Clinical question: Does pulse variability on plethysmography, or the Pleth Variability Index (PVI), correlate with disease severity in obstructive airway disease in children?

Background: Asthma is the most common reason for hospitalization in the United S. for children 3-12 years old. Asthma accounts for a quarter of ED visits for children aged 1-9 years old.¹ Although systems have been developed to assess asthma exacerbation severity and the need for hospitalization, many of these depend on reassessments over time or have been proven to be invalid in larger studies.^2,3,4 Pulsus paradoxus (PP), which is defined as a drop in systolic blood pressure greater than 10 mm Hg, correlates with the severity of obstruction in asthma exacerbations, but it is not practical in the children being evaluated in the ED or hospital.^5,6 PP measurement using plethysmography has been found to correlate with measurement by sphygmomanometry.⁷ Furthermore, PVI, which is derived from amplitude variability in the pulse oximeter waveform, has been found to correlate with fluid responsiveness in mechanically ventilated patients. To this date, no study has assessed the correlation between PVI and exacerbation severity in asthma.

A printout of the first ED pulse oximetry reading was used to obtain the PImax and PImin as below:

Researchers followed patients after the initial evaluation to determine disposition from the ED, which included either discharge to home, admission to a general pediatrics floor, or admission to the PICU. The hospital utilized specific criteria for disposition from the ED (see Table 1).

References

1. Care of children and adolescents in U.S. hospitals. Agency for Healthcare Research and Quality website. Available at: https://archive.ahrq.gov/data/hcup/factbk4/factbk4.htm. Accessed Nov. 18, 2016.

2. Kelly AM, Kerr D, Powell C. Is severity assessment after one hour of treatment better for predicting the need for admission in acute asthma? Respir Med. 2004;98(8):777-781.

3. Keogh KA, Macarthur C, Parkin PC, et al. Predictors of hospitalization in children with acute asthma. J Pediatr. 2001;139(2):273-277.

4. Keahey L, Bulloch B, Becker AB, et al. Initial oxygen saturation as a predictor of admission in children presenting to the emergency department with acute asthma. Ann Emerg Med. 2002;40(3):300-307.

5. Guntheroth WG, Morgan BC, Mullins GL. Effect of respiration on venous return and stroke volume in cardiac tamponade. Mechanism of pulsus paradoxus. Circ Res. 1967;20(4):381-390.

6. Frey B, Freezer N. Diagnostic value and pathophysiologic basis of pulsus paradoxus in infants and children with respiratory disease. Pediatr Pulmonol. 2001;31(2):138-143.

7. Clark JA, Lieh-Lai M, Thomas R, Raghavan K, Sarnaik AP. Comparison of traditional and plethysmographic methods for measuring pulsus paradoxus. Arch Pediatr Adolesc Med. 2004;158(1):48-51.
 

Clinical question: Does pulse variability on plethysmography, or the Pleth Variability Index (PVI), correlate with disease severity in obstructive airway disease in children?

Background: Asthma is the most common reason for hospitalization in the United S. for children 3-12 years old. Asthma accounts for a quarter of ED visits for children aged 1-9 years old.¹ Although systems have been developed to assess asthma exacerbation severity and the need for hospitalization, many of these depend on reassessments over time or have been proven to be invalid in larger studies.^2,3,4 Pulsus paradoxus (PP), which is defined as a drop in systolic blood pressure greater than 10 mm Hg, correlates with the severity of obstruction in asthma exacerbations, but it is not practical in the children being evaluated in the ED or hospital.^5,6 PP measurement using plethysmography has been found to correlate with measurement by sphygmomanometry.⁷ Furthermore, PVI, which is derived from amplitude variability in the pulse oximeter waveform, has been found to correlate with fluid responsiveness in mechanically ventilated patients. To this date, no study has assessed the correlation between PVI and exacerbation severity in asthma.

A printout of the first ED pulse oximetry reading was used to obtain the PImax and PImin as below:

Researchers followed patients after the initial evaluation to determine disposition from the ED, which included either discharge to home, admission to a general pediatrics floor, or admission to the PICU. The hospital utilized specific criteria for disposition from the ED (see Table 1).

References

1. Care of children and adolescents in U.S. hospitals. Agency for Healthcare Research and Quality website. Available at: https://archive.ahrq.gov/data/hcup/factbk4/factbk4.htm. Accessed Nov. 18, 2016.

2. Kelly AM, Kerr D, Powell C. Is severity assessment after one hour of treatment better for predicting the need for admission in acute asthma? Respir Med. 2004;98(8):777-781.

3. Keogh KA, Macarthur C, Parkin PC, et al. Predictors of hospitalization in children with acute asthma. J Pediatr. 2001;139(2):273-277.

4. Keahey L, Bulloch B, Becker AB, et al. Initial oxygen saturation as a predictor of admission in children presenting to the emergency department with acute asthma. Ann Emerg Med. 2002;40(3):300-307.

5. Guntheroth WG, Morgan BC, Mullins GL. Effect of respiration on venous return and stroke volume in cardiac tamponade. Mechanism of pulsus paradoxus. Circ Res. 1967;20(4):381-390.

6. Frey B, Freezer N. Diagnostic value and pathophysiologic basis of pulsus paradoxus in infants and children with respiratory disease. Pediatr Pulmonol. 2001;31(2):138-143.

7. Clark JA, Lieh-Lai M, Thomas R, Raghavan K, Sarnaik AP. Comparison of traditional and plethysmographic methods for measuring pulsus paradoxus. Arch Pediatr Adolesc Med. 2004;158(1):48-51.
 

Clinical question: Does pulse variability on plethysmography, or the Pleth Variability Index (PVI), correlate with disease severity in obstructive airway disease in children?

Background: Asthma is the most common reason for hospitalization in the United S. for children 3-12 years old. Asthma accounts for a quarter of ED visits for children aged 1-9 years old.¹ Although systems have been developed to assess asthma exacerbation severity and the need for hospitalization, many of these depend on reassessments over time or have been proven to be invalid in larger studies.^2,3,4 Pulsus paradoxus (PP), which is defined as a drop in systolic blood pressure greater than 10 mm Hg, correlates with the severity of obstruction in asthma exacerbations, but it is not practical in the children being evaluated in the ED or hospital.^5,6 PP measurement using plethysmography has been found to correlate with measurement by sphygmomanometry.⁷ Furthermore, PVI, which is derived from amplitude variability in the pulse oximeter waveform, has been found to correlate with fluid responsiveness in mechanically ventilated patients. To this date, no study has assessed the correlation between PVI and exacerbation severity in asthma.

A printout of the first ED pulse oximetry reading was used to obtain the PImax and PImin as below:

Researchers followed patients after the initial evaluation to determine disposition from the ED, which included either discharge to home, admission to a general pediatrics floor, or admission to the PICU. The hospital utilized specific criteria for disposition from the ED (see Table 1).

References

1. Care of children and adolescents in U.S. hospitals. Agency for Healthcare Research and Quality website. Available at: https://archive.ahrq.gov/data/hcup/factbk4/factbk4.htm. Accessed Nov. 18, 2016.

2. Kelly AM, Kerr D, Powell C. Is severity assessment after one hour of treatment better for predicting the need for admission in acute asthma? Respir Med. 2004;98(8):777-781.

3. Keogh KA, Macarthur C, Parkin PC, et al. Predictors of hospitalization in children with acute asthma. J Pediatr. 2001;139(2):273-277.

4. Keahey L, Bulloch B, Becker AB, et al. Initial oxygen saturation as a predictor of admission in children presenting to the emergency department with acute asthma. Ann Emerg Med. 2002;40(3):300-307.

5. Guntheroth WG, Morgan BC, Mullins GL. Effect of respiration on venous return and stroke volume in cardiac tamponade. Mechanism of pulsus paradoxus. Circ Res. 1967;20(4):381-390.

6. Frey B, Freezer N. Diagnostic value and pathophysiologic basis of pulsus paradoxus in infants and children with respiratory disease. Pediatr Pulmonol. 2001;31(2):138-143.

7. Clark JA, Lieh-Lai M, Thomas R, Raghavan K, Sarnaik AP. Comparison of traditional and plethysmographic methods for measuring pulsus paradoxus. Arch Pediatr Adolesc Med. 2004;158(1):48-51.
 

We work in complex environments and in a flawed and rapidly changing health care system. Caregivers, patients, and communities will be led through this complexity by those who embrace change. Last October, I had the privilege of attending and facilitating the SHM Leadership Academy in Orlando, which allowed me the opportunity to meet a group of people who embrace change, including the benefits and challenges that often accompany it.

SHM board member Jeff Glasheen, MD, SFHM, taught one of the first lessons at Leadership Academy, focusing on the importance of meaningful, difficult change. With comparisons to companies that have embraced change, like Apple, and some that have not, like Sears, Jeff summed up how complacency with “good” and a reluctance to tackle the difficulty of change keeps organizations – and people – from becoming great.

“Good is the enemy of great,” Jeff preached.

He largely focused on hospitalists leading organizational change, but the concepts can apply to personal change, too. He explained that “people generally want things to be different, but they don’t want to change.”

Leaders in training

Ten emerging hospitalist leaders sat at my table, soaking in the message. Several of them, like me 8 years ago, had the responsibilities of leadership unexpectedly thrust upon them. Some carried with them the heavy expectations of their colleagues or hospital administration (or both) that by being elevated into a role such as medical director, they would abruptly be able to make improvements in patient care and hospital operations. They had accepted the challenge to change – to move out of purely clinical roles and take on new ones in leadership despite having little or no experience. Doing so, they gingerly but willingly were following in the footsteps of leaders before them, growing their skills, improving their hospitals, and laying a path for future leaders to follow.

A few weeks prior, I had taken a new leadership position myself. The Cleveland Clinic recently acquired a hospital and health system in Akron, Ohio, about 40 miles away from the city. I assumed the role of president of this acquisition, embracing the complex challenge of leading the process of integrating two health systems. After 3 years overseeing a different hospital in the health system, I finally felt I had developed the people, processes, and culture that I had been striving to build. But like the young leaders at Leadership Academy, I had the opportunity to change, grow, develop, take on new risk, and become a stronger leader in this new role. A significant part of the experience of the Leadership Academy involves table exercises. For the first few exercises, the group was quiet, uncertain, tentative. I was struck both by how early these individuals were in their development and by how so much of what is happening today in hospitals and health care is dependent upon the development and success of individuals like these who are enthusiastic and talented but young and overwhelmed.

I believe that successful hospitalists are, through experience, training, and nature, rapid assimilators into their environments. By the third day, the dynamic at my table had gone from tentative and uncertain to much more confident and assertive. To experience this transformation in person at SHM’s Leadership Academy, we welcome you to Scottsdale, Ariz., later this year. Learn more about the program at www.shmleadershipacademy.org.

At Leadership Academy and beyond, I implore hospitalists to look for opportunities to change during this time of New Year’s resolutions and to take the opposite posture and want to change – change how we think, act, and respond; change our roles to take on new, uncomfortable responsibilities; and change how we view change itself.

We will be better for it both personally and professionally, and we will stand out as role models for our colleagues, coworkers, and hospitalists who follow in our footsteps.

Dr. Harte is a practicing hospitalist, president of the Society of Hospital Medicine, and president of Hillcrest Hospital in Mayfield Heights, Ohio, part of the Cleveland Clinic Health System. He is associate professor of medicine at the Cleveland Clinic, Lerner College of Medicine in Cleveland.

We work in complex environments and in a flawed and rapidly changing health care system. Caregivers, patients, and communities will be led through this complexity by those who embrace change. Last October, I had the privilege of attending and facilitating the SHM Leadership Academy in Orlando, which allowed me the opportunity to meet a group of people who embrace change, including the benefits and challenges that often accompany it.

SHM board member Jeff Glasheen, MD, SFHM, taught one of the first lessons at Leadership Academy, focusing on the importance of meaningful, difficult change. With comparisons to companies that have embraced change, like Apple, and some that have not, like Sears, Jeff summed up how complacency with “good” and a reluctance to tackle the difficulty of change keeps organizations – and people – from becoming great.

“Good is the enemy of great,” Jeff preached.

He largely focused on hospitalists leading organizational change, but the concepts can apply to personal change, too. He explained that “people generally want things to be different, but they don’t want to change.”

Leaders in training

Ten emerging hospitalist leaders sat at my table, soaking in the message. Several of them, like me 8 years ago, had the responsibilities of leadership unexpectedly thrust upon them. Some carried with them the heavy expectations of their colleagues or hospital administration (or both) that by being elevated into a role such as medical director, they would abruptly be able to make improvements in patient care and hospital operations. They had accepted the challenge to change – to move out of purely clinical roles and take on new ones in leadership despite having little or no experience. Doing so, they gingerly but willingly were following in the footsteps of leaders before them, growing their skills, improving their hospitals, and laying a path for future leaders to follow.

A few weeks prior, I had taken a new leadership position myself. The Cleveland Clinic recently acquired a hospital and health system in Akron, Ohio, about 40 miles away from the city. I assumed the role of president of this acquisition, embracing the complex challenge of leading the process of integrating two health systems. After 3 years overseeing a different hospital in the health system, I finally felt I had developed the people, processes, and culture that I had been striving to build. But like the young leaders at Leadership Academy, I had the opportunity to change, grow, develop, take on new risk, and become a stronger leader in this new role. A significant part of the experience of the Leadership Academy involves table exercises. For the first few exercises, the group was quiet, uncertain, tentative. I was struck both by how early these individuals were in their development and by how so much of what is happening today in hospitals and health care is dependent upon the development and success of individuals like these who are enthusiastic and talented but young and overwhelmed.

I believe that successful hospitalists are, through experience, training, and nature, rapid assimilators into their environments. By the third day, the dynamic at my table had gone from tentative and uncertain to much more confident and assertive. To experience this transformation in person at SHM’s Leadership Academy, we welcome you to Scottsdale, Ariz., later this year. Learn more about the program at www.shmleadershipacademy.org.

At Leadership Academy and beyond, I implore hospitalists to look for opportunities to change during this time of New Year’s resolutions and to take the opposite posture and want to change – change how we think, act, and respond; change our roles to take on new, uncomfortable responsibilities; and change how we view change itself.

We will be better for it both personally and professionally, and we will stand out as role models for our colleagues, coworkers, and hospitalists who follow in our footsteps.

Dr. Harte is a practicing hospitalist, president of the Society of Hospital Medicine, and president of Hillcrest Hospital in Mayfield Heights, Ohio, part of the Cleveland Clinic Health System. He is associate professor of medicine at the Cleveland Clinic, Lerner College of Medicine in Cleveland.

We work in complex environments and in a flawed and rapidly changing health care system. Caregivers, patients, and communities will be led through this complexity by those who embrace change. Last October, I had the privilege of attending and facilitating the SHM Leadership Academy in Orlando, which allowed me the opportunity to meet a group of people who embrace change, including the benefits and challenges that often accompany it.

SHM board member Jeff Glasheen, MD, SFHM, taught one of the first lessons at Leadership Academy, focusing on the importance of meaningful, difficult change. With comparisons to companies that have embraced change, like Apple, and some that have not, like Sears, Jeff summed up how complacency with “good” and a reluctance to tackle the difficulty of change keeps organizations – and people – from becoming great.

“Good is the enemy of great,” Jeff preached.

He largely focused on hospitalists leading organizational change, but the concepts can apply to personal change, too. He explained that “people generally want things to be different, but they don’t want to change.”

Leaders in training

Ten emerging hospitalist leaders sat at my table, soaking in the message. Several of them, like me 8 years ago, had the responsibilities of leadership unexpectedly thrust upon them. Some carried with them the heavy expectations of their colleagues or hospital administration (or both) that by being elevated into a role such as medical director, they would abruptly be able to make improvements in patient care and hospital operations. They had accepted the challenge to change – to move out of purely clinical roles and take on new ones in leadership despite having little or no experience. Doing so, they gingerly but willingly were following in the footsteps of leaders before them, growing their skills, improving their hospitals, and laying a path for future leaders to follow.

A few weeks prior, I had taken a new leadership position myself. The Cleveland Clinic recently acquired a hospital and health system in Akron, Ohio, about 40 miles away from the city. I assumed the role of president of this acquisition, embracing the complex challenge of leading the process of integrating two health systems. After 3 years overseeing a different hospital in the health system, I finally felt I had developed the people, processes, and culture that I had been striving to build. But like the young leaders at Leadership Academy, I had the opportunity to change, grow, develop, take on new risk, and become a stronger leader in this new role. A significant part of the experience of the Leadership Academy involves table exercises. For the first few exercises, the group was quiet, uncertain, tentative. I was struck both by how early these individuals were in their development and by how so much of what is happening today in hospitals and health care is dependent upon the development and success of individuals like these who are enthusiastic and talented but young and overwhelmed.

I believe that successful hospitalists are, through experience, training, and nature, rapid assimilators into their environments. By the third day, the dynamic at my table had gone from tentative and uncertain to much more confident and assertive. To experience this transformation in person at SHM’s Leadership Academy, we welcome you to Scottsdale, Ariz., later this year. Learn more about the program at www.shmleadershipacademy.org.

At Leadership Academy and beyond, I implore hospitalists to look for opportunities to change during this time of New Year’s resolutions and to take the opposite posture and want to change – change how we think, act, and respond; change our roles to take on new, uncomfortable responsibilities; and change how we view change itself.

We will be better for it both personally and professionally, and we will stand out as role models for our colleagues, coworkers, and hospitalists who follow in our footsteps.

Dr. Harte is a practicing hospitalist, president of the Society of Hospital Medicine, and president of Hillcrest Hospital in Mayfield Heights, Ohio, part of the Cleveland Clinic Health System. He is associate professor of medicine at the Cleveland Clinic, Lerner College of Medicine in Cleveland.

Unveiling the hospitalist specialty code

The Centers for Medicare & Medicaid Services announced in November the official implementation date for the Medicare physician specialty code for hospitalists. On April 3, “hospitalist” will be an official specialty designation under Medicare; the code will be C6. Starting on that date, hospitalists can change their specialty designation on the Medicare enrollment application (Form CMS-855I) or through CMS’ online portal (Provider Enrollment, Chain, and Ownership System, or PECOS).

Appropriate use of specialty codes helps distinguish differences among providers and improves the quality of utilization data. SHM applied for a specialty code for hospitalists nearly 3 years ago, and CMS approved the application in February 2016.

Stand with your fellow hospitalists and make sure to declare, “I’m a C6.”
 

Develop curricula to educate, engage medical students and residents

The ACGME requirements for training in quality and safety are changing – it is no longer an elective. As sponsoring institutions’ residency and fellowship programs mobilize to meet these requirements, leaders may find few faculty members are comfortable enough with the material to teach and create educational content for trainees. These faculty need further development.

Sponsored by SHM, the Quality and Safety Educators Academy (QSEA) responds to that demand by providing medical educators with the knowledge and tools to integrate quality improvement and safety concepts into their curricula. The 2017 meeting is Feb. 26-28 at the Tempe Mission Palms Hotel in Arizona.

This 2½ day meeting aims to fill the current gaps for faculty by offering basic concepts and educational tools in quality improvement and patient safety. Material is presented in an interactive way, providing guidance on career and curriculum development and establishing a national network of quality and safety educators.

For more information and to register, visit www.shmqsea.org.
 

EHRs: blessing or curse?

SHM’s Health Information Technology (HIT) Committee invited you to participate in a brief survey to inform your experiences with inpatient electronic health record (EHR) systems. The results will serve as a foundation for a white paper to be written by the HIT Committee addressing hospitalists’ attitudes toward EHR systems. It will be released next month, so stay tuned then to view the final paper.

SHM chapters: Your connection to local education, networking, leadership opportunities

SHM offers various opportunities to grow professionally, expand your CV, and engage with other hospitalists. With more than 50 chapters across the country, you can network, learn, teach, and continue to improve patient care at a local level. Find a chapter in your area or start a chapter today by visiting www.hospitalmedicine.org/chapters.

Enhance opioid safety for inpatients

SHM enrolled 10 hospitals into a second mentored implementation cohort around Reducing Adverse Drug Events Related to Opioids (RADEO). The program is now in its second month as the sites work with their mentors to enhance safety for patients in the hospital who are prescribed opioid medications by:

• Developing a needs assessment.
• Putting in place formal selections of data collection measures.
• Beginning to take outcomes and process data collection on intervention units.
• Starting to design and implement key interventions.

Even if you’re not in this mentored implementation cohort, visit www.hospitalmedicine.org/RADEO and view the online toolkit or download the implementation guide.
 

Earn recognition for your research with SHM’s Junior Investigator Award

The SHM Junior Investigator Award was created for junior/early-stage investigators, defined as faculty in the first 5 years of their most recent position/appointment. Applicants must be a hospitalist or clinician-investigators whose research interests focus on the care of hospitalized patients, the organization of hospitals, or the practice of hospitalists. Applicants must be members of SHM in good standing. Nominations from mentors and self-nominations are both welcome.

The winner will be invited to receive the award during SHM’s annual meeting, HM17, May 1-4, at Mandalay Bay Resort and Casino in Las Vegas. The winner will receive complimentary registration for this meeting as well as a complimentary 1-year membership to SHM.

