk stratification was not the focus of this review, Mehran et al.56 have developed a scoring system to quantitatively predict CN risk, with weighted parameters including CRI, diabetes, radiocontrast volume, age, hypotension, congestive heart failure, treatment with an intraaortic balloon pump, and anemia. For low‐risk patients, hydration with saline is probably adequate. For high‐risk patients, it would be prudent to initially consider whether sufficient information could be obtained from an alternative, noncontrasted radiologic procedure. If not, it would behoove the prescribing physician to then treat modifiable risk factors, as well as to discontinue potentially nephrotoxic medications.

In high‐risk patients undergoing radiocontrast procedures, we recommend using NAC and volume expansion with NaHCO₃ (Table 2). Although the evidence for this combined approach is limited,43 we believe it is biologically consistent, since the rationale for both strategies is primarily modification of redox state and inhibition of oxygen free radical generation. Because NAC formulations are generally effective, safe and inexpensive ($0.04 for 600 mg oral NAC and $24 for 1200 mg intravenous NAC at our hospital), we recommend the protocol used by Marenzi et al.,39 NAC 1200 mg intravenously once before procedure and then 1200 mg orally twice daily for 48 hours, as prophylaxis for all contrast procedures in high‐risk patients. However, we recognize that this regimen would require formal evaluation in procedures other than emergent coronary artery angioplasty before it could be enthusiastically endorsed. Therefore, if intravenous NAC is not available and/or the procedure is not emergent, NAC 6001200 mg orally twice a day, 2 doses before and 2 doses after the procedure would be a rational alternative. For the NaHCO₃ infusion, we recommend 3 mL/kg for 1 hour before the procedure, followed by 1 mL/kg/hour for 6 hours after.

Hemofiltration is labor‐intensive, expensive, and not readily available in all hospitals that renders it difficult to endorse as a definitive or routine CN prophylaxis modality. However, if a patient is already undergoing acute dialysis with catheter vascular access, it would be reasonable to consider CVVH 6 hours before and for 24 hours after the procedure (Table 2).

For high‐risk patients, we recommend minimizing the radiocontrast dose (reviewed in Ref.57). Although the dose has not consistently been identified as a risk factor (Table 1), we envision no harm in reducing the dose, particularly if adequate information can be obtained by other means, eg, coronary angiogram accompanied by an echocardiogram, rather than a ventriculogram. We would also consider the use of isoosmolar media in high‐risk patients, since the data are relatively compelling.20 Low doses of isoosmolar media should be particularly beneficial to patients with preexisting hypertension or congestive heart failure, for which the osmotic load and excess extracellular volume expansion might be deleterious. However, because isoosmolar media is expensive, a detailed cost‐benefit analysis would be required before definitive recommendations could be made, especially for patients at lower risk for CN. Finally, because of the complex literature, as well as budgetary issues, we encourage communication between the physician ordering the contrast study and the operator (radiologist or cardiologist) concerning the type of procedure and contrast media to be used.

Since contrast nephropathy (CN) was recognized more than 50 years ago,1 there have been continuous efforts to chemically modify radiocontrast agents to be less nephrotoxic. Although radiocontrast media have indeed become safer, which reduces the likelihood of CN per procedure, the indications for radiocontrast administration have dramatically increased, since over 80 million doses are delivered in the world annually.2, 3 Furthermore, the number of patients with CN risks, which are mainly chronic renal insufficiency (CRI) and diabetes (Table 1), has also grown. Currently, more than 26 million people are estimated to have CRI in the United States4 and 200 million people have diabetes worldwide.5 The combination of increased radiocontrast administration frequency and greater prevalence of at‐risk patients is likely to result in continued increases in CN events.

The incidence of CN varies between studies, depending on risk factors of the cohort and definition of CN, but figures have been reported to be as high as 50% in studies enriched with CRI and diabetic patients. However, a very recent study disputes such high incidence rates by demonstrating that patients receiving no radiocontrast media had a similar frequency of serum creatinine increases compared to a comparable group of historical CN patients.6 This study emphasizes that conventional definitions of CN, eg, 25% increase in serum creatinine above baseline, may be too conservative.

A retrospective study of 7586 patients showed 22% in‐hospital mortality in patients who developed CN vs. 1.4% in those who did not, after adjusting for comorbidities. One‐ and 5‐year mortality rates were also higher in the CN group (12.1% vs. 3.7% and 44.6% vs. 14.5%, respectively).7 Another study of 1826 patients, who underwent coronary artery intervention procedures, showed that 14.4% developed CN and 0.8% required hemodialysis. Mortality was 1.1% in patients who did not develop CN, 7.1% in those with CN, and 35.7% in the hemodialysis‐treated CN group.8 Moreover, studies by several other groups also support the position that CN is associated with increased in‐hospital and long‐term mortality.911 Although radiocontrast administration may not be a causal risk factor for mortality, since at‐risk patients have a number of comorbidities, radiocontrast media should nevertheless at least be viewed as an important marker of acute kidney injury and death risk.

Despite the enhanced morbidity and mortality associated with CN, there are no strict guidelines for prevention of CN. Part of the reason is that the literature is controversial regarding most prevention strategies. Several interventions are commonly proposed to help prevent CN, including discriminate selection of the type of radiocontrast, N‐acetylcysteine, volume expansion with saline and/or NaHCO₃, and prophylactic hemofiltration. The major purpose of this review is to discuss these different approaches to CN prevention, with the ultimate goal of offering discrete recommendations.

The basis of this semisystematic review was a literature search using the PubMed database (www.ncbi.nlm.nih.gov/sites/entrez) to identify studies published in English language journals between January 1966 and July 2008 comparing regimens for prophylaxis of CN. Search terms included contrast, radiocontrast, radioiodinated AND nephropathy, nephrotoxicity, renal failure, kidney injury AND N‐acetylcysteine, Mucomyst, sodium bicarbonate, NaHCO₃, hemofiltration, continuous venovenous hemofiltration (CVVH), theophylline, statin, ascorbic acid, dopamine, fenoldopam, adenosine, and endothelin. The total number of articles that met the search criteria exceeded 3000 and over 200 in high profile biomedical journals were scrutinized in detail. The articles cited in this review were independently considered by 2 authors (B.G.A. and J.R.S.) to have the greatest impact.

We report on prophylactic maneuvers that are either commonly considered by nephrology consultants or contain sufficient data to warrant a meta‐analysis study. Studies involving statins, ascorbic acid, dopamine analogs, endothelin antagonists, and theophylline were not addressed in this review due to insufficient, inconclusive, or predominantly negative data. Clinical characteristics and pathogenesis of CN, which include vasoconstriction, ischemia, production of oxygen free radicals, tubular cell apoptosis, and intratubular obstruction, are also not discussed in detail, but have recently been reviewed.12

Risk Associated with Different Types of Radiocontrast Media

There are 3 generations of radiocontrast media: hyperosmolar (14001800 mosm/kg), low osmolar (500850 mosm/kg) and isoosmolar (290 mosm/kg). Note that the low osmolar agents have lower osmolarity relative to the hyperosmolar agents, but are still hyperosmolar compared to serum. Multiple studies have compared effects of radiocontrast with different osmolarities.

The Iohexol Cooperative Study was a double‐blind, randomized, controlled trial (RCT) that randomized 1196 patients to Iohexol (low osmolarity) or diatrizoate (hyperosmolar). Definition of CN was a rise in serum creatinine by >1 mg/dL within 48 to 72 hours after the radiocontrast exposure. Results were in favor of the iohexol group (3% developed CN vs. 7% in the diatrizoate group; P = 0.002). Subgroup analysis of patients with CRI and CRI plus diabetes also revealed less CN in the iohexol vs. diatrizoate groups (7% vs. 16% and 12% vs. 27%, respectively).13

An earlier non‐RCT of 303 patients undergoing femoral angiography compared iohexol/emoxaglate (both are low osmolar) to diatrizoate (hyperosmolar). Six different CN definitions were used. Each comprised a combination of different magnitudes of rise of serum creatinine over various periods of time. Overall, the incidence of CN was 7% in the low osmolar group vs. 26% in the hyperosmolar group (P = 0.001). In subgroup analysis of patients with CRI, and of patients with diabetes, less CN was again observed with low osmolar agents (10% vs. 41%, P = 0.017, in the CRI group; and 10% vs. 31%, P = 0.012, in the diabetes group). Analysis of subjects with baseline serum creatinine <1.5 mg/dL showed no differences between the 2 groups, emphasizing that prior CRI is an important CN risk factor.14

The RECOVER study was a double‐blind RCT of 300 patients undergoing coronary angiography, who were randomized to iodixanol (isoosmolar) or ioxaglate (low osmolarity). CN was defined as a rise in serum creatinine by >25% or 0.5 mg/dL at 24 and 48 hours. CN incidence was 7.9% in the iodixanol group vs. 17% in the ioxaglate group (P = 0.021). Subgroup analyses of patients stratified by severe CRI, diabetes, and contrast volume also favored iodixanol.15 In a similarly designed, double‐blind RCT involving 129 patients with diabetes and CRI randomized to iodixanol or iohexol, CN developed in 3% of iodixanol group vs. 26% in the iohexol group (P = 0.002).16 These results were further supported by a very recent double‐blind RCT comparing iodixanol to iopromide (low osmolar) in 117 patients with baseline serum creatinine 1.5 mg/dL undergoing CT scans. The incidence of serum creatinine increases of 0.5 mg/dL or 25% above baseline or glomerular filtration rate (GFR) reduction of 5 mL/minute was significantly lower in the iodixanol group (P = 0.04, 0.01, and 0.04 respectively).17

In contrast to these reports, 2 double‐blind RCTs showed no differences in CN incidence between iodixanol and low osmolar agents. One study compared iodixanol to iopromide in 64 patients undergoing intravenous pyelography (IVP),18 and the other included 16 nondiabetic patients with CRI and compared iodixanol to iohexol.19 However, because of the small sample sizes, it is likely that neither study is adequately powered to detect differences in outcome between the 2 types of radiocontrast media.

Given the importance of the issue and conflicting results from individual studies, a meta‐analysis of 16 double‐blind RCTs was performed.20 This study included 2727 patients undergoing angiography, compared iodixanol (isoosmolar) to a variety of low osmolar agents, and demonstrated that iodixanol was less nephrotoxic compared to the low osmolarity agents in CRI patients (2.8% vs. 8.4%; P = 0.001) and in patients with CRI plus diabetes (3.5% vs. 15.5%; P = 0.003). Independent predictors of CN were CRI, CRI plus diabetes, and the use of low‐osmolarity media, whereas diabetes, age, and radiocontrast volume were not statistically significant independent predictors.20

Taken together, we conclude that isoosmolar media represents the lowest risk for CN. An additional benefit is that isoosmolar media, on the basis of diminished osmotic load, is less likely to precipitate extracellular fluid volume overload, which is particularly germane for patients with CRI, who have diminished capacity to excrete solute loads. Therefore, we recommend using isoosmolar media, particularly in patients at high risk for CN, such as those with CRI, especially due to diabetic nephropathy.

Oral N‐Acetylcysteine

Based primarily upon in vitro evidence, N‐acetylcysteine (NAC) may theoretically prevent CN by direct antioxidant and vasodilatory effects. However, in vivo, NAC is rapidly metabolized and inactivated by the liver. Therefore, it has been postulated that the mechanism of action may be indirect, and the cysteine metabolite of NAC may stimulate glutathione synthesis, which then inhibits cellular oxidation.21

The first clinical trial to address the prophylactic role of NAC in CN was an RCT of 83 patients with CRI (mean serum creatinine [Cr] = 2.4) undergoing CT scans, who were randomized to NAC plus 0.45% NaCl vs. placebo and 0.9% NaCl.22 The NAC dose was 600 mg orally twice daily for 2 doses before and 2 doses after the procedure. Intravenous fluids were started 12 hours before and stopped 12 hours after the procedure and infused at a rate of 1 ml/kg/hour. CN definition was rise in serum creatinine by >0.5 mg/dL at 48 hours. The results were statistically significant, with a relative risk of CN = 0.1 (95%CI, 0.020.9) in subjects treated with NAC.

There have been many subsequent reports that have evaluated NAC in small numbers of patients with mild to moderate CRI. In general, results from these trials have been inconsistent, which has led to several meta‐analyses to delineate NAC efficacy in CN prevention. The most recent and largest meta‐analysis included 26 NAC RCTs, and revealed a statistically significant benefit from NAC (relative risk [RR] = 0.62; 95%CI, 0.440.88).23 Twelve other meta‐analyses, which incorporated fewer studies, have been published,2435 and 7 of the 12 reported a benefit from NAC.25, 27, 29, 30, 32, 34, 35

Although meta‐analysis is considered the most accepted strategy to define conclusions from multiple trials, conflicting results between NAC meta‐analyses highlight the possibility that this approach may still not provide resolution to clinical questions, especially when inclusion criteria differ between meta‐analyses. Therefore, as discussed by Bagshaw et al.,36 meta‐analyses are not always a panacea, and should be avoided if the trials to be included exhibit significant statistical or clinical heterogeneity, as is the case with studies involving NAC prophylaxis of CN. Finally, because meta‐analyses require pooling of data from published studies, which tend to be positive, the possibility of publication bias exists.

In summary, conclusions from trials to assess efficacy of oral NAC in the prevention of CN have been inconsistent, though there has been a general trend toward benefit. Factors contributing to inconsistent results include variable definitions of CN, degree of CRI and diabetes in the cohort, amount and type of contrast used, NAC dosing and intravenous hydration protocols. As a result, a large multicenter RCT would certainly be helpful. However, the size of such trial might be cost‐prohibitive, and unlikely to be underwritten by the pharmaceutical industry because the patent for NAC has expired.36

Intravenous NAC

In addition to the vast literature on oral NAC for CN prophylaxis, there are now studies that have also evaluated efficacy of intravenous NAC. In one of the largest double‐blind RCTs,37 487 patients (mean baseline serum creatinine = 1.6 mg/dL) were randomized to NAC 500 mg intravenously vs. placebo before cardiac catheterization. Both groups received the same hydration protocols. The study was stopped when an interim analysis determined that there was no advantage to NAC (CN incidence, which was defined as a decrease in creatinine clearance by >5 mL/minute at days 1 to 8 postprocedure, was 23.3% vs. 20.7% in the placebo group).

The RAPPID study examined higher intravenous NAC doses in 80 patients undergoing cardiac catheterization.38 Subjects in this study were randomized to either NAC (150 mg/kg in 500 mL 0.9% NaCl before procedure and then 50 mg/kg in 500 mL 0.9% NaCl over 4 hours after procedure) or 0.9% NaCl 12 hours before and 12 hours after procedure. Despite the relatively small study size, intravenous NAC demonstrated a significant benefit in the prevention of CN (RR = 0.28; P = 0.045) defined as rise in serum creatinine by >25% at 2 or 4 days postexposure. Hypersensitivity‐like reactions were observed in 14.5% of patients receiving intravenous NAC, but symptoms were easily recognized and managed.38

A recent study of 354 patients undergoing primary angioplasty evaluated the combination of intravenous and oral NAC in different doses.39 Patients were randomized to 3 groups: (1) NAC 600 mg intravenously once before procedure and then 600 mg orally twice daily for 48 hours; (2) NAC 1200 mg intravenously once before procedure and then 1200 mg orally twice daily for 48 hours; or (3) placebo. The primary outcome was increase in Cr by >25% and secondary outcomes were in‐hospital death and a composite score that included death and need for renal replacement therapy. Results were significantly in favor of the 1200‐mg NAC regimen across all outcomes (P = <0.001, 0.02, and 0.002, respectively). It should be emphasized that this study was restricted to patients undergoing primary angioplasty, which is an emergent procedure. As a result, implementation of this protocol would necessarily require rapid administration of intravenous NAC prior to the procedure, which might even require maintenance of NAC stocks within the catheterization laboratory.

Because there is a trend toward benefit from oral NAC and the benefit from intravenous NAC in trials from limited settings, and both NAC formulations are inexpensive and safe, we recommend that NAC should be included in CN prophylaxis protocols.

Extracellular Fluid Volume Expansion

Since publication of work by Solomon et al.,40 which demonstrated a benefit of intravenous hydration with 0.45% NaCl in the prevention of CN in a group of CKD patients, it has been considered standard practice to prescribe intravenous fluid regimens for CN prophylaxis in high‐risk subjects. In the largest study to test the effect of different hydration protocols for CN prevention, Mueller et al.41 randomized 1620 patients with normal baseline serum creatinine to intravenous 0.9 % NaCl vs. 0.45% NaCl. The definition of CN was rise in serum creatinine by >0.5 mg/dL at 48 hours and the incidence was 0.7% for the 0.9% NaCl group and 2% for the 0.45% NaCl group (P = 0.04).

More recently, several trials have examined the relative efficacy of intravenous NaCl vs. NaHCO₃ for CN prophylaxis. In the first NaHCO₃ RCT, Merten et al.42 compared 0.9% NaHCO₃ to 0.9% NaCl infusion in a population with a mean serum creatinine of 1.8 mg/dL. Both groups received 3 mL/kg intravenous bolus over 1 hour before the radiographic procedure followed by 1 mL/kg/hour for 6 hours. Urine pH was measured to confirm alkalinization of urine in the NaHCO₃‐treated patients and the primary end point was increase in serum creatinine by >25% within 48 hours. The study was terminated early (after enrollment of 119 patients) when the interim analysis showed CN incidence was 1.7% in the NaHCO₃ group vs. 13.6% in the NaCl group (P = 0.02).