For more information on the application process, visit www.hospitalmedicine.org/juniorinvestigator.
 

Unveiling the hospitalist specialty code

The Centers for Medicare & Medicaid Services announced in November the official implementation date for the Medicare physician specialty code for hospitalists. On April 3, “hospitalist” will be an official specialty designation under Medicare; the code will be C6. Starting on that date, hospitalists can change their specialty designation on the Medicare enrollment application (Form CMS-855I) or through CMS’ online portal (Provider Enrollment, Chain, and Ownership System, or PECOS).

Appropriate use of specialty codes helps distinguish differences among providers and improves the quality of utilization data. SHM applied for a specialty code for hospitalists nearly 3 years ago, and CMS approved the application in February 2016.

Stand with your fellow hospitalists and make sure to declare, “I’m a C6.”
 

Develop curricula to educate, engage medical students and residents

The ACGME requirements for training in quality and safety are changing – it is no longer an elective. As sponsoring institutions’ residency and fellowship programs mobilize to meet these requirements, leaders may find few faculty members are comfortable enough with the material to teach and create educational content for trainees. These faculty need further development.

Sponsored by SHM, the Quality and Safety Educators Academy (QSEA) responds to that demand by providing medical educators with the knowledge and tools to integrate quality improvement and safety concepts into their curricula. The 2017 meeting is Feb. 26-28 at the Tempe Mission Palms Hotel in Arizona.

This 2½ day meeting aims to fill the current gaps for faculty by offering basic concepts and educational tools in quality improvement and patient safety. Material is presented in an interactive way, providing guidance on career and curriculum development and establishing a national network of quality and safety educators.

For more information and to register, visit www.shmqsea.org.
 

EHRs: blessing or curse?

SHM’s Health Information Technology (HIT) Committee invited you to participate in a brief survey to inform your experiences with inpatient electronic health record (EHR) systems. The results will serve as a foundation for a white paper to be written by the HIT Committee addressing hospitalists’ attitudes toward EHR systems. It will be released next month, so stay tuned then to view the final paper.

SHM chapters: Your connection to local education, networking, leadership opportunities

SHM offers various opportunities to grow professionally, expand your CV, and engage with other hospitalists. With more than 50 chapters across the country, you can network, learn, teach, and continue to improve patient care at a local level. Find a chapter in your area or start a chapter today by visiting www.hospitalmedicine.org/chapters.

Enhance opioid safety for inpatients

SHM enrolled 10 hospitals into a second mentored implementation cohort around Reducing Adverse Drug Events Related to Opioids (RADEO). The program is now in its second month as the sites work with their mentors to enhance safety for patients in the hospital who are prescribed opioid medications by:

• Developing a needs assessment.
• Putting in place formal selections of data collection measures.
• Beginning to take outcomes and process data collection on intervention units.
• Starting to design and implement key interventions.

Even if you’re not in this mentored implementation cohort, visit www.hospitalmedicine.org/RADEO and view the online toolkit or download the implementation guide.
 

Earn recognition for your research with SHM’s Junior Investigator Award

The SHM Junior Investigator Award was created for junior/early-stage investigators, defined as faculty in the first 5 years of their most recent position/appointment. Applicants must be a hospitalist or clinician-investigators whose research interests focus on the care of hospitalized patients, the organization of hospitals, or the practice of hospitalists. Applicants must be members of SHM in good standing. Nominations from mentors and self-nominations are both welcome.

The winner will be invited to receive the award during SHM’s annual meeting, HM17, May 1-4, at Mandalay Bay Resort and Casino in Las Vegas. The winner will receive complimentary registration for this meeting as well as a complimentary 1-year membership to SHM.

For more information on the application process, visit www.hospitalmedicine.org/juniorinvestigator.
 

Unveiling the hospitalist specialty code

The Centers for Medicare & Medicaid Services announced in November the official implementation date for the Medicare physician specialty code for hospitalists. On April 3, “hospitalist” will be an official specialty designation under Medicare; the code will be C6. Starting on that date, hospitalists can change their specialty designation on the Medicare enrollment application (Form CMS-855I) or through CMS’ online portal (Provider Enrollment, Chain, and Ownership System, or PECOS).

Appropriate use of specialty codes helps distinguish differences among providers and improves the quality of utilization data. SHM applied for a specialty code for hospitalists nearly 3 years ago, and CMS approved the application in February 2016.

Stand with your fellow hospitalists and make sure to declare, “I’m a C6.”
 

Develop curricula to educate, engage medical students and residents

The ACGME requirements for training in quality and safety are changing – it is no longer an elective. As sponsoring institutions’ residency and fellowship programs mobilize to meet these requirements, leaders may find few faculty members are comfortable enough with the material to teach and create educational content for trainees. These faculty need further development.

Sponsored by SHM, the Quality and Safety Educators Academy (QSEA) responds to that demand by providing medical educators with the knowledge and tools to integrate quality improvement and safety concepts into their curricula. The 2017 meeting is Feb. 26-28 at the Tempe Mission Palms Hotel in Arizona.

This 2½ day meeting aims to fill the current gaps for faculty by offering basic concepts and educational tools in quality improvement and patient safety. Material is presented in an interactive way, providing guidance on career and curriculum development and establishing a national network of quality and safety educators.

For more information and to register, visit www.shmqsea.org.
 

EHRs: blessing or curse?

SHM’s Health Information Technology (HIT) Committee invited you to participate in a brief survey to inform your experiences with inpatient electronic health record (EHR) systems. The results will serve as a foundation for a white paper to be written by the HIT Committee addressing hospitalists’ attitudes toward EHR systems. It will be released next month, so stay tuned then to view the final paper.

SHM chapters: Your connection to local education, networking, leadership opportunities

SHM offers various opportunities to grow professionally, expand your CV, and engage with other hospitalists. With more than 50 chapters across the country, you can network, learn, teach, and continue to improve patient care at a local level. Find a chapter in your area or start a chapter today by visiting www.hospitalmedicine.org/chapters.

Enhance opioid safety for inpatients

SHM enrolled 10 hospitals into a second mentored implementation cohort around Reducing Adverse Drug Events Related to Opioids (RADEO). The program is now in its second month as the sites work with their mentors to enhance safety for patients in the hospital who are prescribed opioid medications by:

• Developing a needs assessment.
• Putting in place formal selections of data collection measures.
• Beginning to take outcomes and process data collection on intervention units.
• Starting to design and implement key interventions.

Even if you’re not in this mentored implementation cohort, visit www.hospitalmedicine.org/RADEO and view the online toolkit or download the implementation guide.
 

Earn recognition for your research with SHM’s Junior Investigator Award

The SHM Junior Investigator Award was created for junior/early-stage investigators, defined as faculty in the first 5 years of their most recent position/appointment. Applicants must be a hospitalist or clinician-investigators whose research interests focus on the care of hospitalized patients, the organization of hospitals, or the practice of hospitalists. Applicants must be members of SHM in good standing. Nominations from mentors and self-nominations are both welcome.

The winner will be invited to receive the award during SHM’s annual meeting, HM17, May 1-4, at Mandalay Bay Resort and Casino in Las Vegas. The winner will receive complimentary registration for this meeting as well as a complimentary 1-year membership to SHM.

For more information on the application process, visit www.hospitalmedicine.org/juniorinvestigator.
 

Here are 5 articles in the January issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Gluten-free Adherence Triples While Celiac Disease Prevalence Remains Stable

To take the posttest, go to: http://bit.ly/2h2LFDu
Expires September 6, 2017

2. Fluoxetine Appears Safer  for Bone Health in At-risk Older Patients

To take the posttest, go to: http://bit.ly/2he1FTD
Expires September 15, 2017

3. High Free T4 Levels Linked to Sudden Cardiac Death

To take the posttest, go to: http://bit.ly/2gMJqUz
Expires September 16, 2017

4. Morning Sickness Linked to Lower Risk for Pregnancy Loss

To take the posttest, go to: http://bit.ly/2uaWMkH
Expires September 26, 2017

5. Anxiety, Depression May Precede Parkinson's by 25 Years

To take the posttest, go to: http://bit.ly/2gMFQtr
Expires September 27, 2017

Here are 5 articles in the January issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Gluten-free Adherence Triples While Celiac Disease Prevalence Remains Stable

To take the posttest, go to: http://bit.ly/2h2LFDu
Expires September 6, 2017

2. Fluoxetine Appears Safer  for Bone Health in At-risk Older Patients

To take the posttest, go to: http://bit.ly/2he1FTD
Expires September 15, 2017

3. High Free T4 Levels Linked to Sudden Cardiac Death

To take the posttest, go to: http://bit.ly/2gMJqUz
Expires September 16, 2017

4. Morning Sickness Linked to Lower Risk for Pregnancy Loss

To take the posttest, go to: http://bit.ly/2uaWMkH
Expires September 26, 2017

5. Anxiety, Depression May Precede Parkinson's by 25 Years

To take the posttest, go to: http://bit.ly/2gMFQtr
Expires September 27, 2017

Here are 5 articles in the January issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Gluten-free Adherence Triples While Celiac Disease Prevalence Remains Stable

To take the posttest, go to: http://bit.ly/2h2LFDu
Expires September 6, 2017

2. Fluoxetine Appears Safer  for Bone Health in At-risk Older Patients

To take the posttest, go to: http://bit.ly/2he1FTD
Expires September 15, 2017

3. High Free T4 Levels Linked to Sudden Cardiac Death

To take the posttest, go to: http://bit.ly/2gMJqUz
Expires September 16, 2017

4. Morning Sickness Linked to Lower Risk for Pregnancy Loss

To take the posttest, go to: http://bit.ly/2uaWMkH
Expires September 26, 2017

5. Anxiety, Depression May Precede Parkinson's by 25 Years

To take the posttest, go to: http://bit.ly/2gMFQtr
Expires September 27, 2017

Did mother’s allergic reaction cause fetal injury?

When a mother was admitted to the labor and delivery unit, she had strep throat; ampicillin was administered. She experienced anaphylactic symptoms that were attended to. The baby, delivered vaginally 3 hours later, was severely distressed and showed signs of asphyxia. He was found to have a permanent brain injury.

PARENTS’ CLAIM:

The ObGyn and hospital nurses failed to properly manage the mother’s anaphylactic reaction to ampicillin. Fetal heart-rate tracings indicated fetal distress. Standard of care required prompt intervention with epinephrine and/or emergency cesarean delivery. Brain injury occurred because these procedures were not performed.

DEFENDANTS’ DEFENSE:

The nurses denied fault and explained that they appropriately and immediately responded to mild anaphylactic symptoms in the mother. They could not administer epinephrine because the ObGyn did not order it.

The ObGyn denied violating the standard of care that included minimizing the mother’s allergic reaction. Because the mother didn’t have a rash, it was not necessary to order epinephrine. The baby sustained an unknown injury earlier in the pregnancy that was unrelated to labor.

VERDICT:

A Tennessee defense verdict was returned.

Resident blamed for shoulder dystocia

A mother presented to a federally funded health center in labor. A first-year resident managed labor and delivery under the supervision of the attending physician. Shoulder dystocia was encountered and the baby suffered a permanent brachial plexus injury.

PARENTS’ CLAIM:

Negligence occurred when the resident used excessive force by pulling on the infant’s neck during delivery. The resident, who had just received his medical license, was poorly supervised by the attending physician.

DEFENDANTS’ DEFENSE:

Suit was brought against the resident, the attending physician, the federal government, and the hospital’s residency program. The resident denied using excessive force. As soon as delivery became complex, the attending physician completed the delivery. The baby’s injuries were unpredictable and unavoidable.

VERDICT:

A $290,000 settlement with the federal government was reached before trial. A Pennsylvania defense verdict was returned for the other parties.

Related Article:
Tackle the challenging shoulder dystocia emergency by practicing delivery of the posterior arm

What caused brachial plexus injury?

An experienced midwife delivered a baby who sustained a brachial plexus injury resulting in flail arm syndrome.

PARENTS’ CLAIM:

The midwife mismanaged the delivery causing permanent injury. The child has gained little improvement with surgery and physical therapy.

DEFENDANTS’ DEFENSE:

The injury was caused by the natural forces of labor. The midwife used appropriate techniques during the birth.

VERDICT:

A Washington defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Did mother’s allergic reaction cause fetal injury?

When a mother was admitted to the labor and delivery unit, she had strep throat; ampicillin was administered. She experienced anaphylactic symptoms that were attended to. The baby, delivered vaginally 3 hours later, was severely distressed and showed signs of asphyxia. He was found to have a permanent brain injury.

PARENTS’ CLAIM:

The ObGyn and hospital nurses failed to properly manage the mother’s anaphylactic reaction to ampicillin. Fetal heart-rate tracings indicated fetal distress. Standard of care required prompt intervention with epinephrine and/or emergency cesarean delivery. Brain injury occurred because these procedures were not performed.

DEFENDANTS’ DEFENSE:

The nurses denied fault and explained that they appropriately and immediately responded to mild anaphylactic symptoms in the mother. They could not administer epinephrine because the ObGyn did not order it.

The ObGyn denied violating the standard of care that included minimizing the mother’s allergic reaction. Because the mother didn’t have a rash, it was not necessary to order epinephrine. The baby sustained an unknown injury earlier in the pregnancy that was unrelated to labor.

VERDICT:

A Tennessee defense verdict was returned.

Resident blamed for shoulder dystocia

A mother presented to a federally funded health center in labor. A first-year resident managed labor and delivery under the supervision of the attending physician. Shoulder dystocia was encountered and the baby suffered a permanent brachial plexus injury.

PARENTS’ CLAIM:

Negligence occurred when the resident used excessive force by pulling on the infant’s neck during delivery. The resident, who had just received his medical license, was poorly supervised by the attending physician.

DEFENDANTS’ DEFENSE:

Suit was brought against the resident, the attending physician, the federal government, and the hospital’s residency program. The resident denied using excessive force. As soon as delivery became complex, the attending physician completed the delivery. The baby’s injuries were unpredictable and unavoidable.

VERDICT:

A $290,000 settlement with the federal government was reached before trial. A Pennsylvania defense verdict was returned for the other parties.

Related Article:
Tackle the challenging shoulder dystocia emergency by practicing delivery of the posterior arm

What caused brachial plexus injury?

An experienced midwife delivered a baby who sustained a brachial plexus injury resulting in flail arm syndrome.

PARENTS’ CLAIM:

The midwife mismanaged the delivery causing permanent injury. The child has gained little improvement with surgery and physical therapy.

DEFENDANTS’ DEFENSE:

The injury was caused by the natural forces of labor. The midwife used appropriate techniques during the birth.

VERDICT:

A Washington defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Did mother’s allergic reaction cause fetal injury?

When a mother was admitted to the labor and delivery unit, she had strep throat; ampicillin was administered. She experienced anaphylactic symptoms that were attended to. The baby, delivered vaginally 3 hours later, was severely distressed and showed signs of asphyxia. He was found to have a permanent brain injury.

PARENTS’ CLAIM:

The ObGyn and hospital nurses failed to properly manage the mother’s anaphylactic reaction to ampicillin. Fetal heart-rate tracings indicated fetal distress. Standard of care required prompt intervention with epinephrine and/or emergency cesarean delivery. Brain injury occurred because these procedures were not performed.

DEFENDANTS’ DEFENSE:

The nurses denied fault and explained that they appropriately and immediately responded to mild anaphylactic symptoms in the mother. They could not administer epinephrine because the ObGyn did not order it.

The ObGyn denied violating the standard of care that included minimizing the mother’s allergic reaction. Because the mother didn’t have a rash, it was not necessary to order epinephrine. The baby sustained an unknown injury earlier in the pregnancy that was unrelated to labor.

VERDICT:

A Tennessee defense verdict was returned.

Resident blamed for shoulder dystocia

A mother presented to a federally funded health center in labor. A first-year resident managed labor and delivery under the supervision of the attending physician. Shoulder dystocia was encountered and the baby suffered a permanent brachial plexus injury.

PARENTS’ CLAIM:

Negligence occurred when the resident used excessive force by pulling on the infant’s neck during delivery. The resident, who had just received his medical license, was poorly supervised by the attending physician.

DEFENDANTS’ DEFENSE:

Suit was brought against the resident, the attending physician, the federal government, and the hospital’s residency program. The resident denied using excessive force. As soon as delivery became complex, the attending physician completed the delivery. The baby’s injuries were unpredictable and unavoidable.

VERDICT:

A $290,000 settlement with the federal government was reached before trial. A Pennsylvania defense verdict was returned for the other parties.

Related Article:
Tackle the challenging shoulder dystocia emergency by practicing delivery of the posterior arm

What caused brachial plexus injury?

An experienced midwife delivered a baby who sustained a brachial plexus injury resulting in flail arm syndrome.

PARENTS’ CLAIM:

The midwife mismanaged the delivery causing permanent injury. The child has gained little improvement with surgery and physical therapy.

DEFENDANTS’ DEFENSE:

The injury was caused by the natural forces of labor. The midwife used appropriate techniques during the birth.

VERDICT:

A Washington defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Removal of wrong ovary?

Several years earlier, a patient had undergone a hysterectomy but retained her ovaries and fallopian tubes. She reported recurrent pelvic pain, especially on the left side, to a gynecologic surgeon. Ultrasonography (US) results showed a small follicular cyst on the right ovary and a simple cyst on the left ovary. The patient consented to diagnostic laparoscopy with possible left salpingo-oophorectomy. During the procedure, the surgeon removed the right fallopian tube and ovary. After recovery, the patient continued to have left-sided pelvic pain. When she saw another surgeon a year later, US results showed that the left ovary and tube were still intact. The patient underwent left salpingo-oophorectomy.

PATIENT’S CLAIM:

The surgeon removed the wrong ovary and tube, a breach of the standard of care, and didn’t adequately explain his surgical actions.

DEFENDANTS’ DEFENSE:

Standard of care was maintained. During surgery, the surgeon encountered severe adhesions on the patient’s left side and was unable to visualize her left ovary. He decided that what had appeared to be an ovary on US most likely was a fluid collection, and that the patient’s left ovary must have been removed at hysterectomy. The surgeon concluded that the hemorrhagic cyst on the right ovary and adhesions were causing the patient’s pain, and removed them. The patient had given him permission to perform laparoscopic surgery, but he did not have her consent to convert to laparotomy, which would have been necessary to confirm the absence of her left ovary.

VERDICT:

An Alabama defense verdict was returned.

Related Article:
Medical errors: Meeting ethical obligations and reducing liability with proper communication

Was wrong hysterectomy procedure chosen?

After being treated by her ObGyn for postmenopausal bleeding with medication and dilation and curettage, a 50-year-old woman underwent total abdominal hysterectomy (TAH). At an office visit 3 weeks postsurgery, she reported uncontrollable urination. The patient was admitted to a hospital, where cystogram results showed a vesico-vaginal fistula (VVF). She was treated with catheter drainage and referred to a urologist. The patient underwent 2 unsuccessful repair operations. A third repair, performed 10 months after the TAH, was successful.

PATIENT’S CLAIM:

The ObGyn should have performed laparoscopic supracervical hysterectomy (LSH) instead of TAH because the patient’s cervix would have remained intact and VVF would not have developed. Medical bills totaled $194,000.

PHYSICIAN’S DEFENSE:

The standard of care did not require LSH. Had the ObGyn left the cervix intact, the patient could have continued bleeding with increased risk of cervical cancer. A bladder injury is a known complication of hysterectomy.

VERDICT:

A Mississippi defense verdict was returned.

Woman dies after uterine fibroid removal

A 39-year-old woman with a history of hypertension, diabetes, moderate obesity, and end-stage renal disease underwent myomectomy. A first-year resident assisted the attending anesthesiologist during the procedure. While the patient was under general anesthesia, her blood pressure (BP) dropped rapidly and remained at an abnormally low level for 45 minutes. Then the patient’s heart rate dropped to around 30 bpm and remained at that level for 15 minutes before her BP and heart rate were finally restored. The patient never regained consciousness and remained in an irreversible coma until she died 6 days later.

ESTATE’S CLAIM:

The anesthesiologist and resident negligently allowed the patient’s BP and heart rate to fall to dangerously low levels. Because the patient had hypertension, diabetes, and obesity, she required a higher BP to maintain adequate cerebral perfusion. The physicians precipitated the patient’s hypotension by giving her an excessive dose of morphine and bupivacaine via epidural catheter prior to induction of general anesthesia, and then failed to give her sufficient doses of vasopressors to increase her BP to safe levels. They failed to properly treat the condition in a timely manner, causing brain damage, and ultimately, death.

DEFENDANTS’ DEFENSE:

The case was settled during mediation.

VERDICT:

A $900,000 Massachusetts settlement was reached.