These results were corroborated in the recent REMEDIAL trial,43 which enrolled 326 patients with serum creatinine >2 mg/dL, who were randomized to 1 of 3 arms. One group received intravenous saline (0.9% NaCl for 12 hours before and 12 hours after the procedure) and oral NAC; a second group received intravenous NaHCO₃ (3 mL/kg intravenous bolus over 1 hour before the radiographic procedure followed by 1 mL/kg/hour for 6 hours) and oral NAC; and a third group received intravenous 0.9% NaCl plus oral NAC and ascorbic acid. Patients had similar baseline characteristics and the primary end point was an increase in serum creatinine by >25% within 48 hours. The best results were observed in the NaHCO₃ plus NAC group; 1.9% developed CN in this group vs. 9.9% in the NaCl plus NAC group vs. 10.3% in the NaCl plus NAC plus ascorbic acid group (P = 0.019). Three additional prospective but smaller studies also showed the superiority of NaHCO₃.4446

In contrast to studies supporting a role for prophylactic NaHCO₃, a recent RCT showed no superiority of NaHCO₃ infusion regimens.47 In this trial, 352 patients undergoing coronary angiography were randomized to receive either NaHCO₃ or 0.9% NaCl. Both solutions were administered at rates of 3 mL/kg for 1 hour before the procedure and 1.5 mL/kg/hour for 4 hours postprocedure. The primary endpoint (>25% decrease in estimated GFR during the first 4 days after contrast exposure) was met in 13.3% of NaHCO₃ group vs. 14.6% of the 0.9% NaCl group (P = 0.82). Moreover, there were no differences in the rates of secondary outcomes, which included death, dialysis, and cardiovascular and cerebrovascular events.

Results from a very recent retrospective cohort study of 7977 patients demonstrated that NaHCO₃ infusion was associated with increased risk of CN compared to no treatment (odds ratio [OR] = 3.1; P < 0.001), whereas NAC alone or in combination with NaHCO₃ was associated with no significant difference in the incidence of CN.48 However, multiple weaknesses associated with the retrospective study design, such as inclusion of few patients at high CN risk, and acceptance of serum creatinine values within 7 days before and after the contrast procedure, which likely captures causes of acute kidney injury other than CN, preclude abandonment of NaHCO₃ prophylaxis for CN solely on the basis of this study.

In an effort to resolve the conflicting NaHCO₃ prophylaxis literature, a meta‐analysis was recently conducted.49 This study encompassed 1307 patients enrolled in 7 RCTs that examined outcomes for NaHCO₃ vs. saline prevention of CN. The main finding was a significant benefit of NaHCO₃ for protection against CN (RR = 0.37; P = 0.005). No benefit of NaHCO₃ infusion could be shown for postprocedure renal replacement therapy or death.

Therefore, based upon the results of multiple prospective trials, the recent meta‐analysis, the relative safety of NaHCO₃ infusion with appropriate monitoring, and a plausible biological mechanism whereby bicarbonate may have antioxidant properties and scavenge oxygen‐derived free radicals, which have been implicated in CN pathogenesis,50 we advocate a prophylactic regimen employing NaHCO₃ for patients at high risk for CN.

Renal Replacement Therapies

Two studies have been conducted by the same group (Marenzi et al.51, 52) to examine efficacy of continuous hemofiltration (CVVH) in preventing CN (hemofiltration clears solute by convection, and involves administration of a HCO‐rich replacement solution, whereas hemodialysis clears solute by both diffusion and convection, and there is routinely no replacement fluid). In the first study,51 114 patients with baseline serum creatinine greater than 2 mg/dL undergoing coronary angiography were randomized to hemofiltration vs. 0.9% NaCl infusion. Isovolemic hemofiltration was implemented for 4 to 6 hours before and 18 to 24 hours after the radiographic procedure. The primary endpoint was increase in creatinine by >25% within 72 hours. CN incidence was 5% in the hemofiltration group vs. 50% in the 0.9% NaCl group (P < 0.001). The secondary outcomes including in‐hospital mortality, 1‐year mortality and temporary renal replacement were also superior in the hemofiltration group. In the second study, the same investigators compared 2 different hemofiltration protocols, using the same definition of CN.52 Patients with baseline creatinine clearance <30 mL/minute (n = 92) were randomized to 0.9% NaCl infusion, postprocedure isovolemic hemofiltration only, or preprocedure plus postprocedure hemofiltration (same protocol as previous study). The incidence of CN was significantly lower in the preprocedure plus postprocedure hemofiltration group (3% vs. 26% in the postprocedure hemofiltration group vs. 40% in the 0.9% NaCl without hemofiltration group; P = 0.0001). The preprocedure plus postprocedure hemofiltration group also had reductions in in‐hospital mortality and temporary renal replacement therapy rates.

Although the mechanism of hemofiltration prevention of CN is unknown, it is certainly not enhanced clearance of contrast material, inasmuch as hemofiltration was discontinued during the angiography procedure in all protocols, and radiocontrast was therefore not cleared by hemofiltration until the process was reinstituted. Furthermore, the second study indicates that the major benefit was derived from the preprocedure hemofiltration component. Contributing factors might be control of extracellular pH and redox potential with bicarbonate replacement fluid during hemofiltration. Important confounding issues to consider are that patients receiving hemofiltration were in controlled, monitored settings and thus received more intensive care than the hydration group, and that serum creatinine, the major outcome parameter, is cleared by hemofiltration. Before hemofiltration can be recommended as routine prophylactic therapy for CN, the data will need to be corroborated by other groups, preferably involving larger numbers of study subjects and including cost‐benefit analyses.

Multiple small studies have examined the possibility that dialysis immediately following radiocontrast exposure could prevent CN, presumably by accelerating radiocontrast clearance. Most of these reports were negative, including a well‐designed meta‐analysis of RCTs, which showed no benefit of hemodialysis.53 Of note, one report suggested that hemodialysis might be potentially harmful.54 The single prospective trial that showed benefit from prophylactic hemodialysis analyzed 82 patients with advanced CRI (baseline creatinine clearance 13 mL/minute) referred for coronary angiography55 These subjects were randomly assigned to intravenous 0.9% NaCl and hemodialysis vs. intravenous 0.9% NaCl alone. Subsequent renal replacement therapy was required in 35% of control patients and in only 2% in the prophylactic dialysis group. One potential limitation of this study is that the investigators were more cognizant of volume status in the hemodialysis group to avoid fluid shifts and volume depletion during dialysis, while the control group appeared to experience no comparable intravascular volume management. Moreover, this study was conducted in patients with extremely advanced renal insufficiency, and therefore does not reflect the vast majority of patients at risk for CN.

Conclusions

CN is associated with increased morbidity and mortality, and efforts to minimize CN are therefore warranted. However, the overwhelming majority of CN trials were designed to investigate the effects of prophylaxis strategies on surrogate endpoints for estimates of GFR. Therefore, conclusions regarding the effect of these regimens on definitive outcomes, such as death and vascular events, cannot be drawn. On balance, there is evidence that oral and intravenous NAC, as well as extracellular volume expansion with intravenous NaHCO₃ are effective measures to prevent CN, whereas the data for renal replacement therapies are more equivocal. We emphasize though, that the literature on this topic is vast, and includes a large number of conflicting studies, including multiple meta‐analyses. As a result, we refrain from being too dogmatic about the best approach, and therefore cautiously offer the following recommendations for prevention of CN.

The first step is to identify high‐risk patients, who are most likely to benefit from prophylaxis (Table 1). Although risk stratification was not the focus of this review, Mehran et al.56 have developed a scoring system to quantitatively predict CN risk, with weighted parameters including CRI, diabetes, radiocontrast volume, age, hypotension, congestive heart failure, treatment with an intraaortic balloon pump, and anemia. For low‐risk patients, hydration with saline is probably adequate. For high‐risk patients, it would be prudent to initially consider whether sufficient information could be obtained from an alternative, noncontrasted radiologic procedure. If not, it would behoove the prescribing physician to then treat modifiable risk factors, as well as to discontinue potentially nephrotoxic medications.

In high‐risk patients undergoing radiocontrast procedures, we recommend using NAC and volume expansion with NaHCO₃ (Table 2). Although the evidence for this combined approach is limited,43 we believe it is biologically consistent, since the rationale for both strategies is primarily modification of redox state and inhibition of oxygen free radical generation. Because NAC formulations are generally effective, safe and inexpensive ($0.04 for 600 mg oral NAC and $24 for 1200 mg intravenous NAC at our hospital), we recommend the protocol used by Marenzi et al.,39 NAC 1200 mg intravenously once before procedure and then 1200 mg orally twice daily for 48 hours, as prophylaxis for all contrast procedures in high‐risk patients. However, we recognize that this regimen would require formal evaluation in procedures other than emergent coronary artery angioplasty before it could be enthusiastically endorsed. Therefore, if intravenous NAC is not available and/or the procedure is not emergent, NAC 6001200 mg orally twice a day, 2 doses before and 2 doses after the procedure would be a rational alternative. For the NaHCO₃ infusion, we recommend 3 mL/kg for 1 hour before the procedure, followed by 1 mL/kg/hour for 6 hours after.

Hemofiltration is labor‐intensive, expensive, and not readily available in all hospitals that renders it difficult to endorse as a definitive or routine CN prophylaxis modality. However, if a patient is already undergoing acute dialysis with catheter vascular access, it would be reasonable to consider CVVH 6 hours before and for 24 hours after the procedure (Table 2).

For high‐risk patients, we recommend minimizing the radiocontrast dose (reviewed in Ref.57). Although the dose has not consistently been identified as a risk factor (Table 1), we envision no harm in reducing the dose, particularly if adequate information can be obtained by other means, eg, coronary angiogram accompanied by an echocardiogram, rather than a ventriculogram. We would also consider the use of isoosmolar media in high‐risk patients, since the data are relatively compelling.20 Low doses of isoosmolar media should be particularly beneficial to patients with preexisting hypertension or congestive heart failure, for which the osmotic load and excess extracellular volume expansion might be deleterious. However, because isoosmolar media is expensive, a detailed cost‐benefit analysis would be required before definitive recommendations could be made, especially for patients at lower risk for CN. Finally, because of the complex literature, as well as budgetary issues, we encourage communication between the physician ordering the contrast study and the operator (radiologist or cardiologist) concerning the type of procedure and contrast media to be used.

Public health concerns such as the aging population¹ and the increasing prevalence of obesity² are also important issues to hospitals. However, little attention has been given to the interface of obesity and the elderly, largely due to the dearth of studies that include elderly patients. An aging population leads to an increase in geriatric syndromes, such as osteoporosis³ and its most devastating complication, hip fracture.⁴ These frail, hip‐fracture patients pose management challenges to practicing geriatricians and hospitalists.^5,6 Furthermore, although fracture risk is inversely correlated to body mass index (BMI),⁷ this relationship has yet to be fully examined in the postoperative hip‐fracture population. In other surgical settings, there is disagreement as to whether underweight or obese patients are at higher risk of developing medical complications,^8‐11 but for orthopedic patients, data have been limited to elective orthopedic populations.^12‐14 We previously demonstrated that underweight hip‐fracture patients are at higher risk of postoperative cardiac complications at 1 year,¹⁵ consistent with studies of cardiac risk indices determining long‐term events. Because of different pathophysiologic mechanisms, the purpose of this study was to ascertain the influence of BMI on inpatient postoperative noncardiac medical complications and to assess predictors of such complications following urgent hip fracture repair.

Patients and Methods

All Olmsted County, Minnesota, residents undergoing urgent hip repair due to fracture were identified using the Rochester Epidemiology Project, a medical‐record linkage system funded by the Federal government since 1966 to support disease‐related epidemiology studies.¹⁶ All patient medical care is indexed, and both inpatient and outpatient visits are captured and available for review, allowing for complete case ascertainment. Medical care in Olmsted County is primarily provided by Mayo Clinic with its affiliated hospitals (St. Mary's and Rochester Methodist) and the Olmsted Medical Center, in addition to a few individual providers. Over 95% of all Olmsted County hip fracture surgeries are ultimately managed at St. Mary's Hospital.

Following approval by the Institutional Review Board we used this unique data resource to identify all residents with an International Classification of Diseases, 9th edition (ICD‐9) diagnosis code of 820 to 829 for hip fracture (n = 1310). Both sexes were included, and all patients included in the study provided research authorization for use of their medical records for research purposes.¹⁷ We excluded patients who were managed conservatively (n = 56), had a pathological fracture (n = 20), had multiple injuries (n = 19), were operated on >72 hours after fracture (n = 5), were aged <65 years (n = 2), or were admitted for reasons other than a fracture and experienced an in‐hospital fracture (n = 3). We subsequently excluded patients with missing information (n = 10). World Health Organization (WHO) criteria were used for classifying BMI: underweight (BMI < 18.5); normal (BMI = 18.5‐24.9); overweight (BMI = 25.0‐29.9); and obese (BMI 30.0).¹⁸

All data were abstracted using standardized collection forms by trained nurse abstractors blinded to the study hypothesis. Patients' admission height and weight were documented; if unavailable, the nearest data within 2 months prior to surgery were recorded. Patients' preadmission residence, functional status, baseline comorbidities, admission medications, discharge destination, as well as whether patients had an intensive care unit stay or any major surgeries in the past 90 days were abstracted. In addition, American Society of Anesthesia (ASA) class, type of anesthesia, and length of stay were also obtained. Inpatient complications that had been identified by the treating physicians and documented in the medical record or identified on imaging studies were assessed from the time of hip fracture repair to the time of discharge using standardized clinical criteria (Table 1). For criteria that were based on either objective findings or clinical documentation/suspicion, the patient was considered to meet the criteria of having a complication if they fulfilled either one. We did not include any cardiac outcomes, including congestive heart failure, angina, myocardial infarction, or arrhythmias that had been previously reported.¹⁵ Noncardiac complications were classified broadly: respiratory (respiratory failure, respiratory depression, or pulmonary hypoxemia); neurologic (any cerebral event including hemorrhagic or ischemic stroke, transient ischemic attack, or delirium); gastrointestinal (ileus or gastrointestinal bleeding); vascular (pulmonary embolus, or deep vein thrombosis); infectious (pneumonia, sepsis, urinary tract, wound, or cellulitis); renal/metabolic (acute renal failure, dehydration, or electrolyte abnormalities); or other (fractures or falls).

Continuous data are presented as means standard deviation and categorical data as counts and percentages. In testing for differences in patient demographics, past medical history, and baseline clinical data among BMI groups, Kruskal‐Wallis tests were performed for continuous variables and Fisher's Exact or Cochran‐Mantel‐Haenszel tests were used for discrete variables. Bonferroni adjustments were performed where appropriate. The primary outcome was the risk of any noncardiac medical complication during the postoperative hospitalization, based on patients with complications. Incidence rates were calculated for the overall group as well as for each BMI category. BMI was evaluated categorically according to the WHO criteria, as a continuous variable dichotomized as a BMI 18.5 kg/m² to 24.9 kg/m² (normal) vs. all others, and above/below 25.0 kg/m². The effect of BMI and other potential risk factors on the complication rate was evaluated using logistic regression. The effect of BMI category on the overall complication rate was adjusted for the a priori risk factors of age, sex, surgical year, and ASA class both univariately (Model 1) and multivariately (Model 2). In addition to these variables, we also evaluated other potential risk factors, including baseline demographic and baseline clinical variables that were significant (P < 0.05) univariately using a stepwise selection; first forcing in BMI as a categorical variable (Model 3), then repeating the stepwise selection process without forcing in BMI (Model 4). Using data from Lawrence et al.,¹⁹ we estimated that we would have 80% power to detect differences in rates of inpatient noncardiac complications equal to an odds ratio (OR) = 2.2 (normal vs. underweight), OR = 2.0 (normal vs. overweight), and OR = 2.4 (normal vs. obese). Finally, because of power considerations, as an exploratory analysis, we additionally identified predictors of inpatient complications within each BMI category using stepwise selection. All statistical tests were 2‐sided, and P values <0.05 were considered significant. All analyses were performed using SAS for UNIX (version 9.1.3; SAS Institute, Inc., Cary, NC).

Results

Between 1988 and 2002, 1195 urgent repairs for hip fracture met our inclusion/exclusion criteria. We subsequently excluded 15 repairs with missing BMI data, and, of the 7 patients with >1 repair, we included only their first fracture episode in our analysis. Two were subsequently excluded due to an administrative error. Ultimately, 1180 hip fracture repairs were included in the analysis cohort. There were 184 (15.6%) patients in the underweight group, 640 (54.2%) with normal BMI, 251 (21.3%) with a BMI 25.0 to 29.9 kg/m², and 105 (8.9%) with a BMI 30 kg/m². Baseline characteristics are otherwise shown in Table 2. Normal BMI patients were significantly older than the other groups, and underweight patients were less likely to be admitted from home. Past history of having a cardiovascular risk factor or a cardiovascular diagnosis appeared to increase with increasing BMI. Underweight patients were more likely to have chronic obstructive pulmonary disease (COPD) than patients with normal BMI (P = 0.03) or overweight patients (P = 0.009), but not more than obese patients (P = 0.21). There were no differences across BMI groups in ASA class, type of anesthesia, intensive care unit stay, or length of stay.

There were 77 (41.8%) postoperative inpatient noncardiac complications in the underweight group, 234 (36.6%) in the normal BMI group, 90 (35.9%) in the overweight group, and 42 (40.0%) in the obese group (P = 0.49). Figure 1 demonstrates the main subcategory complication rates by BMI group, and Table 3 outlines the univariate unadjusted complication rates. Other than gastrointestinal complications being more prevalent as BMI increases (P = 0.005), there were no significant differences in crude complication rates across BMI categories (all P > 0.05) for the other complication subcategories. A multiple comparisons analysis did not demonstrate any differences between normal and any of the other BMI categories for ileus. Normal BMI patients were more likely to be discharged to a nursing facility than overweight or obese patients (85.5% vs. 79.3%, P = 0.03; and 85.5% vs. 79.0%, P = 0.03, respectively). The proportion of in‐hospital deaths among underweight patients was significantly higher than in any of the other groups (9.3% vs. 4.4%; P = 0.01), but mean length of stay was not significantly different.