Related Article:
Total abdominal hysterectomy the Mayo Clinic way

Ureter injured during hysterectomy

A 47-year-old woman’s right ureter was damaged during laparoscopic hysterectomy. During surgery, the gynecologist called in a urologist to repair the injury. The patient reported postsurgical complications including renal function impairment. A computed tomography scan showed a right ureter obstruction. When surgery confirmed complete obstruction of the ureter, she had a temporary nephrostomy drain placed. After 4 weeks, the patient returned to the operating room to have the right ureter implanted into the bladder. The patient reported occasional painful urination with increased urinary frequency and decreased right kidney size.

PATIENT’S CLAIM:

The gynecologist lacerated the ureter because he did not adequately identify and protect the ureter; this error represented a departure from the standard of care. The urologist failed to properly repair the injury. The patient sought recovery of $990,000 for past and future pain and suffering.

DEFENDANTS’ CLAIM:

The suit against the urologist and hospital was dropped, but continued against the gynecologist. The gynecologist claimed that the patient’s injury was a thermal burn, and is a known complication of the procedure.

VERDICT:

A $500,000 New York verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Removal of wrong ovary?

Several years earlier, a patient had undergone a hysterectomy but retained her ovaries and fallopian tubes. She reported recurrent pelvic pain, especially on the left side, to a gynecologic surgeon. Ultrasonography (US) results showed a small follicular cyst on the right ovary and a simple cyst on the left ovary. The patient consented to diagnostic laparoscopy with possible left salpingo-oophorectomy. During the procedure, the surgeon removed the right fallopian tube and ovary. After recovery, the patient continued to have left-sided pelvic pain. When she saw another surgeon a year later, US results showed that the left ovary and tube were still intact. The patient underwent left salpingo-oophorectomy.

PATIENT’S CLAIM:

The surgeon removed the wrong ovary and tube, a breach of the standard of care, and didn’t adequately explain his surgical actions.

DEFENDANTS’ DEFENSE:

Standard of care was maintained. During surgery, the surgeon encountered severe adhesions on the patient’s left side and was unable to visualize her left ovary. He decided that what had appeared to be an ovary on US most likely was a fluid collection, and that the patient’s left ovary must have been removed at hysterectomy. The surgeon concluded that the hemorrhagic cyst on the right ovary and adhesions were causing the patient’s pain, and removed them. The patient had given him permission to perform laparoscopic surgery, but he did not have her consent to convert to laparotomy, which would have been necessary to confirm the absence of her left ovary.

VERDICT:

An Alabama defense verdict was returned.

Related Article:
Medical errors: Meeting ethical obligations and reducing liability with proper communication

Was wrong hysterectomy procedure chosen?

After being treated by her ObGyn for postmenopausal bleeding with medication and dilation and curettage, a 50-year-old woman underwent total abdominal hysterectomy (TAH). At an office visit 3 weeks postsurgery, she reported uncontrollable urination. The patient was admitted to a hospital, where cystogram results showed a vesico-vaginal fistula (VVF). She was treated with catheter drainage and referred to a urologist. The patient underwent 2 unsuccessful repair operations. A third repair, performed 10 months after the TAH, was successful.

PATIENT’S CLAIM:

The ObGyn should have performed laparoscopic supracervical hysterectomy (LSH) instead of TAH because the patient’s cervix would have remained intact and VVF would not have developed. Medical bills totaled $194,000.

PHYSICIAN’S DEFENSE:

The standard of care did not require LSH. Had the ObGyn left the cervix intact, the patient could have continued bleeding with increased risk of cervical cancer. A bladder injury is a known complication of hysterectomy.

VERDICT:

A Mississippi defense verdict was returned.

Woman dies after uterine fibroid removal

A 39-year-old woman with a history of hypertension, diabetes, moderate obesity, and end-stage renal disease underwent myomectomy. A first-year resident assisted the attending anesthesiologist during the procedure. While the patient was under general anesthesia, her blood pressure (BP) dropped rapidly and remained at an abnormally low level for 45 minutes. Then the patient’s heart rate dropped to around 30 bpm and remained at that level for 15 minutes before her BP and heart rate were finally restored. The patient never regained consciousness and remained in an irreversible coma until she died 6 days later.

ESTATE’S CLAIM:

The anesthesiologist and resident negligently allowed the patient’s BP and heart rate to fall to dangerously low levels. Because the patient had hypertension, diabetes, and obesity, she required a higher BP to maintain adequate cerebral perfusion. The physicians precipitated the patient’s hypotension by giving her an excessive dose of morphine and bupivacaine via epidural catheter prior to induction of general anesthesia, and then failed to give her sufficient doses of vasopressors to increase her BP to safe levels. They failed to properly treat the condition in a timely manner, causing brain damage, and ultimately, death.

DEFENDANTS’ DEFENSE:

The case was settled during mediation.

VERDICT:

A $900,000 Massachusetts settlement was reached.

Related Article:
Total abdominal hysterectomy the Mayo Clinic way

Ureter injured during hysterectomy

A 47-year-old woman’s right ureter was damaged during laparoscopic hysterectomy. During surgery, the gynecologist called in a urologist to repair the injury. The patient reported postsurgical complications including renal function impairment. A computed tomography scan showed a right ureter obstruction. When surgery confirmed complete obstruction of the ureter, she had a temporary nephrostomy drain placed. After 4 weeks, the patient returned to the operating room to have the right ureter implanted into the bladder. The patient reported occasional painful urination with increased urinary frequency and decreased right kidney size.

PATIENT’S CLAIM:

The gynecologist lacerated the ureter because he did not adequately identify and protect the ureter; this error represented a departure from the standard of care. The urologist failed to properly repair the injury. The patient sought recovery of $990,000 for past and future pain and suffering.

DEFENDANTS’ CLAIM:

The suit against the urologist and hospital was dropped, but continued against the gynecologist. The gynecologist claimed that the patient’s injury was a thermal burn, and is a known complication of the procedure.

VERDICT:

A $500,000 New York verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Removal of wrong ovary?

Several years earlier, a patient had undergone a hysterectomy but retained her ovaries and fallopian tubes. She reported recurrent pelvic pain, especially on the left side, to a gynecologic surgeon. Ultrasonography (US) results showed a small follicular cyst on the right ovary and a simple cyst on the left ovary. The patient consented to diagnostic laparoscopy with possible left salpingo-oophorectomy. During the procedure, the surgeon removed the right fallopian tube and ovary. After recovery, the patient continued to have left-sided pelvic pain. When she saw another surgeon a year later, US results showed that the left ovary and tube were still intact. The patient underwent left salpingo-oophorectomy.

PATIENT’S CLAIM:

The surgeon removed the wrong ovary and tube, a breach of the standard of care, and didn’t adequately explain his surgical actions.

DEFENDANTS’ DEFENSE:

Standard of care was maintained. During surgery, the surgeon encountered severe adhesions on the patient’s left side and was unable to visualize her left ovary. He decided that what had appeared to be an ovary on US most likely was a fluid collection, and that the patient’s left ovary must have been removed at hysterectomy. The surgeon concluded that the hemorrhagic cyst on the right ovary and adhesions were causing the patient’s pain, and removed them. The patient had given him permission to perform laparoscopic surgery, but he did not have her consent to convert to laparotomy, which would have been necessary to confirm the absence of her left ovary.

VERDICT:

An Alabama defense verdict was returned.

Related Article:
Medical errors: Meeting ethical obligations and reducing liability with proper communication

Was wrong hysterectomy procedure chosen?

After being treated by her ObGyn for postmenopausal bleeding with medication and dilation and curettage, a 50-year-old woman underwent total abdominal hysterectomy (TAH). At an office visit 3 weeks postsurgery, she reported uncontrollable urination. The patient was admitted to a hospital, where cystogram results showed a vesico-vaginal fistula (VVF). She was treated with catheter drainage and referred to a urologist. The patient underwent 2 unsuccessful repair operations. A third repair, performed 10 months after the TAH, was successful.

PATIENT’S CLAIM:

The ObGyn should have performed laparoscopic supracervical hysterectomy (LSH) instead of TAH because the patient’s cervix would have remained intact and VVF would not have developed. Medical bills totaled $194,000.

PHYSICIAN’S DEFENSE:

The standard of care did not require LSH. Had the ObGyn left the cervix intact, the patient could have continued bleeding with increased risk of cervical cancer. A bladder injury is a known complication of hysterectomy.

VERDICT:

A Mississippi defense verdict was returned.

Woman dies after uterine fibroid removal

A 39-year-old woman with a history of hypertension, diabetes, moderate obesity, and end-stage renal disease underwent myomectomy. A first-year resident assisted the attending anesthesiologist during the procedure. While the patient was under general anesthesia, her blood pressure (BP) dropped rapidly and remained at an abnormally low level for 45 minutes. Then the patient’s heart rate dropped to around 30 bpm and remained at that level for 15 minutes before her BP and heart rate were finally restored. The patient never regained consciousness and remained in an irreversible coma until she died 6 days later.

ESTATE’S CLAIM:

The anesthesiologist and resident negligently allowed the patient’s BP and heart rate to fall to dangerously low levels. Because the patient had hypertension, diabetes, and obesity, she required a higher BP to maintain adequate cerebral perfusion. The physicians precipitated the patient’s hypotension by giving her an excessive dose of morphine and bupivacaine via epidural catheter prior to induction of general anesthesia, and then failed to give her sufficient doses of vasopressors to increase her BP to safe levels. They failed to properly treat the condition in a timely manner, causing brain damage, and ultimately, death.

DEFENDANTS’ DEFENSE:

The case was settled during mediation.

VERDICT:

A $900,000 Massachusetts settlement was reached.

Related Article:
Total abdominal hysterectomy the Mayo Clinic way

Ureter injured during hysterectomy

A 47-year-old woman’s right ureter was damaged during laparoscopic hysterectomy. During surgery, the gynecologist called in a urologist to repair the injury. The patient reported postsurgical complications including renal function impairment. A computed tomography scan showed a right ureter obstruction. When surgery confirmed complete obstruction of the ureter, she had a temporary nephrostomy drain placed. After 4 weeks, the patient returned to the operating room to have the right ureter implanted into the bladder. The patient reported occasional painful urination with increased urinary frequency and decreased right kidney size.

PATIENT’S CLAIM:

The gynecologist lacerated the ureter because he did not adequately identify and protect the ureter; this error represented a departure from the standard of care. The urologist failed to properly repair the injury. The patient sought recovery of $990,000 for past and future pain and suffering.

DEFENDANTS’ CLAIM:

The suit against the urologist and hospital was dropped, but continued against the gynecologist. The gynecologist claimed that the patient’s injury was a thermal burn, and is a known complication of the procedure.

VERDICT:

A $500,000 New York verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The article by Hagerty and Rich in this issue of the Cleveland Clinic Journal of Medicine¹ covers an important topic—whether elderly patients with atrial fibrillation should receive anticoagulant therapy for it, or whether the risk of bleeding with this therapy outweighs the benefit of preventing stroke.

See related article

BETTER RISK PREDICTORS ARE NEEDED

Prediction tools are available for estimating the risk of stroke in patients with atrial fibrillation without anticoagulation^2,3 and to estimate bleeding risk from anticoagulation^4–7 (Table 1). Both tools have limitations, but as Hagerty and Rich point out, the stroke risk scales are likely better than the bleeding risk scales.

For example, Fang et al⁸ note that the risk of intracranial hemorrhage increases significantly after age 85. The bleeding risk scales use lower age cutoffs than this, perhaps increasing their sensitivity but decreasing their specificity.

Although HAS-BLED^5,6 includes antiplatelet drugs such as nonsteroidal anti-inflammatory drugs and aspirin as risk factors for bleeding, ATRIA⁴ and HEMORR₂HAGES⁷ do not.

Other drugs such as macrolides, quinolones, and high-dose corticosteroids raise the international normalized ratio (INR). These are typically used short-term, but can cause major fluctuations in the INR that may not be detected by monthly INR checks. Incorporating the short-term use of such drugs into bleeding risk scales would be difficult if not impossible a priori. Yet clinicians should be aware that these drugs can affect bleeding risk.

As Hagerty and Rich note,¹ the bleeding risk scores were developed for warfarin, and their applicability to patients treated with novel oral anticoagulants is uncertain.

All three of the available bleeding risk scales consider prior bleeding as a risk factor, but the severity of the prior bleeding varies. Although it is understandable to include major bleeding as a risk factor since it carries an increased risk of death, minor bleeding can affect morbidity and quality of life. Only the ATRIA score⁴ considers both major and minor bleeding, while HEMORR₂HAGES⁷ does not specify bleeding severity, and HAS-BLED^5,6 considers only major bleeding. Clearly, there is a need to update these existing bleeding risk scores so that they can apply to novel oral anticoagulants and consider both major and minor bleeding.

As the authors note, for predicting the risk of stroke, the CHA₂DS₂-VASc score³ provides more precision than the CHADS₂ score² at the lower end of the benefit spectrum. Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum.

THE PATIENT’S PREFERENCES MATTER

The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not. It is the responsibility of clinicians who care for older adults to make sure that these two important considerations are included in any anticoagulation decision-making for this group of patients.

The article by Hagerty and Rich in this issue of the Cleveland Clinic Journal of Medicine¹ covers an important topic—whether elderly patients with atrial fibrillation should receive anticoagulant therapy for it, or whether the risk of bleeding with this therapy outweighs the benefit of preventing stroke.

See related article

BETTER RISK PREDICTORS ARE NEEDED

Prediction tools are available for estimating the risk of stroke in patients with atrial fibrillation without anticoagulation^2,3 and to estimate bleeding risk from anticoagulation^4–7 (Table 1). Both tools have limitations, but as Hagerty and Rich point out, the stroke risk scales are likely better than the bleeding risk scales.

For example, Fang et al⁸ note that the risk of intracranial hemorrhage increases significantly after age 85. The bleeding risk scales use lower age cutoffs than this, perhaps increasing their sensitivity but decreasing their specificity.

Although HAS-BLED^5,6 includes antiplatelet drugs such as nonsteroidal anti-inflammatory drugs and aspirin as risk factors for bleeding, ATRIA⁴ and HEMORR₂HAGES⁷ do not.

Other drugs such as macrolides, quinolones, and high-dose corticosteroids raise the international normalized ratio (INR). These are typically used short-term, but can cause major fluctuations in the INR that may not be detected by monthly INR checks. Incorporating the short-term use of such drugs into bleeding risk scales would be difficult if not impossible a priori. Yet clinicians should be aware that these drugs can affect bleeding risk.

As Hagerty and Rich note,¹ the bleeding risk scores were developed for warfarin, and their applicability to patients treated with novel oral anticoagulants is uncertain.

All three of the available bleeding risk scales consider prior bleeding as a risk factor, but the severity of the prior bleeding varies. Although it is understandable to include major bleeding as a risk factor since it carries an increased risk of death, minor bleeding can affect morbidity and quality of life. Only the ATRIA score⁴ considers both major and minor bleeding, while HEMORR₂HAGES⁷ does not specify bleeding severity, and HAS-BLED^5,6 considers only major bleeding. Clearly, there is a need to update these existing bleeding risk scores so that they can apply to novel oral anticoagulants and consider both major and minor bleeding.

As the authors note, for predicting the risk of stroke, the CHA₂DS₂-VASc score³ provides more precision than the CHADS₂ score² at the lower end of the benefit spectrum. Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum.

THE PATIENT’S PREFERENCES MATTER

The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not. It is the responsibility of clinicians who care for older adults to make sure that these two important considerations are included in any anticoagulation decision-making for this group of patients.

The article by Hagerty and Rich in this issue of the Cleveland Clinic Journal of Medicine¹ covers an important topic—whether elderly patients with atrial fibrillation should receive anticoagulant therapy for it, or whether the risk of bleeding with this therapy outweighs the benefit of preventing stroke.

See related article

BETTER RISK PREDICTORS ARE NEEDED

Prediction tools are available for estimating the risk of stroke in patients with atrial fibrillation without anticoagulation^2,3 and to estimate bleeding risk from anticoagulation^4–7 (Table 1). Both tools have limitations, but as Hagerty and Rich point out, the stroke risk scales are likely better than the bleeding risk scales.

For example, Fang et al⁸ note that the risk of intracranial hemorrhage increases significantly after age 85. The bleeding risk scales use lower age cutoffs than this, perhaps increasing their sensitivity but decreasing their specificity.

Although HAS-BLED^5,6 includes antiplatelet drugs such as nonsteroidal anti-inflammatory drugs and aspirin as risk factors for bleeding, ATRIA⁴ and HEMORR₂HAGES⁷ do not.

Other drugs such as macrolides, quinolones, and high-dose corticosteroids raise the international normalized ratio (INR). These are typically used short-term, but can cause major fluctuations in the INR that may not be detected by monthly INR checks. Incorporating the short-term use of such drugs into bleeding risk scales would be difficult if not impossible a priori. Yet clinicians should be aware that these drugs can affect bleeding risk.

As Hagerty and Rich note,¹ the bleeding risk scores were developed for warfarin, and their applicability to patients treated with novel oral anticoagulants is uncertain.

All three of the available bleeding risk scales consider prior bleeding as a risk factor, but the severity of the prior bleeding varies. Although it is understandable to include major bleeding as a risk factor since it carries an increased risk of death, minor bleeding can affect morbidity and quality of life. Only the ATRIA score⁴ considers both major and minor bleeding, while HEMORR₂HAGES⁷ does not specify bleeding severity, and HAS-BLED^5,6 considers only major bleeding. Clearly, there is a need to update these existing bleeding risk scores so that they can apply to novel oral anticoagulants and consider both major and minor bleeding.

As the authors note, for predicting the risk of stroke, the CHA₂DS₂-VASc score³ provides more precision than the CHADS₂ score² at the lower end of the benefit spectrum. Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum.

THE PATIENT’S PREFERENCES MATTER

The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not. It is the responsibility of clinicians who care for older adults to make sure that these two important considerations are included in any anticoagulation decision-making for this group of patients.

People who have been exposed to an infectious disease should be evaluated promptly and systematically, whether they are healthcare professionals at work,¹ patients, or contacts of patients. The primary goals are to prevent acquisition and transmission of the infection, allay the exposed person’s anxiety, and avoid unnecessary interventions and loss of work days.^1,2 Some may need postexposure prophylaxis.

ESSENTIAL ELEMENTS OF POSTEXPOSURE MANAGEMENT

Because postexposure management can be challenging, an experienced clinician or expert consultant (eg, infectious disease specialist, infection control provider, or public health officer) should be involved. Institution-specific policies and procedures for postexposure prophylaxis and testing should be followed.^1,2

Postexposure management should include the following elements:

• Immediate care of the wound or other site of exposure in cases of blood-borne exposures and tetanus- and rabies-prone injuries. This includes thoroughly washing with soap and water or cleansing with an antiseptic agent, flushing affected mucous membranes with water, and debridement of devitalized tissue.^1–6
• Deciding whether postexposure prophylaxis is indicated and, if so, the type, dose, route, and duration.
• Initiating prophylaxis as soon as possible.
• Determining an appropriate baseline assessment and follow-up plan for the exposed individual.
• Counseling exposed women who are pregnant or breast-feeding about the risks and benefits of postexposure prophylaxis to mother, fetus, and infant.
• Identifying required infection control precautions, including work and school restriction, for exposed and source individuals.
• Counseling and psychological support for exposed individuals, who need to know about the risks of acquiring the infection and transmitting it to others, infection control precautions, benefits, and adverse effects of postexposure prophylaxis, the importance of adhering to the regimen, and the follow-up plan. They must understand that this treatment may not completely prevent the infection, and they should seek medical attention if they develop fever or any symptoms or signs of the infection of concern.^1,2

IS POSTEXPOSURE PROPHYLAXIS INDICATED?

Postexposure management begins with an assessment to determine whether the exposure is likely to result in infection; whether the exposed individual is susceptible to the infection of concern or is at greater risk of complications from it than the general population; and whether postexposure prophylaxis is needed. This involves a complete focused history, physical examination, and laboratory testing of the potentially exposed individual and of the source, if possible.^1,2

Postexposure prophylaxis should begin as soon as possible to maximize its effects while awaiting the results of further diagnostic tests. However, if the exposed individual seeks care after the recommended period, prophylactic therapy can still be effective for certain infections that have a long incubation period, such as tetanus and rabies.^5,6 The choice of regimen should be guided by efficacy, safety, cost, toxicity, ease of adherence, drug interactions, and antimicrobial resistance.^1,2

HOW GREAT IS THE RISK OF INFECTION?

Exposed individuals are not all at the same risk of acquiring a given infection. The risk depends on:

• Type and extent of exposure (see below)
• Characteristics of the infectious agent (eg, virulence, infectious dose)
• Status of the infectious source (eg, whether the disease is in its infectious period or is being treated); effective treatment can shorten the duration of microbial shedding and subsequently reduce risk of transmission of certain infections such as tuberculosis, meningococcal infection, invasive group A streptococcal infection, and pertussis^7–10
• Immune status of the exposed individual (eg, prior infection or vaccination), since people who are immune to the infection of concern usually do not need postexposure prophylaxis²
• Adherence to infection prevention and control principles; postexposure prophylaxis may not be required if the potentially exposed individual was wearing appropriate personal protective equipment such as a surgical mask, gown, and gloves and was following standard precautions.¹

WHO SHOULD BE RESTRICTED FROM WORK OR SCHOOL?