Figure 1

Significant univariate predictors of the composite outcome of any noncardiac complication included: age (OR, 1.04 95% confidence interval [CI>], 1.02‐1.06; P < 0.001), age 75 years (OR, 2.25; 95% CI, 1.52‐3.33; P < 0.001), age 85 years (OR, 1.49; 95% CI, 1.17‐1.89; P < 0.001), male sex (OR, 1.41; 95% CI, 1.05‐1.90; P = 0.02), admission from home (OR, 0.77; 95% CI, 0.61‐0.98; P = 0.03), a history of cerebrovascular disease (OR, 1.41; 95% CI, 1.08‐1.83; P = 0.01), myocardial infarction (OR, 1.41; 95% CI, 1.07‐1.86; P = 0.02), angina (OR, 1.32; 95% CI, 1.03‐1.69; P = 0.03), congestive heart failure (OR, 1.45; 95% CI, 1.11‐1.89; P = 0.006), dementia (OR, 1.39; 95% CI, 1.08‐1.78; P = 0.01), peripheral vascular disease (OR, 1.47; 95% CI, 1.06‐2.03; P = 0.02), COPD/asthma (OR, 1.56; 95% CI, 1.18‐2.08; P = 0.002), osteoarthritis (OR, 1.29; 95% CI, 1.01‐1.65; P = 0.04), code status as Do Not Resuscitate (OR, 0.74; 95% CI, 0.58‐0.94; P = 0.015), or ASA class III‐V (OR, 2.24; 95% CI, 1.53‐3.29; P < 0.001). Results were no different after using the Charlson comorbidity index in place of ASA class (data not shown). No significant differences in overall noncardiac complications were observed when examining BMI as a continuous variable, as a categorical variable, as 25 kg/m² vs. <25 kg/m², or as 18.5 kg/m² to 24.9 kg/m² vs. all others. Examining renal, respiratory, peripheral vascular, or neurologic complications univariately within these aforementioned strata also did not demonstrate any significant differences among BMI categories (data not shown).

Multivariable analyses (Models 1‐4) are shown for any overall noncardiac inpatient medical complication in Table 4. BMI was not a significant predictor in any of our models, specifically in our main model that examined the effect of BMI adjusting for a priori variables (Model 2). However, older age, male sex, and ASA class were highly significant predictors of complications in all four models; however, surgical year was nonsignificant. Notably, after stepwise selection for other demographic and premorbid variables, a history of COPD or asthma was found to be an additional significant factor both in Model 3 (forcing BMI in the model) and Model 4 (without BMI in the model). Exploratory analysis of individual predictors of inpatient noncardiac complications within each BMI category demonstrated that, in underweight patients, admission use of ‐blockers was a significant predictor of having any medical complication (OR, 3.1; 95% CI, 1.1‐8.60; P = 0.03). In normal BMI patients, age 75 years (OR, 2.6; 95% CI, 1.4‐4.9; P = 0.003), ASA class III‐V (OR, 2.3; 95% CI, 1.3‐3.9; P = 0.003), and a history of cerebrovascular disease (OR, 1.5; 95%CI, 1.04‐2.1; P = 0.03) were predictors; and, in obese patients, only age (OR, 1.1; 95% CI, 1.00‐1.12; P = 0.05) was significant. There were no significant predictors of having a medical complication in the overweight group.

Discussion

Most research describing the association of BMI with postoperative outcomes has concentrated on cardiac surgery, general surgical procedures, and intensive care unit utilization.^8‐11,20 In the orthopedic literature, an elevated BMI has been associated with a higher number of short‐term complications, but this was limited to elective knee arthroplasty and spine surgery populations.^12,13,21 Conversely, no differences were observed in obese patients undergoing hip arthroplasties.^14,22 To the best of our knowledge, this study may be the first to examine the impact of BMI on inpatient hospital outcomes following urgent hip fracture repair. Our results suggest the risk of developing a noncardiac medical complication is the same regardless of BMI.

Our overall complication rate was higher (38%) than previous reports by others.^19,23‐26 Thus, Lawrence et al.,¹⁹ in their retrospective study of 20 facilities, demonstrated an overall complication rate of 17%, even though they also included postoperative cardiac complications. Although their study period overlapped our own (1982‐1993), they additionally included patients aged 60 to 65 years, a population known to have fewer comorbidities and fewer postoperative complications than the elderly hip‐fracture patients studied here. In addition, their population may have been healthier at baseline, in that a higher proportion lived at home (73%) and a lower percentage were ASA class III‐V (71%) than our cohort. These differences in baseline characteristics may explain the higher complication rates observed in our study.

Our findings did not suggest any relationship of BMI with noncardiac postoperative medical complications in any of the 4 methods we used to stratify BMI (continuous, categorical, normal vs. abnormal, and 25 kg/m²). Evidence is contradictory as to what the effect of BMI has on postoperative complications. An elevated BMI (30 kg/m²) has been shown to lead to increased sternal wound infection and saphenous vein harvest infection in a cardiac surgery population,²⁷ but other studies^10,28,29 have demonstrated the opposite effect. Among 6336 patients undergoing elective general surgery procedures, the incidence of complications were similar by body mass.³⁰ A matched study design that included urgent and emergent surgeries also did not find any appreciable increased perioperative risk in noncardiac surgery.²⁸ Whether this may be due to the elective nature of the surgeries in these studies, hence leading to selection bias, is unknown.

In geriatric patients, multiple baseline comorbid conditions often are reflected in a higher ASA class, which increases the risk of significant perioperative complications. Our multivariate modeling showed that a high ASA class strongly predicts morbidity and mortality following hip fracture repair, in line with other studies.^19,31,32 Although the Charlson comorbidity index could alternatively been used, we elected to adjust for ASA class as it is more commonly used and is simple to use. Interestingly, surgical year did not significantly predict any complication, which can suggest that practice changes play a minimal impact on patient outcomes. However, we caution that because the individual event rates, particularly vascular, were low, we were unable to fully determine whether changes in practice management, such as improved thromboprophylaxis, would impact event rates over time. Finally, other predictors such as older age³³ and a concomitant history of either COPD or asthma,³⁴ are well‐accepted predictors of inpatient complications. Our attempt to examine specific predictors of complications in each BMI category revealed differing results, making interpretations difficult. Because of power considerations, this was meant solely as an exploratory analysis, and larger cohorts are needed to further ascertain whether predictors are different in these groups. Such a study may in fact identify perioperative issues that allow practitioners caring for this population to modify these factors.

One of the major limitations in our study was our inability to adjust for individual complications using multivariable models, such as deep vein thrombosis or delirium, within each BMI stratum, because of statistical power issues. Such a study would require large numbers of individual complications or events to allow for appropriate adjustments. The authors acknowledge that such individual complication rates may vary dramatically. We were aware of this potential problem, and therefore a priori ascertained a composite outcome of any noncardiac medical complication. However, our results do provide preliminary information regarding the impact of BMI on noncardiac medical complications. Further studies would be needed, though, to fully determine the effect of BMI on the number of cases with each complication.

Obesity (or BMI) is a known cardiovascular risk factor, and our previous study's aim was to determine cardiovascular events in a comparable manner to the way risk indices, such as the Goldman, Lee, or the AHA preoperative algorithm function. The surgical literature often presents noncardiac complications separately, allowing us to directly compare our own data to other published studies. We used 2 separate approaches, focusing on the inpatient stay (ascertaining noncardiac complications) and 1‐year cardiac outcomes (cardiac complications), as these are mediated by different mechanisms and factors. Furthermore, the intent of both studies was to dispel any concerns that an elevated BMI would in fact lead to an increased number of complications. Whether cardiac complications, though, would impact noncardiac complications, or vice‐versa, is unknown, and would require further investigation.

Although we relied on well‐established definitions for body mass, they have often been challenged, as they may underestimate adiposity in the elderly population due to age‐related reductions in lean mass.^35,36 Studies have demonstrated a poor correlation between percent body fat and BMI in the >65 year age group,³⁷ which could impact our results and outcomes by misclassifying patients. Yet, as an anthropometric measurement, BMI is easily obtainable and its variables are routinely documented in patients' medical records, as compared to other anthropometric measurements. Other means of estimating adiposity, such as densitometry or computed tomography (CT) scanning, are impractical, expensive, and not used clinically but routinely in research settings. The lack of standardization in obtaining height and weight, despite nurse‐initiated protocols for bed calibration, may have introduced a degree of measurement bias. Furthermore, the extent of lean mass lost and volume status changes lead to further challenges of using BMI in hospital settings. Whether other anthropometric measurements, including hip circumference, waist circumference, or waist‐hip ratio, should be used in this group of patients requires further examination. However, despite its shortcomings in elderly patients, BMI is still deemed an appropriate surrogate for obesity.

Our main strength was the use of the Rochester Epidemiology Project medical record linkage system to ascertain all patient data. This focuses on patients from a single geographically‐defined community minimizing referral biases often observed in studies originating from a tertiary care referral center. Previous disease‐related epidemiology studies using the Olmsted County population have demonstrated excellent external validity to the U.S. white population.¹⁶ We relied on the medical documentation of the treating clinician for many diagnoses in our data abstraction. Although we attempted to use standardized definitions, clinicians may have inadvertently forgotten to document subjective signs or symptoms that would assist in the categorization of these complications. Hence, added inpatient complications may have been overlooked, suggesting that our results may slightly underestimate the true incidence in this population. Additionally, certain complications may overlap categories, such as pneumonia and infections. We agree with Lawrence et al.¹⁹ that long periods of time are necessary to accumulate data of this kind in an effort to describe complication rates epidemiologically.