Most people without symptoms who were exposed to most types of infections do not need to stay home from work or school. However, susceptible people, particularly healthcare providers exposed to measles, mumps, rubella, and varicella, should be excluded from work while they are capable of transmitting these diseases, even if they have no symptoms.^11,12 Moreover, people with symptoms with infections primarily transmitted via the airborne, droplet, or contact route should be restricted from work until no longer infectious.^1,2,7,9–15

Most healthcare institutions have clear protocols for managing occupational exposures to infectious diseases, in particular for blood-borne pathogens such as human immunodeficiency virus (HIV). The protocol should include appropriate evaluation and laboratory testing of the source patient and exposed healthcare provider, as well as procedures for counseling the exposed provider, identifying and procuring an initial prophylactic regimen for timely administration, a mechanism for formal expert consultation (eg, with an in-house infectious diseases consultant), and a plan for outpatient follow-up.

The next section reviews postexposure management of common infections categorized by mode of transmission, including the risk of transmission, initial and follow-up evaluation, and considerations for postexposure prophylaxis.

BLOOD-BORNE INFECTIONS

Blood-borne pathogens can be transmitted by accidental needlesticks or cuts or by exposure of the eyes, mucous membranes, or nonintact skin to blood, tissue, or other potentially infectious body fluids—cerebrospinal, pericardial, pleural, peritoneal, synovial, and amniotic fluid, semen, and vaginal secretions. (Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are considered noninfectious for blood-borne pathogens unless they contain blood.¹⁶)

Healthcare professionals are commonly exposed to blood-borne pathogens as a result of needlestick injuries, and these exposures tend to be underreported.¹⁷

When someone has been exposed to blood or other infectious body fluids, the source individual and the exposed individual should be assessed for risk factors for hepatitis B virus, hepatitis C virus, HIV, and other blood-borne pathogens.^3,4,16,18 If the disease status for these viruses is unknown, the source and exposed individual should be tested in accordance with institutional policies regarding consent to testing. Testing of needles or sharp instruments implicated in an exposure is not recommended.^3,4,16,18

Determining the need for prophylaxis after exposure to an unknown source such as a disposed needle can be challenging. Assessment should be made on a case-by-case basis, depending on the known prevalence of the infection of concern in the local community. The risk of transmission in most source-unknown exposures is negligible.^3,4,18 However, hepatitis B vaccine and hepatitis B immunoglobulin should be used liberally as postexposure prophylaxis for previously unvaccinated healthcare providers exposed to an unknown source.^3,4,16,18

Hepatitis B

Hepatitis B virus (Table 1) is the most infectious of the common blood-borne viruses. The risk of transmission after percutaneous exposure to hepatitis B-infected blood ranges from 1% to 30% based on hepatitis Be antigen status and viral load (based on hepatitis B viral DNA).^1,2,4,16

Hepatitis B vaccine or immunoglobulin, or both, are recommended for postexposure prophylaxis in pregnant women, based on evidence that perinatal transmission was reduced by 70% to 90% when these were given within 12 to 24 hours of exposure.^4,16,19

Hepatitis C

The risk of infection after percutaneous exposure to hepatitis C virus-infected blood is estimated to be 1.8% per exposure.¹⁶ The risk is lower with exposure of a mucous membrane or nonintact skin to blood, fluids, or tissues from hepatitis C-infected patients.^16,18

Since there is no effective postexposure prophylactic regimen, the goal of postexposure assessment of hepatitis C is early identification of infection (by monitoring the patient to see if he or she seroconverts) and, if infection is present, referral to an experienced clinician for further evaluation (Table 1). However, data supporting the utility of direct-acting anti-hepatitis C antiviral drugs as postexposure prophylaxis after occupational exposure to hepatitis C are lacking.

Human immunodeficiency virus

The estimated risk of HIV transmission from a known infected source after percutaneous exposure is 0.3%, and after mucosal exposures it is 0.09%.²⁰

If postexposure prophylaxis is indicated, it should be a three-drug regimen (Table 1).^3,18 The recommended antiretroviral therapies have been proven effective in clinical trials of HIV treatment, not for postexposure prophylaxis per se, but they are recommended because they are effective, safe, tolerable, and associated with high adherence rates.^3,16,18,21 If the source individual is known to have HIV infection, information about his or her stage of infection, CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic viral resistance testing will guide the choice of postexposure prophylactic regimen.^3,18

The clinician should give the exposed patient a starter pack of 5 to 7 days of medication, give the first dose then and there, and arrange follow-up with an experienced clinician within a few days of the exposure to determine whether a complete 30-day course is needed.^3,16,18

SEXUALLY TRANSMITTED INFECTIONS

In the case of sexually transmitted infections, “exposure” means unprotected sexual contact with someone who has a sexually transmitted infection.²² People with sexually transmitted infections often have no symptoms but can still transmit the infection. Thus, people at risk should be identified and screened for all suspected sexually transmitted infections.^23–25

Patients with sexually transmitted infections should be instructed to refer their sex partners for evaluation and treatment to prevent further transmission and reinfection. Assessment of exposed partners includes a medical history, physical examination, microbiologic testing for all potential sexually transmitted infections, and eligibility for hepatitis A virus, hepatitis B virus, and human papillomavirus vaccines.²² Ideally, exposed partners should be reassessed within 1 to 2 weeks to follow up testing results and to monitor for side effects of and adherence to postexposure prophylaxis, if applicable.

Public health departments should be notified of sexually transmitted infections such as gonorrhea, chlamydia, chancroid, and syphilis.²²

Expedited partner therapy, in which index patients deliver the medication or a prescription for it directly to their partners, is an alternative for partner management where legally allowed by state and local health departments (see www.cdc.gov/std/ept/legal/).²²

Recommended postexposure prophylactic regimens for sexually transmitted infections (Table 2) are based on their efficacy in the treatment of these infections.^22,26–28 The regimen for HIV prophylaxis is the same as in Table 1.^3,18,26

Chlamydia

Chlamydia is the most commonly reported communicable disease in the United States. The risk of transmission after sexual intercourse with a person who has an active infection is approximately 65% and increases with the number of exposures.^22,29

Gonorrhea

Infection with Neisseria gonorrhoeae is the second most commonly reported communicable disease in the United States. The transmission rate of gonorrhea after sex with someone who has it ranges from 50% to 93%.²² When prescribing postexposure prophylaxis for gonorrhea, it is essential to consider the risk of antimicrobial resistance and local susceptibility data.²²

Human immunodeficiency virus

Risk of HIV transmission through sexual contact varies depending on the nature of the exposure, ranging from 0.05% to 0.5%.³⁰

Syphilis

The risk of transmission of syphilis in its early stages (primary and secondary) after sexual exposure is approximately 30%. Transmission requires open lesions such as chancres in primary syphilis and mucocutaneous lesions (mucous patches, condyloma lata) in secondary syphilis.²²

After sexual assault

In cases of sexual assault, the risk of sexually transmitted infections may be increased due to trauma and bleeding. Testing for all sexually transmitted infections, including HIV, should be considered on a case-by-case basis.²²

Survivors of sexual assault have been shown to be poorly compliant with follow-up visits, and thus provision of postexposure prophylaxis at the time of initial assessment is preferable to deferred treatment.²² The recommended regimen should cover chlamydia, gonorrhea, and trichomoniasis (a single dose of intramuscular ceftriaxone 250 mg, oral azithromycin 1 g, and either oral metronidazole 2 g or tinidazole 2 g), in addition to HIV if the victim presents within 72 hours of exposure (Table 2).^22,26

Hepatitis B virus vaccine, not immunoglobulin, should be given if the hepatitis status of the assailant is unknown and the survivor has not been previously vaccinated. Both hepatitis B vaccine and immunoglobulin should be given to unvaccinated survivors if the assailant is known to be hepatitis B surface antigen-positive.²²

Human papillomavirus vaccination is recommended for female survivors ages 9 to 26 and male survivors ages 9 to 21.

Emergency contraception should be given if there is a risk of pregnancy.^22,26

In many jurisdictions, sexual assault centers provide trained examiners through Sexual Assault Nurse Examiners to perform evidence collection and to provide initial contact with the aftercare resources of the center. 

Advice on medical management of sexual assault can be obtained by calling National PEPline (888–448–4911).

INFECTIONS TRANSMITTED BY THE AIRBORNE ROUTE

Airborne transmission of infections occurs by inhalation of droplet nuclei (diameter ≤ 5 μm) generated by coughing and sneezing. Certain procedures (eg, administration of nebulized medication, sputum induction, bronchoscopy) also generate droplets and aerosols, which can transmit organisms.¹

Measles

Measles (Table 3) is highly contagious; up to 90% of susceptible individuals develop measles after exposure. The virus is transmitted by direct contact with infectious droplets and by the airborne route. It remains infectious in the air and on surfaces for up to 2 hours; therefore, any type of exposure, even transient, is an indication for postexposure prophylaxis in susceptible individuals.¹¹

Both the measles, mumps, rubella (MMR) vaccine and immune globulin may prevent or modify disease severity in susceptible exposed individuals if given within 3 days of exposure (for the vaccine) or within 6 days of exposure (for immune globulin).^31,32

Tuberculosis

Mycobacterium tuberculosis is transmitted from patients with pulmonary or laryngeal tuberculosis, particularly if patients cough and are sputum-positive for acid-fast bacilli. Patients with extrapulmonary tuberculosis or latent tuberculosis infection are not infectious.^1,7

Postexposure management of tuberculosis occurs through contact investigation of a newly diagnosed index case of tuberculosis disease. Contacts are categorized as household contacts, close nonhousehold contacts (those having regular, extensive contact with the index case), casual contacts, and transient community contacts. The highest priority for contact investigations should be household contacts, close nonhousehold or casual contacts at high risk of progressing to tuberculosis disease (eg, those with HIV, those on dialysis, or transplant recipients), and unprotected healthcare providers exposed during aerosol-generating procedures.^7,33

Postexposure management includes screening exposed individuals for tuberculosis symptoms and performing tuberculin skin testing or interferon-gamma release assay (blood testing) for those who had previously negative results (Table 3). Chest radiography is recommended for exposed immunocompromised individuals, due to high risk of tuberculosis disease and low sensitivity of skin or blood testing, and for those with a documented history of tuberculosis or previous positive skin or blood test.^7,33,34

A positive tuberculin skin test for persons with recent contact with tuberculosis is defined as a wheal 5 mm or larger on baseline or follow-up screening. Prior bacillus Calmette-Guérin vaccination status should not be used in the interpretation of tuberculin skin testing in the setting of contact investigation.^7,33

All exposed asymptomatic people with a positive result on testing should be treated for latent tuberculosis infection, since treatment reduces the risk of progression to tuberculosis disease by 60% to 90% .^7,33,35–37

Varicella and disseminated herpes zoster

Varicella zoster virus is transmitted by direct contact with vesicular fluid of skin lesions and inhalation of aerosols from vesicular fluid or respiratory tract secretions. Varicella (chickenpox) is highly contagious, with a secondary attack rate in susceptible household contacts of 85%.¹² Herpes zoster is less contagious than varicella.³⁸

Postexposure prophylaxis against varicella is recommended for susceptible individuals who had household exposure, had face-to-face contact with an infectious patient while indoors, or shared the same hospital room with the patient.¹²

Postexposure prophylactic options for varicella and herpes zoster include varicella vaccine (not zoster vaccine) and varicella zoster immune globulin (Table 3).^12,38–40

Varicella vaccine is approximately 90% effective if given within 3 days of exposure, and 70% effective if given within 5 days.^12,39

Antiviral agents should be given if the exposed individual develops manifestations of varicella or herpes zoster.^12,38

INFECTIONS TRANSMITTED BY THE DROPLET ROUTE

Droplet transmission occurs when respiratory droplets carrying infectious agents travel directly across short distances (3–6 feet) from the respiratory tract of the infected to mucosal surfaces of the susceptible exposed individual. Droplets are generated during coughing, sneezing, talking, and aerosol-generating procedures. Indirect contact with droplets can also transmit infection.¹

Group A streptococcal infection

Although group A streptococcal infection (Table 4) may spread to close contacts of the index case and in closed populations (eg, military recruit camps, schools, institutions), secondary cases of invasive group A streptococcal infection rarely occur in family and institutional contacts.^9,41,42

Postexposure prophylaxis for contacts of people with invasive group A streptococcal infection is debated, because it is unknown if antibiotic therapy will decrease the risk of acquiring the infection. It is generally agreed that it should not be routinely given to all contacts. The decision should be based on the clinician’s assessment of each individual’s risk and guidance from the local institution. If indicated, postexposure prophylaxis should be given to household and close contacts, particularly in high-risk groups (eg, Native Americans  and those with risk factors such as old age, HIV infection, diabetes mellitus, heart disease, chickenpox, cancer, systemic corticosteroid therapy, other immunosuppressive medications, intravenous drug use, recent surgery or childbirth).^9,41,42

Influenza

Influenza (Table 4) causes a significant burden in healthcare settings, given its prevalence and potential to cause outbreaks of severe respiratory illness in hospitalized patients and residents of long-term-care facilities.^13,43

Neuraminidase inhibitors are effective as prophylaxis after unprotected exposure to influenza, particularly in outbreak situations. However, their use is not widely recommended, since overuse could lead to antiviral resistance. In selected cases, postexposure prophylaxis may be indicated for close contacts who are at high risk of complications of influenza (eg, age 65 or older, in third trimester of pregnancy or 2 weeks postpartum, morbid obesity, chronic comorbid conditions such as a cardiopulmonary and renal disorder, immunocompromising condition) or who are in close contact with persons at high risk of influenza-related complications.^13,44,45

Meningococcal disease

N meningitidis is transmitted from individuals with meningococcal disease or from asymptomatic carriers.⁸

Postexposure prophylaxis is effective in eradicating N meningiditis and is recommended for all close contacts of patients with invasive meningococcal disease (Table 4).⁴⁶­ Close contacts include household contacts, childcare and preschool contacts, contacts exposed in dormitories or military training centers, those who had direct contact with the index case’s respiratory secretions (eg, intimate kissing, mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or endotracheal tube management), and passengers seated directly next to an index case on airplane flights of longer than 8 hours.

Postexposure prophylaxis is not indicated for those who had brief contact, those who had contact that did not involve exposure to oral or respiratory secretions, or for close contacts of patients with N meningitidis isolated in nonsterile sites only (eg, oropharynyx, trachea, conjunctiva).^8,46

Pertussis

Pertussis is highly contagious, with a secondary attack rate of approximately 80% in susceptible individuals. Approximately one-third of susceptible household contacts develop pertussis after exposure.¹⁰

Postexposure prophylaxis for pertussis should be given to all household and close contacts (Table 4).^10,47

Rubella

Transmission occurs through droplets or direct contact with nasopharyngeal secretions of an infectious case. Neither MMR vaccine nor immunoglobulin has been shown to prevent rubella in exposed contacts, and they are not recommended.¹¹

INFECTIONS TRANSMITTED BY DIRECT CONTACT

Direct contact transmission includes infectious agents transmitted from an infected or colonized individual to another, whereas indirect contact transmission involves a contaminated intermediate object or person (eg, hands of healthcare providers, electronic thermometers, surgical instruments).¹

There are no available postexposure prophylactic regimens for the organisms most commonly transmitted by this route (eg, methicillin-resistant Staphylococcus aureus, Clostridium difficile), but transmission can be prevented with adherence to standard precautions, including hand hygiene.¹

Hepatitis A

Person-to-person transmission of hepatitis A virus occurs via the fecal-oral route. Common-source outbreaks and sporadic cases can occur from exposure to food or water contaminated with feces.^1,15

Postexposure prophylaxis is indicated only for nonimmune close contacts (eg, household and sexual contacts) (Table 5). Without this treatment, secondary attack rates of 15% to 30% have been reported among households.^15,48 Both hepatitis A vaccine and immune globulin are effective in preventing and ameliorating symptomatic hepatitis A infection. Advantages of vaccination include induction of longer-lasting immunity (at least 2 years), greater ease of administration, and lower cost than immune globulin.^15,48

Scabies

Scabies is an infestation of the skin by the mite Sarcoptes scabiei var hominis. Person-to-person transmission typically occurs through direct, prolonged skin-to-skin contact with an infested person (eg, household and sexual contacts). However, crusted scabies can be transmitted after brief skin-to-skin contact or by exposure to bedding, clothing, or furniture used by the infested person.

All potentially infested persons should be treated concomitantly (Table 5).^14,49

INFECTIONS TRANSMITTED BY MAMMAL BITES AND INJURIES

Bites and injury wounds account for approximately 1% of all visits to emergency departments.⁵⁰ Human bites are associated with a risk of infection by blood-borne pathogens, herpes simplex infection, and bacterial infections (eg, skin and soft-tissue infections, bacteremia). Animal bites are associated with a risk of bacterial infections, rabies, tetanus, hepatitis B virus, and monkeypox.⁵⁰

Rabies

Human rabies (Table 5) is almost always fatal. Essential factors in determining the need for postexposure prophylaxis include knowledge of the epidemiology of animal rabies in the area where the contact occurred and the species of animal involved, availability of the animal for observation or rabies testing, health status of the biting animal, and vaccination history of both the animal and exposed individual.⁶ Clinicians should seek assistance from public health officials for evaluating exposures and determining the need for postexposure prophylaxis in situations that are not routine.⁵¹

High-risk wild animals associated with rabies in North America include bats, raccoons, skunks, foxes, coyotes, bobcats, and woodchucks. Bats are the most common source of human rabies infections in the United States, and transmission can occur from minor, sometimes unnoticed, bites. The types of exposures that require postexposure prophylaxis include bites, abrasions, scratches, and contamination of mucous membranes or open wound with saliva or neural tissue of a suspected rabid animal.

Human-to-human transmission of rabies can rarely occur through exposure of mucous membrane or nonintact skin to an infectious material (saliva, tears, neural tissue), in addition to organ transplantation.⁶

Animal capture and testing is a strategy for excluding rabies risk and reducing the need for postexposure prophylaxis. A dog, cat, or ferret that bites a person should be confined and observed for 10 days without administering postexposure prophylaxis for rabies, unless the bite or exposure is on the face or neck, in which case this treatment should be given immediately.⁶ If the observed biting animal lives and remains healthy, postexposure prophylaxis is not recommended. However, if signs suggestive of rabies develop, postexposure prophylaxis should be given and the animal should be euthanized, with testing of brain tissue for rabies virus. Postexposure prophylaxis should be discontinued if rabies testing is negative.

The combination of rabies vaccine and human rabies immunoglobulin is nearly 100% effective in preventing rabies if administered in a timely and accurate fashion after exposure (Table 5).⁶

Tetanus

Tetanus transmission can occur through injuries ranging from small cuts to severe trauma and through contact with contaminated objects (eg, bites, nails, needles, splinters, neonates whose umbilical cord is cut with contaminated surgical instruments, and during circumcision or piercing with contaminated instruments).⁵

Tetanus is almost completely preventable with vaccination, and timely administration of postexposure prophylaxis (tetanus toxoid-containing vaccine, tetanus immune globulin) decreases disease severity (Table 5).^2,5,52

People who have been exposed to an infectious disease should be evaluated promptly and systematically, whether they are healthcare professionals at work,¹ patients, or contacts of patients. The primary goals are to prevent acquisition and transmission of the infection, allay the exposed person’s anxiety, and avoid unnecessary interventions and loss of work days.^1,2 Some may need postexposure prophylaxis.

ESSENTIAL ELEMENTS OF POSTEXPOSURE MANAGEMENT

Because postexposure management can be challenging, an experienced clinician or expert consultant (eg, infectious disease specialist, infection control provider, or public health officer) should be involved. Institution-specific policies and procedures for postexposure prophylaxis and testing should be followed.^1,2

Postexposure management should include the following elements:

• Immediate care of the wound or other site of exposure in cases of blood-borne exposures and tetanus- and rabies-prone injuries. This includes thoroughly washing with soap and water or cleansing with an antiseptic agent, flushing affected mucous membranes with water, and debridement of devitalized tissue.^1–6
• Deciding whether postexposure prophylaxis is indicated and, if so, the type, dose, route, and duration.
• Initiating prophylaxis as soon as possible.
• Determining an appropriate baseline assessment and follow-up plan for the exposed individual.
• Counseling exposed women who are pregnant or breast-feeding about the risks and benefits of postexposure prophylaxis to mother, fetus, and infant.
• Identifying required infection control precautions, including work and school restriction, for exposed and source individuals.
• Counseling and psychological support for exposed individuals, who need to know about the risks of acquiring the infection and transmitting it to others, infection control precautions, benefits, and adverse effects of postexposure prophylaxis, the importance of adhering to the regimen, and the follow-up plan. They must understand that this treatment may not completely prevent the infection, and they should seek medical attention if they develop fever or any symptoms or signs of the infection of concern.^1,2

IS POSTEXPOSURE PROPHYLAXIS INDICATED?

Postexposure management begins with an assessment to determine whether the exposure is likely to result in infection; whether the exposed individual is susceptible to the infection of concern or is at greater risk of complications from it than the general population; and whether postexposure prophylaxis is needed. This involves a complete focused history, physical examination, and laboratory testing of the potentially exposed individual and of the source, if possible.^1,2

Postexposure prophylaxis should begin as soon as possible to maximize its effects while awaiting the results of further diagnostic tests. However, if the exposed individual seeks care after the recommended period, prophylactic therapy can still be effective for certain infections that have a long incubation period, such as tetanus and rabies.^5,6 The choice of regimen should be guided by efficacy, safety, cost, toxicity, ease of adherence, drug interactions, and antimicrobial resistance.^1,2

HOW GREAT IS THE RISK OF INFECTION?

Exposed individuals are not all at the same risk of acquiring a given infection. The risk depends on:

• Type and extent of exposure (see below)
• Characteristics of the infectious agent (eg, virulence, infectious dose)
• Status of the infectious source (eg, whether the disease is in its infectious period or is being treated); effective treatment can shorten the duration of microbial shedding and subsequently reduce risk of transmission of certain infections such as tuberculosis, meningococcal infection, invasive group A streptococcal infection, and pertussis^7–10
• Immune status of the exposed individual (eg, prior infection or vaccination), since people who are immune to the infection of concern usually do not need postexposure prophylaxis²
• Adherence to infection prevention and control principles; postexposure prophylaxis may not be required if the potentially exposed individual was wearing appropriate personal protective equipment such as a surgical mask, gown, and gloves and was following standard precautions.¹

WHO SHOULD BE RESTRICTED FROM WORK OR SCHOOL?

Most people without symptoms who were exposed to most types of infections do not need to stay home from work or school. However, susceptible people, particularly healthcare providers exposed to measles, mumps, rubella, and varicella, should be excluded from work while they are capable of transmitting these diseases, even if they have no symptoms.^11,12 Moreover, people with symptoms with infections primarily transmitted via the airborne, droplet, or contact route should be restricted from work until no longer infectious.^1,2,7,9–15

Most healthcare institutions have clear protocols for managing occupational exposures to infectious diseases, in particular for blood-borne pathogens such as human immunodeficiency virus (HIV). The protocol should include appropriate evaluation and laboratory testing of the source patient and exposed healthcare provider, as well as procedures for counseling the exposed provider, identifying and procuring an initial prophylactic regimen for timely administration, a mechanism for formal expert consultation (eg, with an in-house infectious diseases consultant), and a plan for outpatient follow-up.

The next section reviews postexposure management of common infections categorized by mode of transmission, including the risk of transmission, initial and follow-up evaluation, and considerations for postexposure prophylaxis.

BLOOD-BORNE INFECTIONS

Blood-borne pathogens can be transmitted by accidental needlesticks or cuts or by exposure of the eyes, mucous membranes, or nonintact skin to blood, tissue, or other potentially infectious body fluids—cerebrospinal, pericardial, pleural, peritoneal, synovial, and amniotic fluid, semen, and vaginal secretions. (Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are considered noninfectious for blood-borne pathogens unless they contain blood.¹⁶)

Healthcare professionals are commonly exposed to blood-borne pathogens as a result of needlestick injuries, and these exposures tend to be underreported.¹⁷

When someone has been exposed to blood or other infectious body fluids, the source individual and the exposed individual should be assessed for risk factors for hepatitis B virus, hepatitis C virus, HIV, and other blood-borne pathogens.^3,4,16,18 If the disease status for these viruses is unknown, the source and exposed individual should be tested in accordance with institutional policies regarding consent to testing. Testing of needles or sharp instruments implicated in an exposure is not recommended.^3,4,16,18

Determining the need for prophylaxis after exposure to an unknown source such as a disposed needle can be challenging. Assessment should be made on a case-by-case basis, depending on the known prevalence of the infection of concern in the local community. The risk of transmission in most source-unknown exposures is negligible.^3,4,18 However, hepatitis B vaccine and hepatitis B immunoglobulin should be used liberally as postexposure prophylaxis for previously unvaccinated healthcare providers exposed to an unknown source.^3,4,16,18

Hepatitis B

Hepatitis B virus (Table 1) is the most infectious of the common blood-borne viruses. The risk of transmission after percutaneous exposure to hepatitis B-infected blood ranges from 1% to 30% based on hepatitis Be antigen status and viral load (based on hepatitis B viral DNA).^1,2,4,16

Hepatitis B vaccine or immunoglobulin, or both, are recommended for postexposure prophylaxis in pregnant women, based on evidence that perinatal transmission was reduced by 70% to 90% when these were given within 12 to 24 hours of exposure.^4,16,19

Hepatitis C

The risk of infection after percutaneous exposure to hepatitis C virus-infected blood is estimated to be 1.8% per exposure.¹⁶ The risk is lower with exposure of a mucous membrane or nonintact skin to blood, fluids, or tissues from hepatitis C-infected patients.^16,18

Since there is no effective postexposure prophylactic regimen, the goal of postexposure assessment of hepatitis C is early identification of infection (by monitoring the patient to see if he or she seroconverts) and, if infection is present, referral to an experienced clinician for further evaluation (Table 1). However, data supporting the utility of direct-acting anti-hepatitis C antiviral drugs as postexposure prophylaxis after occupational exposure to hepatitis C are lacking.

Human immunodeficiency virus

The estimated risk of HIV transmission from a known infected source after percutaneous exposure is 0.3%, and after mucosal exposures it is 0.09%.²⁰

If postexposure prophylaxis is indicated, it should be a three-drug regimen (Table 1).^3,18 The recommended antiretroviral therapies have been proven effective in clinical trials of HIV treatment, not for postexposure prophylaxis per se, but they are recommended because they are effective, safe, tolerable, and associated with high adherence rates.^3,16,18,21 If the source individual is known to have HIV infection, information about his or her stage of infection, CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic viral resistance testing will guide the choice of postexposure prophylactic regimen.^3,18

The clinician should give the exposed patient a starter pack of 5 to 7 days of medication, give the first dose then and there, and arrange follow-up with an experienced clinician within a few days of the exposure to determine whether a complete 30-day course is needed.^3,16,18

SEXUALLY TRANSMITTED INFECTIONS

In the case of sexually transmitted infections, “exposure” means unprotected sexual contact with someone who has a sexually transmitted infection.²² People with sexually transmitted infections often have no symptoms but can still transmit the infection. Thus, people at risk should be identified and screened for all suspected sexually transmitted infections.^23–25

Patients with sexually transmitted infections should be instructed to refer their sex partners for evaluation and treatment to prevent further transmission and reinfection. Assessment of exposed partners includes a medical history, physical examination, microbiologic testing for all potential sexually transmitted infections, and eligibility for hepatitis A virus, hepatitis B virus, and human papillomavirus vaccines.²² Ideally, exposed partners should be reassessed within 1 to 2 weeks to follow up testing results and to monitor for side effects of and adherence to postexposure prophylaxis, if applicable.

Public health departments should be notified of sexually transmitted infections such as gonorrhea, chlamydia, chancroid, and syphilis.²²

Expedited partner therapy, in which index patients deliver the medication or a prescription for it directly to their partners, is an alternative for partner management where legally allowed by state and local health departments (see www.cdc.gov/std/ept/legal/).²²

Recommended postexposure prophylactic regimens for sexually transmitted infections (Table 2) are based on their efficacy in the treatment of these infections.^22,26–28 The regimen for HIV prophylaxis is the same as in Table 1.^3,18,26

Chlamydia

Chlamydia is the most commonly reported communicable disease in the United States. The risk of transmission after sexual intercourse with a person who has an active infection is approximately 65% and increases with the number of exposures.^22,29

Gonorrhea

Infection with Neisseria gonorrhoeae is the second most commonly reported communicable disease in the United States. The transmission rate of gonorrhea after sex with someone who has it ranges from 50% to 93%.²² When prescribing postexposure prophylaxis for gonorrhea, it is essential to consider the risk of antimicrobial resistance and local susceptibility data.²²

Human immunodeficiency virus

Risk of HIV transmission through sexual contact varies depending on the nature of the exposure, ranging from 0.05% to 0.5%.³⁰

Syphilis

The risk of transmission of syphilis in its early stages (primary and secondary) after sexual exposure is approximately 30%. Transmission requires open lesions such as chancres in primary syphilis and mucocutaneous lesions (mucous patches, condyloma lata) in secondary syphilis.²²

After sexual assault

In cases of sexual assault, the risk of sexually transmitted infections may be increased due to trauma and bleeding. Testing for all sexually transmitted infections, including HIV, should be considered on a case-by-case basis.²²

Survivors of sexual assault have been shown to be poorly compliant with follow-up visits, and thus provision of postexposure prophylaxis at the time of initial assessment is preferable to deferred treatment.²² The recommended regimen should cover chlamydia, gonorrhea, and trichomoniasis (a single dose of intramuscular ceftriaxone 250 mg, oral azithromycin 1 g, and either oral metronidazole 2 g or tinidazole 2 g), in addition to HIV if the victim presents within 72 hours of exposure (Table 2).^22,26

Hepatitis B virus vaccine, not immunoglobulin, should be given if the hepatitis status of the assailant is unknown and the survivor has not been previously vaccinated. Both hepatitis B vaccine and immunoglobulin should be given to unvaccinated survivors if the assailant is known to be hepatitis B surface antigen-positive.²²

Human papillomavirus vaccination is recommended for female survivors ages 9 to 26 and male survivors ages 9 to 21.

Emergency contraception should be given if there is a risk of pregnancy.^22,26

In many jurisdictions, sexual assault centers provide trained examiners through Sexual Assault Nurse Examiners to perform evidence collection and to provide initial contact with the aftercare resources of the center. 

Advice on medical management of sexual assault can be obtained by calling National PEPline (888–448–4911).

INFECTIONS TRANSMITTED BY THE AIRBORNE ROUTE

Airborne transmission of infections occurs by inhalation of droplet nuclei (diameter ≤ 5 μm) generated by coughing and sneezing. Certain procedures (eg, administration of nebulized medication, sputum induction, bronchoscopy) also generate droplets and aerosols, which can transmit organisms.¹

Measles

Measles (Table 3) is highly contagious; up to 90% of susceptible individuals develop measles after exposure. The virus is transmitted by direct contact with infectious droplets and by the airborne route. It remains infectious in the air and on surfaces for up to 2 hours; therefore, any type of exposure, even transient, is an indication for postexposure prophylaxis in susceptible individuals.¹¹

Both the measles, mumps, rubella (MMR) vaccine and immune globulin may prevent or modify disease severity in susceptible exposed individuals if given within 3 days of exposure (for the vaccine) or within 6 days of exposure (for immune globulin).^31,32

Tuberculosis

Mycobacterium tuberculosis is transmitted from patients with pulmonary or laryngeal tuberculosis, particularly if patients cough and are sputum-positive for acid-fast bacilli. Patients with extrapulmonary tuberculosis or latent tuberculosis infection are not infectious.^1,7

Postexposure management of tuberculosis occurs through contact investigation of a newly diagnosed index case of tuberculosis disease. Contacts are categorized as household contacts, close nonhousehold contacts (those having regular, extensive contact with the index case), casual contacts, and transient community contacts. The highest priority for contact investigations should be household contacts, close nonhousehold or casual contacts at high risk of progressing to tuberculosis disease (eg, those with HIV, those on dialysis, or transplant recipients), and unprotected healthcare providers exposed during aerosol-generating procedures.^7,33

Postexposure management includes screening exposed individuals for tuberculosis symptoms and performing tuberculin skin testing or interferon-gamma release assay (blood testing) for those who had previously negative results (Table 3). Chest radiography is recommended for exposed immunocompromised individuals, due to high risk of tuberculosis disease and low sensitivity of skin or blood testing, and for those with a documented history of tuberculosis or previous positive skin or blood test.^7,33,34

A positive tuberculin skin test for persons with recent contact with tuberculosis is defined as a wheal 5 mm or larger on baseline or follow-up screening. Prior bacillus Calmette-Guérin vaccination status should not be used in the interpretation of tuberculin skin testing in the setting of contact investigation.^7,33

All exposed asymptomatic people with a positive result on testing should be treated for latent tuberculosis infection, since treatment reduces the risk of progression to tuberculosis disease by 60% to 90% .^7,33,35–37

Varicella and disseminated herpes zoster

Varicella zoster virus is transmitted by direct contact with vesicular fluid of skin lesions and inhalation of aerosols from vesicular fluid or respiratory tract secretions. Varicella (chickenpox) is highly contagious, with a secondary attack rate in susceptible household contacts of 85%.¹² Herpes zoster is less contagious than varicella.³⁸

Postexposure prophylaxis against varicella is recommended for susceptible individuals who had household exposure, had face-to-face contact with an infectious patient while indoors, or shared the same hospital room with the patient.¹²

Postexposure prophylactic options for varicella and herpes zoster include varicella vaccine (not zoster vaccine) and varicella zoster immune globulin (Table 3).^12,38–40

Varicella vaccine is approximately 90% effective if given within 3 days of exposure, and 70% effective if given within 5 days.^12,39

Antiviral agents should be given if the exposed individual develops manifestations of varicella or herpes zoster.^12,38

INFECTIONS TRANSMITTED BY THE DROPLET ROUTE

Droplet transmission occurs when respiratory droplets carrying infectious agents travel directly across short distances (3–6 feet) from the respiratory tract of the infected to mucosal surfaces of the susceptible exposed individual. Droplets are generated during coughing, sneezing, talking, and aerosol-generating procedures. Indirect contact with droplets can also transmit infection.¹

Group A streptococcal infection

Although group A streptococcal infection (Table 4) may spread to close contacts of the index case and in closed populations (eg, military recruit camps, schools, institutions), secondary cases of invasive group A streptococcal infection rarely occur in family and institutional contacts.^9,41,42

Postexposure prophylaxis for contacts of people with invasive group A streptococcal infection is debated, because it is unknown if antibiotic therapy will decrease the risk of acquiring the infection. It is generally agreed that it should not be routinely given to all contacts. The decision should be based on the clinician’s assessment of each individual’s risk and guidance from the local institution. If indicated, postexposure prophylaxis should be given to household and close contacts, particularly in high-risk groups (eg, Native Americans  and those with risk factors such as old age, HIV infection, diabetes mellitus, heart disease, chickenpox, cancer, systemic corticosteroid therapy, other immunosuppressive medications, intravenous drug use, recent surgery or childbirth).^9,41,42

Influenza

Influenza (Table 4) causes a significant burden in healthcare settings, given its prevalence and potential to cause outbreaks of severe respiratory illness in hospitalized patients and residents of long-term-care facilities.^13,43

Neuraminidase inhibitors are effective as prophylaxis after unprotected exposure to influenza, particularly in outbreak situations. However, their use is not widely recommended, since overuse could lead to antiviral resistance. In selected cases, postexposure prophylaxis may be indicated for close contacts who are at high risk of complications of influenza (eg, age 65 or older, in third trimester of pregnancy or 2 weeks postpartum, morbid obesity, chronic comorbid conditions such as a cardiopulmonary and renal disorder, immunocompromising condition) or who are in close contact with persons at high risk of influenza-related complications.^13,44,45

Meningococcal disease

N meningitidis is transmitted from individuals with meningococcal disease or from asymptomatic carriers.⁸

Postexposure prophylaxis is effective in eradicating N meningiditis and is recommended for all close contacts of patients with invasive meningococcal disease (Table 4).⁴⁶­ Close contacts include household contacts, childcare and preschool contacts, contacts exposed in dormitories or military training centers, those who had direct contact with the index case’s respiratory secretions (eg, intimate kissing, mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or endotracheal tube management), and passengers seated directly next to an index case on airplane flights of longer than 8 hours.

Postexposure prophylaxis is not indicated for those who had brief contact, those who had contact that did not involve exposure to oral or respiratory secretions, or for close contacts of patients with N meningitidis isolated in nonsterile sites only (eg, oropharynyx, trachea, conjunctiva).^8,46

Pertussis

Pertussis is highly contagious, with a secondary attack rate of approximately 80% in susceptible individuals. Approximately one-third of susceptible household contacts develop pertussis after exposure.¹⁰

Postexposure prophylaxis for pertussis should be given to all household and close contacts (Table 4).^10,47

Rubella

Transmission occurs through droplets or direct contact with nasopharyngeal secretions of an infectious case. Neither MMR vaccine nor immunoglobulin has been shown to prevent rubella in exposed contacts, and they are not recommended.¹¹

INFECTIONS TRANSMITTED BY DIRECT CONTACT

Direct contact transmission includes infectious agents transmitted from an infected or colonized individual to another, whereas indirect contact transmission involves a contaminated intermediate object or person (eg, hands of healthcare providers, electronic thermometers, surgical instruments).¹

There are no available postexposure prophylactic regimens for the organisms most commonly transmitted by this route (eg, methicillin-resistant Staphylococcus aureus, Clostridium difficile), but transmission can be prevented with adherence to standard precautions, including hand hygiene.¹

Hepatitis A

Person-to-person transmission of hepatitis A virus occurs via the fecal-oral route. Common-source outbreaks and sporadic cases can occur from exposure to food or water contaminated with feces.^1,15

Postexposure prophylaxis is indicated only for nonimmune close contacts (eg, household and sexual contacts) (Table 5). Without this treatment, secondary attack rates of 15% to 30% have been reported among households.^15,48 Both hepatitis A vaccine and immune globulin are effective in preventing and ameliorating symptomatic hepatitis A infection. Advantages of vaccination include induction of longer-lasting immunity (at least 2 years), greater ease of administration, and lower cost than immune globulin.^15,48

Scabies

Scabies is an infestation of the skin by the mite Sarcoptes scabiei var hominis. Person-to-person transmission typically occurs through direct, prolonged skin-to-skin contact with an infested person (eg, household and sexual contacts). However, crusted scabies can be transmitted after brief skin-to-skin contact or by exposure to bedding, clothing, or furniture used by the infested person.

All potentially infested persons should be treated concomitantly (Table 5).^14,49

INFECTIONS TRANSMITTED BY MAMMAL BITES AND INJURIES

Bites and injury wounds account for approximately 1% of all visits to emergency departments.⁵⁰ Human bites are associated with a risk of infection by blood-borne pathogens, herpes simplex infection, and bacterial infections (eg, skin and soft-tissue infections, bacteremia). Animal bites are associated with a risk of bacterial infections, rabies, tetanus, hepatitis B virus, and monkeypox.⁵⁰

Rabies

Human rabies (Table 5) is almost always fatal. Essential factors in determining the need for postexposure prophylaxis include knowledge of the epidemiology of animal rabies in the area where the contact occurred and the species of animal involved, availability of the animal for observation or rabies testing, health status of the biting animal, and vaccination history of both the animal and exposed individual.⁶ Clinicians should seek assistance from public health officials for evaluating exposures and determining the need for postexposure prophylaxis in situations that are not routine.⁵¹

High-risk wild animals associated with rabies in North America include bats, raccoons, skunks, foxes, coyotes, bobcats, and woodchucks. Bats are the most common source of human rabies infections in the United States, and transmission can occur from minor, sometimes unnoticed, bites. The types of exposures that require postexposure prophylaxis include bites, abrasions, scratches, and contamination of mucous membranes or open wound with saliva or neural tissue of a suspected rabid animal.

Human-to-human transmission of rabies can rarely occur through exposure of mucous membrane or nonintact skin to an infectious material (saliva, tears, neural tissue), in addition to organ transplantation.⁶

Animal capture and testing is a strategy for excluding rabies risk and reducing the need for postexposure prophylaxis. A dog, cat, or ferret that bites a person should be confined and observed for 10 days without administering postexposure prophylaxis for rabies, unless the bite or exposure is on the face or neck, in which case this treatment should be given immediately.⁶ If the observed biting animal lives and remains healthy, postexposure prophylaxis is not recommended. However, if signs suggestive of rabies develop, postexposure prophylaxis should be given and the animal should be euthanized, with testing of brain tissue for rabies virus. Postexposure prophylaxis should be discontinued if rabies testing is negative.

The combination of rabies vaccine and human rabies immunoglobulin is nearly 100% effective in preventing rabies if administered in a timely and accurate fashion after exposure (Table 5).⁶

Tetanus

Tetanus transmission can occur through injuries ranging from small cuts to severe trauma and through contact with contaminated objects (eg, bites, nails, needles, splinters, neonates whose umbilical cord is cut with contaminated surgical instruments, and during circumcision or piercing with contaminated instruments).⁵

Tetanus is almost completely preventable with vaccination, and timely administration of postexposure prophylaxis (tetanus toxoid-containing vaccine, tetanus immune globulin) decreases disease severity (Table 5).^2,5,52

People who have been exposed to an infectious disease should be evaluated promptly and systematically, whether they are healthcare professionals at work,¹ patients, or contacts of patients. The primary goals are to prevent acquisition and transmission of the infection, allay the exposed person’s anxiety, and avoid unnecessary interventions and loss of work days.^1,2 Some may need postexposure prophylaxis.