Despite no difference in outcomes among BMI categories, our results have striking implications for the hospitalized patient. Thus, underweight elderly patients, often considered frail with minimal functional reserve, are at no higher risk for developing inpatient medical complications than patients with higher BMIs. This is contrary to our study focusing on cardiac complications, where underweight patients were at higher risk.¹⁵ Conversely, obese patients, who have been demonstrated to be at higher risk of medical complications (particularly pulmonary), had no greater risk than patients with normal BMI. To the practicing geriatrician and hospitalist, this information provides important prognostication regarding additional perioperative measures that need to be implemented in these different groups. Based on our results, BMI does not play a particular role in noncardiac medical complications, dispelling any myths of the added burden of excess weight on surgical outcomes in this population. From a hospital perspective, this may be important since additional testing or preventative management in these patients may lead to additional resource use. However, in‐hospital deaths were higher in underweight patients than in patients with a normal BMI. Although we were underpowered to detect any differences in mortality between groups and could therefore not adjust for additional variables, it is unknown whether cardiac or noncardiac complications may be a stronger predictor of death in the underweight patient population. Further studies would be needed to better ascertain this relationship.

Conclusions

In elderly patients undergoing urgent hip fracture repair, BMI does not appear to lead to an excess rate of inpatient noncardiac complications. Our results are the first to demonstrate that BMI has no impact on morbidity in this patient population. Further research on the influence of body composition on inpatient complications in this population is needed to accurately allow for appropriate perioperative prophylaxis. Whether BMI impacts specific complications or in‐patient mortality in this population still requires investigation.

Public health concerns such as the aging population¹ and the increasing prevalence of obesity² are also important issues to hospitals. However, little attention has been given to the interface of obesity and the elderly, largely due to the dearth of studies that include elderly patients. An aging population leads to an increase in geriatric syndromes, such as osteoporosis³ and its most devastating complication, hip fracture.⁴ These frail, hip‐fracture patients pose management challenges to practicing geriatricians and hospitalists.^5,6 Furthermore, although fracture risk is inversely correlated to body mass index (BMI),⁷ this relationship has yet to be fully examined in the postoperative hip‐fracture population. In other surgical settings, there is disagreement as to whether underweight or obese patients are at higher risk of developing medical complications,^8‐11 but for orthopedic patients, data have been limited to elective orthopedic populations.^12‐14 We previously demonstrated that underweight hip‐fracture patients are at higher risk of postoperative cardiac complications at 1 year,¹⁵ consistent with studies of cardiac risk indices determining long‐term events. Because of different pathophysiologic mechanisms, the purpose of this study was to ascertain the influence of BMI on inpatient postoperative noncardiac medical complications and to assess predictors of such complications following urgent hip fracture repair.

Patients and Methods

All Olmsted County, Minnesota, residents undergoing urgent hip repair due to fracture were identified using the Rochester Epidemiology Project, a medical‐record linkage system funded by the Federal government since 1966 to support disease‐related epidemiology studies.¹⁶ All patient medical care is indexed, and both inpatient and outpatient visits are captured and available for review, allowing for complete case ascertainment. Medical care in Olmsted County is primarily provided by Mayo Clinic with its affiliated hospitals (St. Mary's and Rochester Methodist) and the Olmsted Medical Center, in addition to a few individual providers. Over 95% of all Olmsted County hip fracture surgeries are ultimately managed at St. Mary's Hospital.

Following approval by the Institutional Review Board we used this unique data resource to identify all residents with an International Classification of Diseases, 9th edition (ICD‐9) diagnosis code of 820 to 829 for hip fracture (n = 1310). Both sexes were included, and all patients included in the study provided research authorization for use of their medical records for research purposes.¹⁷ We excluded patients who were managed conservatively (n = 56), had a pathological fracture (n = 20), had multiple injuries (n = 19), were operated on >72 hours after fracture (n = 5), were aged <65 years (n = 2), or were admitted for reasons other than a fracture and experienced an in‐hospital fracture (n = 3). We subsequently excluded patients with missing information (n = 10). World Health Organization (WHO) criteria were used for classifying BMI: underweight (BMI < 18.5); normal (BMI = 18.5‐24.9); overweight (BMI = 25.0‐29.9); and obese (BMI 30.0).¹⁸

All data were abstracted using standardized collection forms by trained nurse abstractors blinded to the study hypothesis. Patients' admission height and weight were documented; if unavailable, the nearest data within 2 months prior to surgery were recorded. Patients' preadmission residence, functional status, baseline comorbidities, admission medications, discharge destination, as well as whether patients had an intensive care unit stay or any major surgeries in the past 90 days were abstracted. In addition, American Society of Anesthesia (ASA) class, type of anesthesia, and length of stay were also obtained. Inpatient complications that had been identified by the treating physicians and documented in the medical record or identified on imaging studies were assessed from the time of hip fracture repair to the time of discharge using standardized clinical criteria (Table 1). For criteria that were based on either objective findings or clinical documentation/suspicion, the patient was considered to meet the criteria of having a complication if they fulfilled either one. We did not include any cardiac outcomes, including congestive heart failure, angina, myocardial infarction, or arrhythmias that had been previously reported.¹⁵ Noncardiac complications were classified broadly: respiratory (respiratory failure, respiratory depression, or pulmonary hypoxemia); neurologic (any cerebral event including hemorrhagic or ischemic stroke, transient ischemic attack, or delirium); gastrointestinal (ileus or gastrointestinal bleeding); vascular (pulmonary embolus, or deep vein thrombosis); infectious (pneumonia, sepsis, urinary tract, wound, or cellulitis); renal/metabolic (acute renal failure, dehydration, or electrolyte abnormalities); or other (fractures or falls).

Continuous data are presented as means standard deviation and categorical data as counts and percentages. In testing for differences in patient demographics, past medical history, and baseline clinical data among BMI groups, Kruskal‐Wallis tests were performed for continuous variables and Fisher's Exact or Cochran‐Mantel‐Haenszel tests were used for discrete variables. Bonferroni adjustments were performed where appropriate. The primary outcome was the risk of any noncardiac medical complication during the postoperative hospitalization, based on patients with complications. Incidence rates were calculated for the overall group as well as for each BMI category. BMI was evaluated categorically according to the WHO criteria, as a continuous variable dichotomized as a BMI 18.5 kg/m² to 24.9 kg/m² (normal) vs. all others, and above/below 25.0 kg/m². The effect of BMI and other potential risk factors on the complication rate was evaluated using logistic regression. The effect of BMI category on the overall complication rate was adjusted for the a priori risk factors of age, sex, surgical year, and ASA class both univariately (Model 1) and multivariately (Model 2). In addition to these variables, we also evaluated other potential risk factors, including baseline demographic and baseline clinical variables that were significant (P < 0.05) univariately using a stepwise selection; first forcing in BMI as a categorical variable (Model 3), then repeating the stepwise selection process without forcing in BMI (Model 4). Using data from Lawrence et al.,¹⁹ we estimated that we would have 80% power to detect differences in rates of inpatient noncardiac complications equal to an odds ratio (OR) = 2.2 (normal vs. underweight), OR = 2.0 (normal vs. overweight), and OR = 2.4 (normal vs. obese). Finally, because of power considerations, as an exploratory analysis, we additionally identified predictors of inpatient complications within each BMI category using stepwise selection. All statistical tests were 2‐sided, and P values <0.05 were considered significant. All analyses were performed using SAS for UNIX (version 9.1.3; SAS Institute, Inc., Cary, NC).

Results

Between 1988 and 2002, 1195 urgent repairs for hip fracture met our inclusion/exclusion criteria. We subsequently excluded 15 repairs with missing BMI data, and, of the 7 patients with >1 repair, we included only their first fracture episode in our analysis. Two were subsequently excluded due to an administrative error. Ultimately, 1180 hip fracture repairs were included in the analysis cohort. There were 184 (15.6%) patients in the underweight group, 640 (54.2%) with normal BMI, 251 (21.3%) with a BMI 25.0 to 29.9 kg/m², and 105 (8.9%) with a BMI 30 kg/m². Baseline characteristics are otherwise shown in Table 2. Normal BMI patients were significantly older than the other groups, and underweight patients were less likely to be admitted from home. Past history of having a cardiovascular risk factor or a cardiovascular diagnosis appeared to increase with increasing BMI. Underweight patients were more likely to have chronic obstructive pulmonary disease (COPD) than patients with normal BMI (P = 0.03) or overweight patients (P = 0.009), but not more than obese patients (P = 0.21). There were no differences across BMI groups in ASA class, type of anesthesia, intensive care unit stay, or length of stay.

There were 77 (41.8%) postoperative inpatient noncardiac complications in the underweight group, 234 (36.6%) in the normal BMI group, 90 (35.9%) in the overweight group, and 42 (40.0%) in the obese group (P = 0.49). Figure 1 demonstrates the main subcategory complication rates by BMI group, and Table 3 outlines the univariate unadjusted complication rates. Other than gastrointestinal complications being more prevalent as BMI increases (P = 0.005), there were no significant differences in crude complication rates across BMI categories (all P > 0.05) for the other complication subcategories. A multiple comparisons analysis did not demonstrate any differences between normal and any of the other BMI categories for ileus. Normal BMI patients were more likely to be discharged to a nursing facility than overweight or obese patients (85.5% vs. 79.3%, P = 0.03; and 85.5% vs. 79.0%, P = 0.03, respectively). The proportion of in‐hospital deaths among underweight patients was significantly higher than in any of the other groups (9.3% vs. 4.4%; P = 0.01), but mean length of stay was not significantly different.