ESSENTIAL ELEMENTS OF POSTEXPOSURE MANAGEMENT

Because postexposure management can be challenging, an experienced clinician or expert consultant (eg, infectious disease specialist, infection control provider, or public health officer) should be involved. Institution-specific policies and procedures for postexposure prophylaxis and testing should be followed.^1,2

Postexposure management should include the following elements:

• Immediate care of the wound or other site of exposure in cases of blood-borne exposures and tetanus- and rabies-prone injuries. This includes thoroughly washing with soap and water or cleansing with an antiseptic agent, flushing affected mucous membranes with water, and debridement of devitalized tissue.^1–6
• Deciding whether postexposure prophylaxis is indicated and, if so, the type, dose, route, and duration.
• Initiating prophylaxis as soon as possible.
• Determining an appropriate baseline assessment and follow-up plan for the exposed individual.
• Counseling exposed women who are pregnant or breast-feeding about the risks and benefits of postexposure prophylaxis to mother, fetus, and infant.
• Identifying required infection control precautions, including work and school restriction, for exposed and source individuals.
• Counseling and psychological support for exposed individuals, who need to know about the risks of acquiring the infection and transmitting it to others, infection control precautions, benefits, and adverse effects of postexposure prophylaxis, the importance of adhering to the regimen, and the follow-up plan. They must understand that this treatment may not completely prevent the infection, and they should seek medical attention if they develop fever or any symptoms or signs of the infection of concern.^1,2

IS POSTEXPOSURE PROPHYLAXIS INDICATED?

Postexposure management begins with an assessment to determine whether the exposure is likely to result in infection; whether the exposed individual is susceptible to the infection of concern or is at greater risk of complications from it than the general population; and whether postexposure prophylaxis is needed. This involves a complete focused history, physical examination, and laboratory testing of the potentially exposed individual and of the source, if possible.^1,2

Postexposure prophylaxis should begin as soon as possible to maximize its effects while awaiting the results of further diagnostic tests. However, if the exposed individual seeks care after the recommended period, prophylactic therapy can still be effective for certain infections that have a long incubation period, such as tetanus and rabies.^5,6 The choice of regimen should be guided by efficacy, safety, cost, toxicity, ease of adherence, drug interactions, and antimicrobial resistance.^1,2

HOW GREAT IS THE RISK OF INFECTION?

Exposed individuals are not all at the same risk of acquiring a given infection. The risk depends on:

• Type and extent of exposure (see below)
• Characteristics of the infectious agent (eg, virulence, infectious dose)
• Status of the infectious source (eg, whether the disease is in its infectious period or is being treated); effective treatment can shorten the duration of microbial shedding and subsequently reduce risk of transmission of certain infections such as tuberculosis, meningococcal infection, invasive group A streptococcal infection, and pertussis^7–10
• Immune status of the exposed individual (eg, prior infection or vaccination), since people who are immune to the infection of concern usually do not need postexposure prophylaxis²
• Adherence to infection prevention and control principles; postexposure prophylaxis may not be required if the potentially exposed individual was wearing appropriate personal protective equipment such as a surgical mask, gown, and gloves and was following standard precautions.¹

WHO SHOULD BE RESTRICTED FROM WORK OR SCHOOL?

Most people without symptoms who were exposed to most types of infections do not need to stay home from work or school. However, susceptible people, particularly healthcare providers exposed to measles, mumps, rubella, and varicella, should be excluded from work while they are capable of transmitting these diseases, even if they have no symptoms.^11,12 Moreover, people with symptoms with infections primarily transmitted via the airborne, droplet, or contact route should be restricted from work until no longer infectious.^1,2,7,9–15

Most healthcare institutions have clear protocols for managing occupational exposures to infectious diseases, in particular for blood-borne pathogens such as human immunodeficiency virus (HIV). The protocol should include appropriate evaluation and laboratory testing of the source patient and exposed healthcare provider, as well as procedures for counseling the exposed provider, identifying and procuring an initial prophylactic regimen for timely administration, a mechanism for formal expert consultation (eg, with an in-house infectious diseases consultant), and a plan for outpatient follow-up.

The next section reviews postexposure management of common infections categorized by mode of transmission, including the risk of transmission, initial and follow-up evaluation, and considerations for postexposure prophylaxis.

BLOOD-BORNE INFECTIONS

Blood-borne pathogens can be transmitted by accidental needlesticks or cuts or by exposure of the eyes, mucous membranes, or nonintact skin to blood, tissue, or other potentially infectious body fluids—cerebrospinal, pericardial, pleural, peritoneal, synovial, and amniotic fluid, semen, and vaginal secretions. (Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are considered noninfectious for blood-borne pathogens unless they contain blood.¹⁶)

Healthcare professionals are commonly exposed to blood-borne pathogens as a result of needlestick injuries, and these exposures tend to be underreported.¹⁷

When someone has been exposed to blood or other infectious body fluids, the source individual and the exposed individual should be assessed for risk factors for hepatitis B virus, hepatitis C virus, HIV, and other blood-borne pathogens.^3,4,16,18 If the disease status for these viruses is unknown, the source and exposed individual should be tested in accordance with institutional policies regarding consent to testing. Testing of needles or sharp instruments implicated in an exposure is not recommended.^3,4,16,18

Determining the need for prophylaxis after exposure to an unknown source such as a disposed needle can be challenging. Assessment should be made on a case-by-case basis, depending on the known prevalence of the infection of concern in the local community. The risk of transmission in most source-unknown exposures is negligible.^3,4,18 However, hepatitis B vaccine and hepatitis B immunoglobulin should be used liberally as postexposure prophylaxis for previously unvaccinated healthcare providers exposed to an unknown source.^3,4,16,18

Hepatitis B

Hepatitis B virus (Table 1) is the most infectious of the common blood-borne viruses. The risk of transmission after percutaneous exposure to hepatitis B-infected blood ranges from 1% to 30% based on hepatitis Be antigen status and viral load (based on hepatitis B viral DNA).^1,2,4,16

Hepatitis B vaccine or immunoglobulin, or both, are recommended for postexposure prophylaxis in pregnant women, based on evidence that perinatal transmission was reduced by 70% to 90% when these were given within 12 to 24 hours of exposure.^4,16,19

Hepatitis C

The risk of infection after percutaneous exposure to hepatitis C virus-infected blood is estimated to be 1.8% per exposure.¹⁶ The risk is lower with exposure of a mucous membrane or nonintact skin to blood, fluids, or tissues from hepatitis C-infected patients.^16,18

Since there is no effective postexposure prophylactic regimen, the goal of postexposure assessment of hepatitis C is early identification of infection (by monitoring the patient to see if he or she seroconverts) and, if infection is present, referral to an experienced clinician for further evaluation (Table 1). However, data supporting the utility of direct-acting anti-hepatitis C antiviral drugs as postexposure prophylaxis after occupational exposure to hepatitis C are lacking.

Human immunodeficiency virus

The estimated risk of HIV transmission from a known infected source after percutaneous exposure is 0.3%, and after mucosal exposures it is 0.09%.²⁰

If postexposure prophylaxis is indicated, it should be a three-drug regimen (Table 1).^3,18 The recommended antiretroviral therapies have been proven effective in clinical trials of HIV treatment, not for postexposure prophylaxis per se, but they are recommended because they are effective, safe, tolerable, and associated with high adherence rates.^3,16,18,21 If the source individual is known to have HIV infection, information about his or her stage of infection, CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic viral resistance testing will guide the choice of postexposure prophylactic regimen.^3,18

The clinician should give the exposed patient a starter pack of 5 to 7 days of medication, give the first dose then and there, and arrange follow-up with an experienced clinician within a few days of the exposure to determine whether a complete 30-day course is needed.^3,16,18

SEXUALLY TRANSMITTED INFECTIONS

In the case of sexually transmitted infections, “exposure” means unprotected sexual contact with someone who has a sexually transmitted infection.²² People with sexually transmitted infections often have no symptoms but can still transmit the infection. Thus, people at risk should be identified and screened for all suspected sexually transmitted infections.^23–25

Patients with sexually transmitted infections should be instructed to refer their sex partners for evaluation and treatment to prevent further transmission and reinfection. Assessment of exposed partners includes a medical history, physical examination, microbiologic testing for all potential sexually transmitted infections, and eligibility for hepatitis A virus, hepatitis B virus, and human papillomavirus vaccines.²² Ideally, exposed partners should be reassessed within 1 to 2 weeks to follow up testing results and to monitor for side effects of and adherence to postexposure prophylaxis, if applicable.

Public health departments should be notified of sexually transmitted infections such as gonorrhea, chlamydia, chancroid, and syphilis.²²

Expedited partner therapy, in which index patients deliver the medication or a prescription for it directly to their partners, is an alternative for partner management where legally allowed by state and local health departments (see www.cdc.gov/std/ept/legal/).²²

Recommended postexposure prophylactic regimens for sexually transmitted infections (Table 2) are based on their efficacy in the treatment of these infections.^22,26–28 The regimen for HIV prophylaxis is the same as in Table 1.^3,18,26

Chlamydia

Chlamydia is the most commonly reported communicable disease in the United States. The risk of transmission after sexual intercourse with a person who has an active infection is approximately 65% and increases with the number of exposures.^22,29

Gonorrhea

Infection with Neisseria gonorrhoeae is the second most commonly reported communicable disease in the United States. The transmission rate of gonorrhea after sex with someone who has it ranges from 50% to 93%.²² When prescribing postexposure prophylaxis for gonorrhea, it is essential to consider the risk of antimicrobial resistance and local susceptibility data.²²

Human immunodeficiency virus

Risk of HIV transmission through sexual contact varies depending on the nature of the exposure, ranging from 0.05% to 0.5%.³⁰

Syphilis

The risk of transmission of syphilis in its early stages (primary and secondary) after sexual exposure is approximately 30%. Transmission requires open lesions such as chancres in primary syphilis and mucocutaneous lesions (mucous patches, condyloma lata) in secondary syphilis.²²

After sexual assault

In cases of sexual assault, the risk of sexually transmitted infections may be increased due to trauma and bleeding. Testing for all sexually transmitted infections, including HIV, should be considered on a case-by-case basis.²²

Survivors of sexual assault have been shown to be poorly compliant with follow-up visits, and thus provision of postexposure prophylaxis at the time of initial assessment is preferable to deferred treatment.²² The recommended regimen should cover chlamydia, gonorrhea, and trichomoniasis (a single dose of intramuscular ceftriaxone 250 mg, oral azithromycin 1 g, and either oral metronidazole 2 g or tinidazole 2 g), in addition to HIV if the victim presents within 72 hours of exposure (Table 2).^22,26

Hepatitis B virus vaccine, not immunoglobulin, should be given if the hepatitis status of the assailant is unknown and the survivor has not been previously vaccinated. Both hepatitis B vaccine and immunoglobulin should be given to unvaccinated survivors if the assailant is known to be hepatitis B surface antigen-positive.²²

Human papillomavirus vaccination is recommended for female survivors ages 9 to 26 and male survivors ages 9 to 21.

Emergency contraception should be given if there is a risk of pregnancy.^22,26

In many jurisdictions, sexual assault centers provide trained examiners through Sexual Assault Nurse Examiners to perform evidence collection and to provide initial contact with the aftercare resources of the center. 

Advice on medical management of sexual assault can be obtained by calling National PEPline (888–448–4911).

INFECTIONS TRANSMITTED BY THE AIRBORNE ROUTE

Airborne transmission of infections occurs by inhalation of droplet nuclei (diameter ≤ 5 μm) generated by coughing and sneezing. Certain procedures (eg, administration of nebulized medication, sputum induction, bronchoscopy) also generate droplets and aerosols, which can transmit organisms.¹

Measles

Measles (Table 3) is highly contagious; up to 90% of susceptible individuals develop measles after exposure. The virus is transmitted by direct contact with infectious droplets and by the airborne route. It remains infectious in the air and on surfaces for up to 2 hours; therefore, any type of exposure, even transient, is an indication for postexposure prophylaxis in susceptible individuals.¹¹

Both the measles, mumps, rubella (MMR) vaccine and immune globulin may prevent or modify disease severity in susceptible exposed individuals if given within 3 days of exposure (for the vaccine) or within 6 days of exposure (for immune globulin).^31,32

Tuberculosis

Mycobacterium tuberculosis is transmitted from patients with pulmonary or laryngeal tuberculosis, particularly if patients cough and are sputum-positive for acid-fast bacilli. Patients with extrapulmonary tuberculosis or latent tuberculosis infection are not infectious.^1,7

Postexposure management of tuberculosis occurs through contact investigation of a newly diagnosed index case of tuberculosis disease. Contacts are categorized as household contacts, close nonhousehold contacts (those having regular, extensive contact with the index case), casual contacts, and transient community contacts. The highest priority for contact investigations should be household contacts, close nonhousehold or casual contacts at high risk of progressing to tuberculosis disease (eg, those with HIV, those on dialysis, or transplant recipients), and unprotected healthcare providers exposed during aerosol-generating procedures.^7,33

Postexposure management includes screening exposed individuals for tuberculosis symptoms and performing tuberculin skin testing or interferon-gamma release assay (blood testing) for those who had previously negative results (Table 3). Chest radiography is recommended for exposed immunocompromised individuals, due to high risk of tuberculosis disease and low sensitivity of skin or blood testing, and for those with a documented history of tuberculosis or previous positive skin or blood test.^7,33,34

A positive tuberculin skin test for persons with recent contact with tuberculosis is defined as a wheal 5 mm or larger on baseline or follow-up screening. Prior bacillus Calmette-Guérin vaccination status should not be used in the interpretation of tuberculin skin testing in the setting of contact investigation.^7,33

All exposed asymptomatic people with a positive result on testing should be treated for latent tuberculosis infection, since treatment reduces the risk of progression to tuberculosis disease by 60% to 90% .^7,33,35–37

Varicella and disseminated herpes zoster

Varicella zoster virus is transmitted by direct contact with vesicular fluid of skin lesions and inhalation of aerosols from vesicular fluid or respiratory tract secretions. Varicella (chickenpox) is highly contagious, with a secondary attack rate in susceptible household contacts of 85%.¹² Herpes zoster is less contagious than varicella.³⁸

Postexposure prophylaxis against varicella is recommended for susceptible individuals who had household exposure, had face-to-face contact with an infectious patient while indoors, or shared the same hospital room with the patient.¹²

Postexposure prophylactic options for varicella and herpes zoster include varicella vaccine (not zoster vaccine) and varicella zoster immune globulin (Table 3).^12,38–40

Varicella vaccine is approximately 90% effective if given within 3 days of exposure, and 70% effective if given within 5 days.^12,39

Antiviral agents should be given if the exposed individual develops manifestations of varicella or herpes zoster.^12,38

INFECTIONS TRANSMITTED BY THE DROPLET ROUTE

Droplet transmission occurs when respiratory droplets carrying infectious agents travel directly across short distances (3–6 feet) from the respiratory tract of the infected to mucosal surfaces of the susceptible exposed individual. Droplets are generated during coughing, sneezing, talking, and aerosol-generating procedures. Indirect contact with droplets can also transmit infection.¹

Group A streptococcal infection

Although group A streptococcal infection (Table 4) may spread to close contacts of the index case and in closed populations (eg, military recruit camps, schools, institutions), secondary cases of invasive group A streptococcal infection rarely occur in family and institutional contacts.^9,41,42

Postexposure prophylaxis for contacts of people with invasive group A streptococcal infection is debated, because it is unknown if antibiotic therapy will decrease the risk of acquiring the infection. It is generally agreed that it should not be routinely given to all contacts. The decision should be based on the clinician’s assessment of each individual’s risk and guidance from the local institution. If indicated, postexposure prophylaxis should be given to household and close contacts, particularly in high-risk groups (eg, Native Americans  and those with risk factors such as old age, HIV infection, diabetes mellitus, heart disease, chickenpox, cancer, systemic corticosteroid therapy, other immunosuppressive medications, intravenous drug use, recent surgery or childbirth).^9,41,42

Influenza

Influenza (Table 4) causes a significant burden in healthcare settings, given its prevalence and potential to cause outbreaks of severe respiratory illness in hospitalized patients and residents of long-term-care facilities.^13,43

Neuraminidase inhibitors are effective as prophylaxis after unprotected exposure to influenza, particularly in outbreak situations. However, their use is not widely recommended, since overuse could lead to antiviral resistance. In selected cases, postexposure prophylaxis may be indicated for close contacts who are at high risk of complications of influenza (eg, age 65 or older, in third trimester of pregnancy or 2 weeks postpartum, morbid obesity, chronic comorbid conditions such as a cardiopulmonary and renal disorder, immunocompromising condition) or who are in close contact with persons at high risk of influenza-related complications.^13,44,45

Meningococcal disease

N meningitidis is transmitted from individuals with meningococcal disease or from asymptomatic carriers.⁸

Postexposure prophylaxis is effective in eradicating N meningiditis and is recommended for all close contacts of patients with invasive meningococcal disease (Table 4).⁴⁶­ Close contacts include household contacts, childcare and preschool contacts, contacts exposed in dormitories or military training centers, those who had direct contact with the index case’s respiratory secretions (eg, intimate kissing, mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or endotracheal tube management), and passengers seated directly next to an index case on airplane flights of longer than 8 hours.

Postexposure prophylaxis is not indicated for those who had brief contact, those who had contact that did not involve exposure to oral or respiratory secretions, or for close contacts of patients with N meningitidis isolated in nonsterile sites only (eg, oropharynyx, trachea, conjunctiva).^8,46

Pertussis

Pertussis is highly contagious, with a secondary attack rate of approximately 80% in susceptible individuals. Approximately one-third of susceptible household contacts develop pertussis after exposure.¹⁰

Postexposure prophylaxis for pertussis should be given to all household and close contacts (Table 4).^10,47

Rubella

Transmission occurs through droplets or direct contact with nasopharyngeal secretions of an infectious case. Neither MMR vaccine nor immunoglobulin has been shown to prevent rubella in exposed contacts, and they are not recommended.¹¹

INFECTIONS TRANSMITTED BY DIRECT CONTACT

Direct contact transmission includes infectious agents transmitted from an infected or colonized individual to another, whereas indirect contact transmission involves a contaminated intermediate object or person (eg, hands of healthcare providers, electronic thermometers, surgical instruments).¹

There are no available postexposure prophylactic regimens for the organisms most commonly transmitted by this route (eg, methicillin-resistant Staphylococcus aureus, Clostridium difficile), but transmission can be prevented with adherence to standard precautions, including hand hygiene.¹

Hepatitis A

Person-to-person transmission of hepatitis A virus occurs via the fecal-oral route. Common-source outbreaks and sporadic cases can occur from exposure to food or water contaminated with feces.^1,15

Postexposure prophylaxis is indicated only for nonimmune close contacts (eg, household and sexual contacts) (Table 5). Without this treatment, secondary attack rates of 15% to 30% have been reported among households.^15,48 Both hepatitis A vaccine and immune globulin are effective in preventing and ameliorating symptomatic hepatitis A infection. Advantages of vaccination include induction of longer-lasting immunity (at least 2 years), greater ease of administration, and lower cost than immune globulin.^15,48

Scabies

Scabies is an infestation of the skin by the mite Sarcoptes scabiei var hominis. Person-to-person transmission typically occurs through direct, prolonged skin-to-skin contact with an infested person (eg, household and sexual contacts). However, crusted scabies can be transmitted after brief skin-to-skin contact or by exposure to bedding, clothing, or furniture used by the infested person.

All potentially infested persons should be treated concomitantly (Table 5).^14,49

INFECTIONS TRANSMITTED BY MAMMAL BITES AND INJURIES

Bites and injury wounds account for approximately 1% of all visits to emergency departments.⁵⁰ Human bites are associated with a risk of infection by blood-borne pathogens, herpes simplex infection, and bacterial infections (eg, skin and soft-tissue infections, bacteremia). Animal bites are associated with a risk of bacterial infections, rabies, tetanus, hepatitis B virus, and monkeypox.⁵⁰

Rabies

Human rabies (Table 5) is almost always fatal. Essential factors in determining the need for postexposure prophylaxis include knowledge of the epidemiology of animal rabies in the area where the contact occurred and the species of animal involved, availability of the animal for observation or rabies testing, health status of the biting animal, and vaccination history of both the animal and exposed individual.⁶ Clinicians should seek assistance from public health officials for evaluating exposures and determining the need for postexposure prophylaxis in situations that are not routine.⁵¹

High-risk wild animals associated with rabies in North America include bats, raccoons, skunks, foxes, coyotes, bobcats, and woodchucks. Bats are the most common source of human rabies infections in the United States, and transmission can occur from minor, sometimes unnoticed, bites. The types of exposures that require postexposure prophylaxis include bites, abrasions, scratches, and contamination of mucous membranes or open wound with saliva or neural tissue of a suspected rabid animal.

Human-to-human transmission of rabies can rarely occur through exposure of mucous membrane or nonintact skin to an infectious material (saliva, tears, neural tissue), in addition to organ transplantation.⁶

Animal capture and testing is a strategy for excluding rabies risk and reducing the need for postexposure prophylaxis. A dog, cat, or ferret that bites a person should be confined and observed for 10 days without administering postexposure prophylaxis for rabies, unless the bite or exposure is on the face or neck, in which case this treatment should be given immediately.⁶ If the observed biting animal lives and remains healthy, postexposure prophylaxis is not recommended. However, if signs suggestive of rabies develop, postexposure prophylaxis should be given and the animal should be euthanized, with testing of brain tissue for rabies virus. Postexposure prophylaxis should be discontinued if rabies testing is negative.

The combination of rabies vaccine and human rabies immunoglobulin is nearly 100% effective in preventing rabies if administered in a timely and accurate fashion after exposure (Table 5).⁶

Tetanus

Tetanus transmission can occur through injuries ranging from small cuts to severe trauma and through contact with contaminated objects (eg, bites, nails, needles, splinters, neonates whose umbilical cord is cut with contaminated surgical instruments, and during circumcision or piercing with contaminated instruments).⁵

Tetanus is almost completely preventable with vaccination, and timely administration of postexposure prophylaxis (tetanus toxoid-containing vaccine, tetanus immune globulin) decreases disease severity (Table 5).^2,5,52

For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.

However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.

This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.

EVIDENCE FROM HEMODILUTION STUDIES

Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.^1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:

• Increasing cardiac output
• Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
• Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.

Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.

Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.⁶

Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.^6–8

Studies in healthy patients

Weiskopf et al⁹ assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.

Leung et al¹⁰ addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.

Hemodilution in healthy elderly patients

Spahn et al¹¹ performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.

The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.

Hemodilution in coronary artery disease

Spahn et al¹² performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.

There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.

Licker et al¹³ studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.

Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).

Hemodilution in mitral regurgitation

Spahn et al¹⁴ performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.

Effect of hemodilution on cognition

Weiskopf et al¹⁵ assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.

There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.¹⁵

Weiskopf et al¹⁶ subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao₂) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study¹⁵ and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.

When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao₂ to 406 mm Hg and normalized neurocognitive performance.

Hemodilution studies in surgical patients

Hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy

A 2015 meta-analysis¹⁷ of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.

However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.

STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES

Studies in critical care and high-risk patients

Hébert et al¹⁸ randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:

• Overall at 30 days 18.7% vs 23.3%, P = .11
• In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
• In the subgroup under age 55, 5.7% vs 13%, P = .02
• In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
• In the hospital, 22.2% vs 28.1%; P = .05.

This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.

Carson et al¹⁹ evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.

There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.

Rao et al²⁰ analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.

At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.

This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.

Carson et al,²¹ however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).

These studies suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients

Murphy et al²² similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):

• Transfusion rates 53.4% vs 92.2%
• Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
  35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30)
• Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
• Total costs did not differ significantly between the groups.

These studies^21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.

Holst et al²³ randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.

This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.

Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.

Villanueva et al²⁴ randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:

• Freedom from transfusion 51% vs 14% (P < .001)
• Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
• Rebleeding 10% vs 16% (P = .01). 


Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.

The RELIEVE trial²⁵ compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.

Meta-analyses and observational studies

Rohde et al²⁶ performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.

The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).

Salpeter et al²⁷ performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:

• In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
• Total mortality (RR 0.80, 95% CI 0.65–0.98)
• Rebleeding (RR 0.64, 95% CI 0.45–0.90)
• Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
• Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
• Bacterial infections (RR 0.86, 95% CI 0.73–1.00).

Wang et al²⁸ performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:

• A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
• A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
• Shorter hospitalizations (P = .009)
• Less blood transfused (P = .0005).

The more units of blood the patients received, the more likely they were to die

Vincent et al,²⁹ in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).

Dunne et al³⁰ performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.

These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.

Brunskill et al,³¹ in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.

Weinberg et al³² found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).

Studies in sickle cell disease

Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).^33,34

In trials in surgical patients,^35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.³⁵

In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.³⁴

Is hemoglobin the most relevant marker?

Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.

Beware of using the hemoglobin concentration as a threshold for transfusion and a marker of benefit

We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.³⁷ Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.

Is fresh blood better than old blood?

Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.^38,39

The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.⁴⁰ Similar poor outcomes have been seen in trauma patients.³²

Lacroix et al,⁴¹ in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).

The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.

RISKS ASSOCIATED WITH TRANSFUSION

Infections

The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.⁴²

Noninfectious complications

Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.⁴²

Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.

Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.

Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.⁴³

Surgery and condition-specific complications of red blood cell transfusion

Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.⁴⁴

Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.^44–47

Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.⁴⁴

ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.⁴⁴

COST OF RED BLOOD CELL TRANSFUSION

Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.⁴² At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.

The Premier Healthcare Alliance⁴⁸ analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.

In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.^49,50

RECOMMENDATIONS FROM THE AABB

In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.⁵¹ Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),⁴² which are similar to the national clinical guideline on blood transfusion in the United Kingdom,⁵² and have recently been updated, confirming the initial recommendations.⁵³

In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.

In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.

In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.

Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,⁵⁴ which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.

The Society of Hospital Medicine⁵⁵ and the American Society of Hematology⁵⁶ concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).⁵⁷

New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.⁵²

CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL

The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.

However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).

Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.

Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.

For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.

However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.

This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.

EVIDENCE FROM HEMODILUTION STUDIES

Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.^1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:

• Increasing cardiac output
• Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
• Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.

Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.

Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.⁶

Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.^6–8

Studies in healthy patients

Weiskopf et al⁹ assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.

Leung et al¹⁰ addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.

Hemodilution in healthy elderly patients

Spahn et al¹¹ performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.

The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.

Hemodilution in coronary artery disease

Spahn et al¹² performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.

There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.

Licker et al¹³ studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.

Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).

Hemodilution in mitral regurgitation

Spahn et al¹⁴ performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.

Effect of hemodilution on cognition

Weiskopf et al¹⁵ assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.

There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.¹⁵

Weiskopf et al¹⁶ subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao₂) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study¹⁵ and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.

When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao₂ to 406 mm Hg and normalized neurocognitive performance.

Hemodilution studies in surgical patients

Hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy

A 2015 meta-analysis¹⁷ of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.

However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.

STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES

Studies in critical care and high-risk patients

Hébert et al¹⁸ randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:

• Overall at 30 days 18.7% vs 23.3%, P = .11
• In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
• In the subgroup under age 55, 5.7% vs 13%, P = .02
• In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
• In the hospital, 22.2% vs 28.1%; P = .05.

This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.

Carson et al¹⁹ evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.

There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.

Rao et al²⁰ analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.

At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.

This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.

Carson et al,²¹ however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).

These studies suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients

Murphy et al²² similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):

• Transfusion rates 53.4% vs 92.2%
• Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
  35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30)
• Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
• Total costs did not differ significantly between the groups.

These studies^21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.

Holst et al²³ randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.

This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.

Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.

Villanueva et al²⁴ randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:

• Freedom from transfusion 51% vs 14% (P < .001)
• Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
• Rebleeding 10% vs 16% (P = .01). 


Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.

The RELIEVE trial²⁵ compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.

Meta-analyses and observational studies

Rohde et al²⁶ performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.

The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).

Salpeter et al²⁷ performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:

• In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
• Total mortality (RR 0.80, 95% CI 0.65–0.98)
• Rebleeding (RR 0.64, 95% CI 0.45–0.90)
• Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
• Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
• Bacterial infections (RR 0.86, 95% CI 0.73–1.00).

Wang et al²⁸ performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:

• A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
• A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
• Shorter hospitalizations (P = .009)
• Less blood transfused (P = .0005).

The more units of blood the patients received, the more likely they were to die

Vincent et al,²⁹ in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).

Dunne et al³⁰ performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.

These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.

Brunskill et al,³¹ in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.

Weinberg et al³² found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).

Studies in sickle cell disease

Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).^33,34

In trials in surgical patients,^35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.³⁵

In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.³⁴

Is hemoglobin the most relevant marker?

Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.

Beware of using the hemoglobin concentration as a threshold for transfusion and a marker of benefit

We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.³⁷ Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.

Is fresh blood better than old blood?

Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.^38,39

The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.⁴⁰ Similar poor outcomes have been seen in trauma patients.³²

Lacroix et al,⁴¹ in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).

The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.

RISKS ASSOCIATED WITH TRANSFUSION

Infections

The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.⁴²

Noninfectious complications

Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.⁴²

Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.

Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.

Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.⁴³

Surgery and condition-specific complications of red blood cell transfusion

Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.⁴⁴

Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.^44–47

Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.⁴⁴

ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.⁴⁴

COST OF RED BLOOD CELL TRANSFUSION

Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.⁴² At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.

The Premier Healthcare Alliance⁴⁸ analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.

In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.^49,50

RECOMMENDATIONS FROM THE AABB

In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.⁵¹ Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),⁴² which are similar to the national clinical guideline on blood transfusion in the United Kingdom,⁵² and have recently been updated, confirming the initial recommendations.⁵³

In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.

In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.

In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.

Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,⁵⁴ which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.

The Society of Hospital Medicine⁵⁵ and the American Society of Hematology⁵⁶ concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).⁵⁷

New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.⁵²

CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL

The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.

However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).

Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.

Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.

For decades, physicians believed in the benefit of prompt transfusion of blood to keep the hemoglobin level at arbitrary, optimum levels, ie, close to normal values, especially in the critically ill, the elderly, and those with coronary syndromes, stroke, or renal failure.

However, the evidence supporting arbitrary hemoglobin values as an indication for transfusion was weak or nonexistent. Also, blood transfusion can have complications and adverse effects, and blood is costly and scarce. These considerations prompted research into when blood transfusion should be considered, and recommendations that it should be used more sparingly than in the past.

This review offers a perspective on the evidence supporting restrictive blood use. First, we focus on hemodilution studies that demonstrated that humans can tolerate anemia. Then, we look at studies that compared a restrictive transfusion strategy with a liberal one in patients with critical illness and active bleeding. We conclude with current recommendations for blood transfusion.

EVIDENCE FROM HEMODILUTION STUDIES

Hemoglobin is essential for tissue oxygenation, but the serum hemoglobin concentration is just one of several factors involved.^1–5 In anemia, the body can adapt not only by increasing production of red blood cells, but also by:

• Increasing cardiac output
• Increasing synthesis of 2,3-diphosphoglycerate (2,3-DPG), with a consequent shift in the oxyhemoglobin dissociation curve to the right, allowing enhanced release of oxygen at the tissue level
• Moving more carbon dioxide into the blood (the Bohr effect), which decreases pH and also shifts the dissociation curve to the right.

Just 20 years ago, physicians were using arbitrary cutoffs such as hemoglobin 10 g/dL or hematocrit 30% as indications for blood transfusion, without reasonable evidence to support these values. Not until acute normovolemic hemodilution studies were performed were we able to progressively appraise how well patients could tolerate lower levels of hemoglobin without significant adverse outcomes.

Acute normovolemic hemodilution involves withdrawing blood and replacing it with crystalloid or colloid solution to maintain the volume.⁶

Initial studies were done in animals and focused on the safety of acute anemia regarding splanchnic perfusion. Subsequently, studies proved that healthy, elderly, and stable cardiac patients can tolerate acute anemia with normal cardiovascular response. The targets in these studies were modest at first, but researchers aimed progressively for more aggressive hemodilution with lower hemoglobin targets and demonstrated that the body can tolerate and adapt to more severe anemia.^6–8

Studies in healthy patients

Weiskopf et al⁹ assessed the effect of severe anemia in 32 conscious healthy patients (11 presurgical patients and 21 volunteers not undergoing surgery) by performing acute normovolemic hemodilution with 5% human albumin, autologous plasma, or both, with a target hemoglobin level of 5 g/dL. The process was done gradually, obtaining aliquots of blood of 500 to 900 mL. Cardiac index increased, along with a mild increase in oxygen consumption with no increase in plasma lactate levels, suggesting that in conscious healthy patients, tissue oxygenation remains adequate even in severe anemia.

Leung et al¹⁰ addressed the electrocardiographic changes that occur with severe anemia (hemoglobin 5 g/dL) in 55 healthy volunteers. Three developed transient, reversible ST-segment depression, which was associated with a higher heart rate than in the volunteers with no electrocardiographic changes; however, the changes were reversible and asymptomatic, and thus were considered physiologic and benign.

Hemodilution in healthy elderly patients

Spahn et al¹¹ performed 6 and 12 mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch in 20 patients older than 65 years (mean age 76, range 65–88) without underlying coronary disease.

The patients’ mean hemoglobin level decreased from 11.6 g/dL to 8.8 g/dL. Their cardiac index and oxygen extraction values increased adequately, with stable oxygen consumption during hemodilution. There were no electrocardiographic signs of ischemia.

Hemodilution in coronary artery disease

Spahn et al¹² performed hemodilution studies in 60 patients (ages 35–81) with coronary artery disease managed chronically with beta-blockers who were scheduled for coronary artery bypass graft surgery. Hemodilution was performed with 6- and 12-mL/kg isovolemic exchange of blood for 6% hydroxyethyl starch maintaining normovolemia and stable filling pressures. Hemoglobin levels decreased from 12.6 g/dL to 9.9 g/dL. The hemodilution process was done before the revascularization. The authors monitored hemodynamic variables, ST-segment deviation, and oxygen consumption before and after each hemodilution.

There was a compensatory increase in cardiac index and oxygen extraction with consequent stable oxygen consumption. These changes were independent of patient age or left ventricular function. In addition, there were no electrocardiographic signs of ischemia.

Licker et al¹³ studied the hemodynamic effect of preoperative hemodilution in 50 patients with coronary artery disease undergoing coronary artery bypass graft surgery, performing transesophageal echocardiography before and after hemodilution. The patients underwent isovolemic exchange with iso-oncotic starch to target a hematocrit of 28%.

Acute normovolemic hemodilution triggered an increase in cardiac stroke volume, which had a direct correlation with an increase in the central venous pressure and the left ventricular end-diastolic area. No signs of ischemia were seen in these patients on electrocardiography or echocardiography (eg, left ventricular wall-motion abnormalities).

Hemodilution in mitral regurgitation

Spahn et al¹⁴ performed acute isovolemic hemodilution with 6% hydroxyethyl starch in 20 patients with mitral regurgitation. The cardiac filling pressures were stable before and after hemodilution; the mean hemoglobin value decreased from 13 to 10.3 g/dL. The cardiac index and oxygen extraction increased proportionally, with stable oxygen consumption; these findings were the same regardless of whether the patient was in normal sinus rhythm or atrial fibrillation.

Effect of hemodilution on cognition

Weiskopf et al¹⁵ assessed the effect of anemia on executive and memory function by inducing progressive acute isovolemic anemia in 90 healthy volunteers (age 29 ± 5), reducing their hemoglobin values to 7, 6, and 5 g/dL and performing repetitive neuropsychological and memory testing before and after the hemodilution, as well as after autologous blood transfusion to return their hemoglobin level to 7 g/dL.

There were no changes in reaction time or error rate at a hemoglobin concentration of 7 g/dL compared with the performance at a baseline hemoglobin concentration of 14 g/dL. The volunteers got slower on a mathematics test at hemoglobin levels of 6 g/dL and 5 g/dL, but their error rate did not increase. Immediate and delayed memory were significantly impaired at hemoglobin of 5 g/dL but not at 6 g/dL. All tests normalized with blood transfusion once the hemoglobin level reached 7 g/dL.¹⁵

Weiskopf et al¹⁶ subsequently investigated whether giving supplemental oxygen to raise the arterial partial pressure of oxygen (Pao₂) to 350 mm Hg or greater would overcome the neurocognitive effects of severe acute anemia. They followed a protocol similar to the one in the earlier study¹⁵ and induced anemia in 31 healthy volunteers, age 28 ± 4 years, with a mean baseline hemoglobin concentration of 12.7 g/dL.

When the volunteers reached a hemoglobin concentration of 5.7 ± 0.3 g/dL, they were significantly slower on the mathematics test, and their delayed memory was significantly impaired. Then, in a double-blind fashion, they were given either room air or oxygen. Oxygen increased the Pao₂ to 406 mm Hg and normalized neurocognitive performance.

Hemodilution studies in surgical patients

Hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy

A 2015 meta-analysis¹⁷ of 63 studies involving 3,819 surgical patients compared the risk of perioperative allogeneic blood transfusion as well as the overall volume of transfused blood in patients undergoing preoperative acute normovolemic hemodilution vs a control group. Though the overall data showed that the patients who underwent acute normovolemic hemodilution needed fewer transfusions and less blood (relative risk [RR] 0.74, 95% confidence interval [CI] 0.63–0.88, P = .0006), the authors noted significant heterogeneity and publication bias.

However, the hemodilution studies paved the way for justifying a more conservative and restrictive transfusion strategy, with a hemoglobin cutoff value of 7 g/dL, and in acute anemia, using oxygen to overcome acute neurocognitive effects while searching for and correcting the cause of the anemia.

STUDIES OF RESTRICTIVE VS LIBERAL TRANSFUSION STRATEGIES

Studies in critical care and high-risk patients

Hébert et al¹⁸ randomized 418 critical care patients to a restrictive transfusion approach (in which they were given red blood cells if their hemoglobin concentration dropped below 7.0 g/dL) and 420 patients to a liberal strategy (given red blood cells if their hemoglobin concentration dropped below 10.0 g/dL). Mortality rates (restrictive vs liberal strategy) were as follows:

• Overall at 30 days 18.7% vs 23.3%, P = .11
• In the subgroup with less-severe disease (Acute Physiology and Chronic Health Evaluation II [APACHE II] score < 20), 8.7% vs 16.1%, P = .03
• In the subgroup under age 55, 5.7% vs 13%, P = .02
• In the subgroup with clinically significant cardiac disease, 20.5% vs 22.9%, P = .69
• In the hospital, 22.2% vs 28.1%; P = .05.

This study demonstrated that parsimonious blood use did not worsen clinical outcomes in critical care patients.

Carson et al¹⁹ evaluated 2,016 patients age 50 and older who had a history of or risk factors for cardiovascular disease and a baseline hemoglobin level below 10 g/dL who underwent surgery for hip fracture. Patients were randomized to two transfusion strategies based on threshold hemoglobin level: restrictive (< 8 g/dL) or liberal (< 10 g/dL). The primary outcome was death or inability to walk without assistance at 60-day follow-up. The median number of units of blood used was 2 in the liberal group and 0 in the restrictive group.

There was no significant difference in the rates of the primary outcome (odds ratio [OR] 1.01, 95% CI 0.84–1.22), infection, venous thromboembolism, or reoperation. This study demonstrated that a liberal transfusion strategy offered no benefit over a restrictive one.

Rao et al²⁰ analyzed the impact of blood transfusion in 24,112 patients with acute coronary syndromes enrolled in three large trials. Ten percent of the patients received at least 1 blood transfusion during their hospitalization, and they were older and had more complex comorbidity.

At 30 days, the group that had received blood had higher rates of death (adjusted hazard ratio [HR] 3.94, 95% CI 3.26–4.75) and the combined outcome of death or myocardial infarction (HR 2.92, 95% CI 2.55–3.35). Transfusion in patients whose nadir hematocrit was higher than 25% was associated with worse outcomes.

This study suggests being cautious about routinely transfusing blood in stable patients with ischemic heart disease solely on the basis of arbitrary hematocrit levels.

Carson et al,²¹ however, in a later trial, found a trend toward worse outcomes with a restrictive strategy than with a liberal one. Here, 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization were randomized to a target hemoglobin level of either at least 8 mg/dL or at least 10 g/dL. The primary outcome (a composite of death, myocardial infarction, or unscheduled revascularization 30 days after randomization) occurred in 14 patients (25.5%) in the restrictive group and 6 patients (10.9%) in the liberal group (P = .054), and 7 (13.0%) vs 1 (1.8%) of the patients died (P = .032).

These studies suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients

Murphy et al²² similarly found trends toward worse outcomes with a restrictive strategy in cardiac patients. The investigators randomized 2,007 elective cardiac surgery patients with a postoperative hemoglobin level lower than 9 g/dL to a hemoglobin transfusion threshold of either 7.5 or 9 g/dL. Outcomes (restrictive vs liberal strategies):

• Transfusion rates 53.4% vs 92.2%
• Rates of the primary outcome (a serious infection [sepsis or wound infection] or ischemic event [stroke, myocardial infarction, mesenteric ischemia, or acute kidney injury] within 3 months):
  35.1% vs 33.0%, OR 1.11, 95% CI 0.91–1.34, P = .30)
• Mortality rates 4.2% vs 2.6%, HR 1.64, 95% CI 1.00–2.67, P = .045
• Total costs did not differ significantly between the groups.

These studies^21,22 suggest the need for more definitive trials in patients with active coronary disease and in cardiac surgery patients.

Holst et al²³ randomized 998 intensive care patients in septic shock to hemoglobin thresholds for transfusion of 7 vs 9 g/dL. Mortality rates at 90 days (the primary outcome) were 43.0% vs 45.0%, RR 0.94, 95% CI 0.78–1.09, P = .44.

This study suggests that even in septic shock, a liberal transfusion strategy has no advantage over a parsimonious one.