Figure 1

Significant univariate predictors of the composite outcome of any noncardiac complication included: age (OR, 1.04 95% confidence interval [CI>], 1.02‐1.06; P < 0.001), age 75 years (OR, 2.25; 95% CI, 1.52‐3.33; P < 0.001), age 85 years (OR, 1.49; 95% CI, 1.17‐1.89; P < 0.001), male sex (OR, 1.41; 95% CI, 1.05‐1.90; P = 0.02), admission from home (OR, 0.77; 95% CI, 0.61‐0.98; P = 0.03), a history of cerebrovascular disease (OR, 1.41; 95% CI, 1.08‐1.83; P = 0.01), myocardial infarction (OR, 1.41; 95% CI, 1.07‐1.86; P = 0.02), angina (OR, 1.32; 95% CI, 1.03‐1.69; P = 0.03), congestive heart failure (OR, 1.45; 95% CI, 1.11‐1.89; P = 0.006), dementia (OR, 1.39; 95% CI, 1.08‐1.78; P = 0.01), peripheral vascular disease (OR, 1.47; 95% CI, 1.06‐2.03; P = 0.02), COPD/asthma (OR, 1.56; 95% CI, 1.18‐2.08; P = 0.002), osteoarthritis (OR, 1.29; 95% CI, 1.01‐1.65; P = 0.04), code status as Do Not Resuscitate (OR, 0.74; 95% CI, 0.58‐0.94; P = 0.015), or ASA class III‐V (OR, 2.24; 95% CI, 1.53‐3.29; P < 0.001). Results were no different after using the Charlson comorbidity index in place of ASA class (data not shown). No significant differences in overall noncardiac complications were observed when examining BMI as a continuous variable, as a categorical variable, as 25 kg/m² vs. <25 kg/m², or as 18.5 kg/m² to 24.9 kg/m² vs. all others. Examining renal, respiratory, peripheral vascular, or neurologic complications univariately within these aforementioned strata also did not demonstrate any significant differences among BMI categories (data not shown).

Multivariable analyses (Models 1‐4) are shown for any overall noncardiac inpatient medical complication in Table 4. BMI was not a significant predictor in any of our models, specifically in our main model that examined the effect of BMI adjusting for a priori variables (Model 2). However, older age, male sex, and ASA class were highly significant predictors of complications in all four models; however, surgical year was nonsignificant. Notably, after stepwise selection for other demographic and premorbid variables, a history of COPD or asthma was found to be an additional significant factor both in Model 3 (forcing BMI in the model) and Model 4 (without BMI in the model). Exploratory analysis of individual predictors of inpatient noncardiac complications within each BMI category demonstrated that, in underweight patients, admission use of ‐blockers was a significant predictor of having any medical complication (OR, 3.1; 95% CI, 1.1‐8.60; P = 0.03). In normal BMI patients, age 75 years (OR, 2.6; 95% CI, 1.4‐4.9; P = 0.003), ASA class III‐V (OR, 2.3; 95% CI, 1.3‐3.9; P = 0.003), and a history of cerebrovascular disease (OR, 1.5; 95%CI, 1.04‐2.1; P = 0.03) were predictors; and, in obese patients, only age (OR, 1.1; 95% CI, 1.00‐1.12; P = 0.05) was significant. There were no significant predictors of having a medical complication in the overweight group.

Discussion

Most research describing the association of BMI with postoperative outcomes has concentrated on cardiac surgery, general surgical procedures, and intensive care unit utilization.^8‐11,20 In the orthopedic literature, an elevated BMI has been associated with a higher number of short‐term complications, but this was limited to elective knee arthroplasty and spine surgery populations.^12,13,21 Conversely, no differences were observed in obese patients undergoing hip arthroplasties.^14,22 To the best of our knowledge, this study may be the first to examine the impact of BMI on inpatient hospital outcomes following urgent hip fracture repair. Our results suggest the risk of developing a noncardiac medical complication is the same regardless of BMI.

Our overall complication rate was higher (38%) than previous reports by others.^19,23‐26 Thus, Lawrence et al.,¹⁹ in their retrospective study of 20 facilities, demonstrated an overall complication rate of 17%, even though they also included postoperative cardiac complications. Although their study period overlapped our own (1982‐1993), they additionally included patients aged 60 to 65 years, a population known to have fewer comorbidities and fewer postoperative complications than the elderly hip‐fracture patients studied here. In addition, their population may have been healthier at baseline, in that a higher proportion lived at home (73%) and a lower percentage were ASA class III‐V (71%) than our cohort. These differences in baseline characteristics may explain the higher complication rates observed in our study.

Our findings did not suggest any relationship of BMI with noncardiac postoperative medical complications in any of the 4 methods we used to stratify BMI (continuous, categorical, normal vs. abnormal, and 25 kg/m²). Evidence is contradictory as to what the effect of BMI has on postoperative complications. An elevated BMI (30 kg/m²) has been shown to lead to increased sternal wound infection and saphenous vein harvest infection in a cardiac surgery population,²⁷ but other studies^10,28,29 have demonstrated the opposite effect. Among 6336 patients undergoing elective general surgery procedures, the incidence of complications were similar by body mass.³⁰ A matched study design that included urgent and emergent surgeries also did not find any appreciable increased perioperative risk in noncardiac surgery.²⁸ Whether this may be due to the elective nature of the surgeries in these studies, hence leading to selection bias, is unknown.

In geriatric patients, multiple baseline comorbid conditions often are reflected in a higher ASA class, which increases the risk of significant perioperative complications. Our multivariate modeling showed that a high ASA class strongly predicts morbidity and mortality following hip fracture repair, in line with other studies.^19,31,32 Although the Charlson comorbidity index could alternatively been used, we elected to adjust for ASA class as it is more commonly used and is simple to use. Interestingly, surgical year did not significantly predict any complication, which can suggest that practice changes play a minimal impact on patient outcomes. However, we caution that because the individual event rates, particularly vascular, were low, we were unable to fully determine whether changes in practice management, such as improved thromboprophylaxis, would impact event rates over time. Finally, other predictors such as older age³³ and a concomitant history of either COPD or asthma,³⁴ are well‐accepted predictors of inpatient complications. Our attempt to examine specific predictors of complications in each BMI category revealed differing results, making interpretations difficult. Because of power considerations, this was meant solely as an exploratory analysis, and larger cohorts are needed to further ascertain whether predictors are different in these groups. Such a study may in fact identify perioperative issues that allow practitioners caring for this population to modify these factors.

One of the major limitations in our study was our inability to adjust for individual complications using multivariable models, such as deep vein thrombosis or delirium, within each BMI stratum, because of statistical power issues. Such a study would require large numbers of individual complications or events to allow for appropriate adjustments. The authors acknowledge that such individual complication rates may vary dramatically. We were aware of this potential problem, and therefore a priori ascertained a composite outcome of any noncardiac medical complication. However, our results do provide preliminary information regarding the impact of BMI on noncardiac medical complications. Further studies would be needed, though, to fully determine the effect of BMI on the number of cases with each complication.

Obesity (or BMI) is a known cardiovascular risk factor, and our previous study's aim was to determine cardiovascular events in a comparable manner to the way risk indices, such as the Goldman, Lee, or the AHA preoperative algorithm function. The surgical literature often presents noncardiac complications separately, allowing us to directly compare our own data to other published studies. We used 2 separate approaches, focusing on the inpatient stay (ascertaining noncardiac complications) and 1‐year cardiac outcomes (cardiac complications), as these are mediated by different mechanisms and factors. Furthermore, the intent of both studies was to dispel any concerns that an elevated BMI would in fact lead to an increased number of complications. Whether cardiac complications, though, would impact noncardiac complications, or vice‐versa, is unknown, and would require further investigation.

Although we relied on well‐established definitions for body mass, they have often been challenged, as they may underestimate adiposity in the elderly population due to age‐related reductions in lean mass.^35,36 Studies have demonstrated a poor correlation between percent body fat and BMI in the >65 year age group,³⁷ which could impact our results and outcomes by misclassifying patients. Yet, as an anthropometric measurement, BMI is easily obtainable and its variables are routinely documented in patients' medical records, as compared to other anthropometric measurements. Other means of estimating adiposity, such as densitometry or computed tomography (CT) scanning, are impractical, expensive, and not used clinically but routinely in research settings. The lack of standardization in obtaining height and weight, despite nurse‐initiated protocols for bed calibration, may have introduced a degree of measurement bias. Furthermore, the extent of lean mass lost and volume status changes lead to further challenges of using BMI in hospital settings. Whether other anthropometric measurements, including hip circumference, waist circumference, or waist‐hip ratio, should be used in this group of patients requires further examination. However, despite its shortcomings in elderly patients, BMI is still deemed an appropriate surrogate for obesity.

Our main strength was the use of the Rochester Epidemiology Project medical record linkage system to ascertain all patient data. This focuses on patients from a single geographically‐defined community minimizing referral biases often observed in studies originating from a tertiary care referral center. Previous disease‐related epidemiology studies using the Olmsted County population have demonstrated excellent external validity to the U.S. white population.¹⁶ We relied on the medical documentation of the treating clinician for many diagnoses in our data abstraction. Although we attempted to use standardized definitions, clinicians may have inadvertently forgotten to document subjective signs or symptoms that would assist in the categorization of these complications. Hence, added inpatient complications may have been overlooked, suggesting that our results may slightly underestimate the true incidence in this population. Additionally, certain complications may overlap categories, such as pneumonia and infections. We agree with Lawrence et al.¹⁹ that long periods of time are necessary to accumulate data of this kind in an effort to describe complication rates epidemiologically.

Despite no difference in outcomes among BMI categories, our results have striking implications for the hospitalized patient. Thus, underweight elderly patients, often considered frail with minimal functional reserve, are at no higher risk for developing inpatient medical complications than patients with higher BMIs. This is contrary to our study focusing on cardiac complications, where underweight patients were at higher risk.¹⁵ Conversely, obese patients, who have been demonstrated to be at higher risk of medical complications (particularly pulmonary), had no greater risk than patients with normal BMI. To the practicing geriatrician and hospitalist, this information provides important prognostication regarding additional perioperative measures that need to be implemented in these different groups. Based on our results, BMI does not play a particular role in noncardiac medical complications, dispelling any myths of the added burden of excess weight on surgical outcomes in this population. From a hospital perspective, this may be important since additional testing or preventative management in these patients may lead to additional resource use. However, in‐hospital deaths were higher in underweight patients than in patients with a normal BMI. Although we were underpowered to detect any differences in mortality between groups and could therefore not adjust for additional variables, it is unknown whether cardiac or noncardiac complications may be a stronger predictor of death in the underweight patient population. Further studies would be needed to better ascertain this relationship.

Conclusions

In elderly patients undergoing urgent hip fracture repair, BMI does not appear to lead to an excess rate of inpatient noncardiac complications. Our results are the first to demonstrate that BMI has no impact on morbidity in this patient population. Further research on the influence of body composition on inpatient complications in this population is needed to accurately allow for appropriate perioperative prophylaxis. Whether BMI impacts specific complications or in‐patient mortality in this population still requires investigation.

Public health concerns such as the aging population¹ and the increasing prevalence of obesity² are also important issues to hospitals. However, little attention has been given to the interface of obesity and the elderly, largely due to the dearth of studies that include elderly patients. An aging population leads to an increase in geriatric syndromes, such as osteoporosis³ and its most devastating complication, hip fracture.⁴ These frail, hip‐fracture patients pose management challenges to practicing geriatricians and hospitalists.^5,6 Furthermore, although fracture risk is inversely correlated to body mass index (BMI),⁷ this relationship has yet to be fully examined in the postoperative hip‐fracture population. In other surgical settings, there is disagreement as to whether underweight or obese patients are at higher risk of developing medical complications,^8‐11 but for orthopedic patients, data have been limited to elective orthopedic populations.^12‐14 We previously demonstrated that underweight hip‐fracture patients are at higher risk of postoperative cardiac complications at 1 year,¹⁵ consistent with studies of cardiac risk indices determining long‐term events. Because of different pathophysiologic mechanisms, the purpose of this study was to ascertain the influence of BMI on inpatient postoperative noncardiac medical complications and to assess predictors of such complications following urgent hip fracture repair.

Patients and Methods

All Olmsted County, Minnesota, residents undergoing urgent hip repair due to fracture were identified using the Rochester Epidemiology Project, a medical‐record linkage system funded by the Federal government since 1966 to support disease‐related epidemiology studies.¹⁶ All patient medical care is indexed, and both inpatient and outpatient visits are captured and available for review, allowing for complete case ascertainment. Medical care in Olmsted County is primarily provided by Mayo Clinic with its affiliated hospitals (St. Mary's and Rochester Methodist) and the Olmsted Medical Center, in addition to a few individual providers. Over 95% of all Olmsted County hip fracture surgeries are ultimately managed at St. Mary's Hospital.

Following approval by the Institutional Review Board we used this unique data resource to identify all residents with an International Classification of Diseases, 9th edition (ICD‐9) diagnosis code of 820 to 829 for hip fracture (n = 1310). Both sexes were included, and all patients included in the study provided research authorization for use of their medical records for research purposes.¹⁷ We excluded patients who were managed conservatively (n = 56), had a pathological fracture (n = 20), had multiple injuries (n = 19), were operated on >72 hours after fracture (n = 5), were aged <65 years (n = 2), or were admitted for reasons other than a fracture and experienced an in‐hospital fracture (n = 3). We subsequently excluded patients with missing information (n = 10). World Health Organization (WHO) criteria were used for classifying BMI: underweight (BMI < 18.5); normal (BMI = 18.5‐24.9); overweight (BMI = 25.0‐29.9); and obese (BMI 30.0).¹⁸

All data were abstracted using standardized collection forms by trained nurse abstractors blinded to the study hypothesis. Patients' admission height and weight were documented; if unavailable, the nearest data within 2 months prior to surgery were recorded. Patients' preadmission residence, functional status, baseline comorbidities, admission medications, discharge destination, as well as whether patients had an intensive care unit stay or any major surgeries in the past 90 days were abstracted. In addition, American Society of Anesthesia (ASA) class, type of anesthesia, and length of stay were also obtained. Inpatient complications that had been identified by the treating physicians and documented in the medical record or identified on imaging studies were assessed from the time of hip fracture repair to the time of discharge using standardized clinical criteria (Table 1). For criteria that were based on either objective findings or clinical documentation/suspicion, the patient was considered to meet the criteria of having a complication if they fulfilled either one. We did not include any cardiac outcomes, including congestive heart failure, angina, myocardial infarction, or arrhythmias that had been previously reported.¹⁵ Noncardiac complications were classified broadly: respiratory (respiratory failure, respiratory depression, or pulmonary hypoxemia); neurologic (any cerebral event including hemorrhagic or ischemic stroke, transient ischemic attack, or delirium); gastrointestinal (ileus or gastrointestinal bleeding); vascular (pulmonary embolus, or deep vein thrombosis); infectious (pneumonia, sepsis, urinary tract, wound, or cellulitis); renal/metabolic (acute renal failure, dehydration, or electrolyte abnormalities); or other (fractures or falls).

Continuous data are presented as means standard deviation and categorical data as counts and percentages. In testing for differences in patient demographics, past medical history, and baseline clinical data among BMI groups, Kruskal‐Wallis tests were performed for continuous variables and Fisher's Exact or Cochran‐Mantel‐Haenszel tests were used for discrete variables. Bonferroni adjustments were performed where appropriate. The primary outcome was the risk of any noncardiac medical complication during the postoperative hospitalization, based on patients with complications. Incidence rates were calculated for the overall group as well as for each BMI category. BMI was evaluated categorically according to the WHO criteria, as a continuous variable dichotomized as a BMI 18.5 kg/m² to 24.9 kg/m² (normal) vs. all others, and above/below 25.0 kg/m². The effect of BMI and other potential risk factors on the complication rate was evaluated using logistic regression. The effect of BMI category on the overall complication rate was adjusted for the a priori risk factors of age, sex, surgical year, and ASA class both univariately (Model 1) and multivariately (Model 2). In addition to these variables, we also evaluated other potential risk factors, including baseline demographic and baseline clinical variables that were significant (P < 0.05) univariately using a stepwise selection; first forcing in BMI as a categorical variable (Model 3), then repeating the stepwise selection process without forcing in BMI (Model 4). Using data from Lawrence et al.,¹⁹ we estimated that we would have 80% power to detect differences in rates of inpatient noncardiac complications equal to an odds ratio (OR) = 2.2 (normal vs. underweight), OR = 2.0 (normal vs. overweight), and OR = 2.4 (normal vs. obese). Finally, because of power considerations, as an exploratory analysis, we additionally identified predictors of inpatient complications within each BMI category using stepwise selection. All statistical tests were 2‐sided, and P values <0.05 were considered significant. All analyses were performed using SAS for UNIX (version 9.1.3; SAS Institute, Inc., Cary, NC).

Results

Between 1988 and 2002, 1195 urgent repairs for hip fracture met our inclusion/exclusion criteria. We subsequently excluded 15 repairs with missing BMI data, and, of the 7 patients with >1 repair, we included only their first fracture episode in our analysis. Two were subsequently excluded due to an administrative error. Ultimately, 1180 hip fracture repairs were included in the analysis cohort. There were 184 (15.6%) patients in the underweight group, 640 (54.2%) with normal BMI, 251 (21.3%) with a BMI 25.0 to 29.9 kg/m², and 105 (8.9%) with a BMI 30 kg/m². Baseline characteristics are otherwise shown in Table 2. Normal BMI patients were significantly older than the other groups, and underweight patients were less likely to be admitted from home. Past history of having a cardiovascular risk factor or a cardiovascular diagnosis appeared to increase with increasing BMI. Underweight patients were more likely to have chronic obstructive pulmonary disease (COPD) than patients with normal BMI (P = 0.03) or overweight patients (P = 0.009), but not more than obese patients (P = 0.21). There were no differences across BMI groups in ASA class, type of anesthesia, intensive care unit stay, or length of stay.