Active bleeding, especially active gastrointestinal bleeding, poses a significant stress that may trigger empirical transfusion even without evidence of the real hemoglobin level.

Villanueva et al²⁴ randomized 921 patients with severe acute upper-gastrointestinal bleeding to two groups, with hemoglobin transfusion triggers of 7 vs 9 g/dL. The findings were impressive:

• Freedom from transfusion 51% vs 14% (P < .001)
• Survival rates at 6 weeks 95% vs 91% (HR 0.55, 95% CI 0.33–0.92, P = .02)
• Rebleeding 10% vs 16% (P = .01). 


Patients with peptic ulcer disease as well as those with cirrhosis stage Child-Pugh class A or B had higher survival rates with a restrictive transfusion strategy.

The RELIEVE trial²⁵ compared the effect of a restrictive transfusion strategy in elderly patients on mechanical ventilation in 6 intensive care units in the United Kingdom. Transfusion triggers were hemoglobin 7 vs 9 g/dL, and the mortality rate at 180 days was 55% vs 37%, RR 0.68, 95% CI 0.44–1.05, P = .073.

Meta-analyses and observational studies

Rohde et al²⁶ performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.

The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).

Salpeter et al²⁷ performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:

• In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
• Total mortality (RR 0.80, 95% CI 0.65–0.98)
• Rebleeding (RR 0.64, 95% CI 0.45–0.90)
• Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
• Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
• Bacterial infections (RR 0.86, 95% CI 0.73–1.00).

Wang et al²⁸ performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:

• A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
• A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
• Shorter hospitalizations (P = .009)
• Less blood transfused (P = .0005).

The more units of blood the patients received, the more likely they were to die

Vincent et al,²⁹ in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).

Dunne et al³⁰ performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.

These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.

Brunskill et al,³¹ in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.

Weinberg et al³² found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).

Studies in sickle cell disease

Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).^33,34

In trials in surgical patients,^35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.³⁵

In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.³⁴

Is hemoglobin the most relevant marker?

Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.

Beware of using the hemoglobin concentration as a threshold for transfusion and a marker of benefit

We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.³⁷ Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.

Is fresh blood better than old blood?

Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.^38,39

The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.⁴⁰ Similar poor outcomes have been seen in trauma patients.³²

Lacroix et al,⁴¹ in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).

The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.

RISKS ASSOCIATED WITH TRANSFUSION

Infections

The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.⁴²

Noninfectious complications

Transfusion-associated circulatory overload occurs in 4% to 6% of patients who receive a transfusion. Therefore, circulatory overload is a greater danger from transfusion than infection is.⁴²

Febrile nonhemolytic transfusion reactions occur in 1.1% of patients with prestorage leukoreduction.

Transfusion-associated acute lung injury occurs in 0.8 per 10,000 blood components transfused.

Errors associated with blood transfusion include, in decreasing order of frequency, transfusion of the wrong blood component, handling and storage errors, inappropriate administration of anti-D immunoglobulin, and avoidable, delayed, or insufficient transfusions.⁴³

Surgery and condition-specific complications of red blood cell transfusion

Cardiovascular surgery. Transfusion is associated with a higher risk of postoperative stroke, respiratory failure, acute respiratory distress syndrome, prolonged intubation time, reintubation, in-hospital death, sepsis, and longer postoperative length of stay.⁴⁴

Malignancy. The use of blood in this setting has been found to be an independent predictor of recurrence, decreased survival, and increased risk of lymphoplasmacytic and marginal-zone lymphomas.^44–47

Vascular, orthopedic, and other surgeries. Transfusion is associated with a higher risk of death, thromboembolic events, acute kidney injury, death, composite morbidity, reoperation, sepsis, and pulmonary complications.⁴⁴

ST-segment elevation myocardial infarction, sepsis, and intensive care unit admissions. Transfusion is associated with an increased risk of rebleeding, death, and secondary infections.⁴⁴

COST OF RED BLOOD CELL TRANSFUSION

Up to 85 million units of red blood cells are transfused per year worldwide, 15 million of them in the United States.⁴² At our hospital in 2013, 1 unit of leukocyte-reduced red blood cells cost $957.27, which included the costs of acquisition, processing, banking, patient testing, administration, and monitoring.

The Premier Healthcare Alliance⁴⁸ analyzed data from 7.4 million discharges from 464 hospitals between April 2011 and March 2012. Blood use varied significantly among hospitals, and the hospitals in the lowest quartile of blood use had better patient outcomes. If all the hospitals used as little blood as those in the lowest quartile and had outcomes as good, blood product use would be reduced by 802,716 units, with savings of up to $165 million annually.

In addition to the economic cost of blood transfusion, the clinician must be aware of the cost in terms of comorbidities caused by unnecessary blood transfusion.^49,50

RECOMMENDATIONS FROM THE AABB

In view of all the current compelling evidence, a restrictive approach to transfusion is the single best strategy to minimize adverse outcomes.⁵¹ Below, we outline the current recommendations from the AABB (formerly the American Association of Blood Banks),⁴² which are similar to the national clinical guideline on blood transfusion in the United Kingdom,⁵² and have recently been updated, confirming the initial recommendations.⁵³

In critical care patients, transfusion should be considered if the hemoglobin concentration is 7 g/dL or less.

In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered if the hemoglobin concentration is 8 g/dL or less or if the patient has signs or symptoms of anemia such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.

In hemodynamically stable patients with acute coronary syndrome, there is not enough evidence to allow a formal recommendation for or against a liberal or restrictive transfusion threshold.

Consider both the hemoglobin concentration and the symptoms when deciding whether to give a transfusion. This recommendation is shared by a National Institutes of Health consensus conference,⁵⁴ which indicates that multiple factors related to the patient’s clinical status and oxygen delivery should be considered before deciding to transfuse red blood cells.

The Society of Hospital Medicine⁵⁵ and the American Society of Hematology⁵⁶ concur with a parsimonious approach to blood use in their Choosing Wisely campaigns. The American Society of Hematology recommends that if transfusion of red blood cells is necessary, the minimum number of units should be given that relieve the symptoms of anemia or achieve a safe hemoglobin range (7–8 g/dL in stable noncardiac inpatients).⁵⁷

New electronic tools can monitor the ordering and use of blood products in real time and can identify the hemoglobin level used as the trigger for transfusion. They also provide data on blood use by physician, hospital, and department. These tools can reveal current practice at a glance and allow sharing of best practices among peers and institutions.⁵²

CONSIDER TRANSFUSION FOR HEMOGLOBIN BELOW 7 G/DL

The routine use of blood has come under scrutiny, given its association with increased healthcare costs and morbidity. The accepted practice in stable medical patients is a restrictive threshold approach for blood transfusion, which is to consider (not necessarily give) a single unit of packed red blood cells for a hemoglobin less than 7 g/dL.

However, studies in acute coronary syndrome patients and postoperative cardiac surgery patients have not shown the restrictive threshold to be superior to a liberal threshold in terms of outcomes and costs. This variability suggests the need for further studies to determine the best course of action in different patient subpopulations (eg, surgical, oncologic, trauma, critical illness).

Also, a limitation of most of the clinical studies was that only the hemoglobin concentration was used as a marker of anemia, with no strict assessment of changes in red cell mass with transfusion.

Despite the variability in certain populations, the overall weight of current evidence favors a restrictive approach to blood transfusion (hemoglobin < 7 g/dL), although perhaps in patients who have active coronary disease or are undergoing cardiac surgery, a more lenient threshold (< 8 g/dL) for transfusion should be considered.

A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.

In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.

Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”

The patient’s laboratory values are shown in Table 1.

WHICH ACID-BASE DISORDER DOES SHE HAVE?

1. Which acid-base disorder does this patient have?

• Metabolic acidosis and respiratory alkalosis
• Metabolic acidosis and respiratory acidosis
• Metabolic acidosis with an elevated anion gap
• A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis

A 5-step approach

Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)¹:

1. Determine the arterial pH status.

2. Determine whether the primary process is respiratory, metabolic, or both.

3. Calculate the anion gap.

4. Check the degree of compensation (respiratory or metabolic).

5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).

Let us apply this approach to the patient described above.

1. What is her pH status?

An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)

Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco₂), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.

Our patient’s pH is 7.25, which is in the acidemic range.

2. Is her acidosis respiratory, metabolic, or both?

Respiratory acidosis and alkalosis affect the Pco₂. The Pco₂ is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).

Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.

Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco₂ can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco₂ can be low (Table 2).

Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco₂ is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.

3. What is her anion gap?

Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.

Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.

Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.²

Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.

4. Is the degree of compensation appropriate for the primary acid-base disturbance?

The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco₂ (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).

In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco₂ should decrease by 1.3 mm Hg.

Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.

Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco₂ should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco₂ is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.

If we use Winter’s formula instead (Pco₂ = [1.5 × the bicarbonate level] + 8 ± 2),³ the lowest calculated Pco₂ would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.³

This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.

5. Is there a delta gap?

Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap. 

In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.

Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.

So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).

‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS

The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).

Methanol and ethylene glycol

We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time. 

In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.

In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).^4,5 Therefore, her osmol gap is elevated.

Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.⁶ A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.⁷ Liquid chromatography identifies these two toxins, but results are not available emergently.

Diethylene glycol ingestion should also be considered.⁸ Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.

Uremia

Renal failure can lead to metabolic acidosis.⁹ Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m²—low, but not uremic.  

Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.

Diabetes

The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).¹⁰

There is another, less common cause of ketoacidosis: alcohol.¹¹ Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.¹¹ Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.¹¹

This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.

THE NEW MUD PILES

2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:

• The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
• There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
• Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
• Salicylates can paradoxically be associated both with elevated and low anion gaps.

Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.

Paraldehyde, isoniazid, lactate

The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.

UPDATING THE ‘P’ IN MUD PILES

Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).^12–20

Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.

5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen

Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).^21,22

Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.

Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,²³ the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.

No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.

Propylene glycol, a component of parenteral lorazepam

Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.^24,25

Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.²³

Isoniazid

Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,²⁶ either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.

The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.²⁷ A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.²⁸

Lactic acidosis

Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.²⁹ However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.²⁹

d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).³⁰ With short bowel syndrome, the neurologic manifestations occur after eating and clear later.³⁰

Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.

Salicylates

Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.

Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.

Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.³¹ Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.

WHAT ELSE MUST BE CONSIDERED?

3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)

• Methanol, ethylene, or diethylene glycol
• Excessive, chronic acetaminophen ingestion
• Salicylate toxicity
• Alcoholic ketoacidosis

All of the above can potentially contribute to metabolic acidosis.

A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.

Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.

The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.

GOLD MARK: ANOTHER WAY TO REMEMBER

Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).³²

ACID-BASE DISORDERS IN DIFFERENT DISEASES

Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:

Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.³³

Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.³⁴

Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.^35,36

Cancer^37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.

An expanding array of toxic ingestions

Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.

As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.

A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.

In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.

Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”

The patient’s laboratory values are shown in Table 1.

WHICH ACID-BASE DISORDER DOES SHE HAVE?

1. Which acid-base disorder does this patient have?

• Metabolic acidosis and respiratory alkalosis
• Metabolic acidosis and respiratory acidosis
• Metabolic acidosis with an elevated anion gap
• A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis

A 5-step approach

Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)¹:

1. Determine the arterial pH status.

2. Determine whether the primary process is respiratory, metabolic, or both.

3. Calculate the anion gap.

4. Check the degree of compensation (respiratory or metabolic).

5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).

Let us apply this approach to the patient described above.

1. What is her pH status?

An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)

Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco₂), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.

Our patient’s pH is 7.25, which is in the acidemic range.

2. Is her acidosis respiratory, metabolic, or both?

Respiratory acidosis and alkalosis affect the Pco₂. The Pco₂ is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).

Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.

Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco₂ can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco₂ can be low (Table 2).

Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco₂ is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.

3. What is her anion gap?

Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.

Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.

Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.²

Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.

4. Is the degree of compensation appropriate for the primary acid-base disturbance?

The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco₂ (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).

In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco₂ should decrease by 1.3 mm Hg.

Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.

Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco₂ should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco₂ is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.

If we use Winter’s formula instead (Pco₂ = [1.5 × the bicarbonate level] + 8 ± 2),³ the lowest calculated Pco₂ would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.³

This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.

5. Is there a delta gap?

Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap. 

In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.

Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.

So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).

‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS

The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).

Methanol and ethylene glycol

We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time. 

In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.

In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).^4,5 Therefore, her osmol gap is elevated.

Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.⁶ A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.⁷ Liquid chromatography identifies these two toxins, but results are not available emergently.

Diethylene glycol ingestion should also be considered.⁸ Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.

Uremia

Renal failure can lead to metabolic acidosis.⁹ Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m²—low, but not uremic.  

Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.

Diabetes

The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).¹⁰

There is another, less common cause of ketoacidosis: alcohol.¹¹ Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.¹¹ Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.¹¹

This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.

THE NEW MUD PILES

2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:

• The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
• There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
• Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
• Salicylates can paradoxically be associated both with elevated and low anion gaps.

Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.

Paraldehyde, isoniazid, lactate

The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.

UPDATING THE ‘P’ IN MUD PILES

Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).^12–20

Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.

5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen

Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).^21,22

Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.

Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,²³ the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.

No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.

Propylene glycol, a component of parenteral lorazepam

Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.^24,25

Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.²³

Isoniazid

Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,²⁶ either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.

The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.²⁷ A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.²⁸

Lactic acidosis

Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.²⁹ However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.²⁹

d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).³⁰ With short bowel syndrome, the neurologic manifestations occur after eating and clear later.³⁰

Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.

Salicylates

Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.

Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.

Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.³¹ Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.

WHAT ELSE MUST BE CONSIDERED?

3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)

• Methanol, ethylene, or diethylene glycol
• Excessive, chronic acetaminophen ingestion
• Salicylate toxicity
• Alcoholic ketoacidosis

All of the above can potentially contribute to metabolic acidosis.

A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.

Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.

The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.

GOLD MARK: ANOTHER WAY TO REMEMBER

Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).³²

ACID-BASE DISORDERS IN DIFFERENT DISEASES

Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:

Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.³³

Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.³⁴

Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.^35,36

Cancer^37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.

An expanding array of toxic ingestions

Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.

As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.

A 78-year-old black woman with a history of osteoarthrosis and chronic diffuse joint pain presents with altered mental status and tachypnea, which began 3 hours earlier. She lives alone, and her family suspects she abuses both alcohol and her pain medications. She has not been eating well and has lost approximately 10 pounds over the past 3 months. Her analgesic regimen includes acetaminophen and acetaminophen-oxycodone.

In the emergency department her temperature is 98.6°F (37.0°C), pulse 100 beats per minute and regular, respiratory rate 22 per minute, and blood pressure 136/98 mm Hg. She is obtunded but has no focal neurologic defects or meningismus. She has no signs of heart failure (jugular venous distention, cardiomegaly, or gallops), and examination of the lungs and abdomen is unremarkable.

Suspecting that the patient may have taken too much oxycodone, the physician gives her naloxone, but her mental status does not improve. Results of chest radiography and cranial computed tomography are unremarkable. The physician’s initial impression is that the patient has “metabolic encephalopathy of unknown etiology.”

The patient’s laboratory values are shown in Table 1.

WHICH ACID-BASE DISORDER DOES SHE HAVE?

1. Which acid-base disorder does this patient have?

• Metabolic acidosis and respiratory alkalosis
• Metabolic acidosis and respiratory acidosis
• Metabolic acidosis with an elevated anion gap
• A triple disturbance: metabolic acidosis, respiratory acidosis, and metabolic alkalosis

A 5-step approach

Acid-base disorders can be diagnosed and characterized using a systematic approach known as the “Rules of 5” (Table 2)¹:

1. Determine the arterial pH status.

2. Determine whether the primary process is respiratory, metabolic, or both.

3. Calculate the anion gap.

4. Check the degree of compensation (respiratory or metabolic).

5. If the patient has metabolic acidosis with an elevated anion gap, check whether the bicarbonate level has decreased as much as the anion gap has increased (ie, whether there is a delta gap).

Let us apply this approach to the patient described above.

1. What is her pH status?

An arterial pH less than 7.40 is acidemic, whereas a pH higher than 7.44 is alkalemic. (Acidemia and alkalemia refer to the abnormal laboratory value, while acidosis and alkalosis refer to the process causing the abnormal value—a subtle distinction, but worth keeping in mind.)

Caveat. A patient may have a significant acid-base disorder even if the pH is normal. Therefore, even if the pH is normal, one should verify that the partial pressure of carbon dioxide (Pco₂), bicarbonate level, and anion gap are normal. If they are not, the patient may have a mixed acid-base disorder such as respiratory acidosis superimposed on metabolic alkalosis.

Our patient’s pH is 7.25, which is in the acidemic range.

2. Is her acidosis respiratory, metabolic, or both?

Respiratory acidosis and alkalosis affect the Pco₂. The Pco₂ is high in respiratory acidosis (due to failure to get rid of excess carbon dioxide), whereas it is low in respiratory alkalosis (due to loss of too much carbon dioxide through hyperventilation).

Metabolic acidosis and alkalosis, on the other hand, affect the serum bicarbonate level. In metabolic acidosis the bicarbonate level is low, whereas in metabolic alkalosis the bicarbonate level is high.

Moreover, in mixed respiratory and metabolic acidosis, the bicarbonate level can be low and the Pco₂ can be high. In mixed metabolic and respiratory alkalosis, the bicarbonate level can be high and the Pco₂ can be low (Table 2).

Our patient’s serum bicarbonate level is low at 16.0 mmol/L, indicating that the process is metabolic. Her Pco₂ is also low (28 mm Hg), which reflects an appropriate response to compensate for the acidosis.

3. What is her anion gap?

Always calculate the anion gap, ie, the serum sodium concentration minus the serum chloride and serum bicarbonate concentrations. If the patient’s serum albumin level is low, for every 1 gram it is below normal, an additional 2.5 mmol/L should be added to the calculated anion gap. We consider an anion gap of 10 mmol/L or less as normal.

Caveats. The blood sample used to calculate the anion gap should be drawn close in time to the arterial blood gas sample.

Although the anion gap is an effective tool in assessing acid-base disorders, further investigation is warranted if clinical judgment suggests that an anion gap calculation is inconsistent with the patient’s circumstances.²

Our patient’s anion gap is elevated (21 mmol/L). Her serum albumin level is in the normal range, so her anion gap does not need to be adjusted.

4. Is the degree of compensation appropriate for the primary acid-base disturbance?

The kidneys compensate for the lungs, and vice versa. That is, in respiratory acidosis or alkalosis, the kidneys adjust the bicarbonate levels, and in metabolic acidosis, the lungs adjust the Pco₂ (although in metabolic alkalosis, it is hard for patients to breathe less, especially if they are already hypoxic).

In metabolic acidosis, people compensate by breathing harder to get rid of more carbon dioxide. For every 1-mmol/L decrease in the bicarbonate level, the Pco₂ should decrease by 1.3 mm Hg.

Compensation does not return pH to normal; rather, it mitigates the impact of an acid or alkali excess or deficit. If the pH is normalized with an underlying acid-base disturbance, there may be mixed acid-base processes rather than compensation.

Our patient’s bicarbonate level is 16 mmol/L, which is 9 mmol/L lower than normal (for acid-base calculations, we use 25 mmol/L as the nominal normal level). If she is compensating appropriately, her Pco₂ should decline from 40 mm Hg (the nominal normal level) by about 11.7 mm Hg (9 × 1.3), to approximately 28.3 mm Hg. Her Pco₂ is, indeed, 28 mm Hg, indicating that she is compensating adequately for her metabolic acidosis.

If we use Winter’s formula instead (Pco₂ = [1.5 × the bicarbonate level] + 8 ± 2),³ the lowest calculated Pco₂ would be 30 mm Hg, which is within 2 mm Hg of the Rules of 5 calculation. Other formulas for calculating compensation are available.³

This information rules out the first two answers to question 1, ie, metabolic acidosis with respiratory alkalosis or acidosis.

5. Is there a delta gap?

Although we know the patient has metabolic acidosis with an elevated anion gap, we have not ruled out the possibility that she may have a triple disturbance. For this reason we need to check her delta gap. 

In metabolic acidosis with an elevated anion gap, as the bicarbonate level decreases, the anion gap should increase by the same amount. If the bicarbonate level decreases more than the anion gap increases, the additional decline is the result of a second process—an additional normal-anion-gap acidosis. If the bicarbonate level does not decrease as much as the anion gap increases, there is an additional metabolic alkalosis.

Our patient’s bicarbonate level decreased 9 mmol/L (from the nominal normal level of 25 to 16), and therefore her anion gap should have increased approximately the same amount—and it did. (A normal anion gap for problem-solving is 10, and this patient’s anion gap has increased to 21. A difference of ± 2 is insignificant.) This conclusion verifies that a triple acid-base disturbance is not present, so the last answer is incorrect.

So, the correct answer to the question posed above is metabolic acidosis with an elevated anion gap (that is, metabolic acidosis with appropriate respiratory compensation).

‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS

The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).

Methanol and ethylene glycol

We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time. 

In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.

In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).^4,5 Therefore, her osmol gap is elevated.

Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.⁶ A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.⁷ Liquid chromatography identifies these two toxins, but results are not available emergently.

Diethylene glycol ingestion should also be considered.⁸ Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.

Uremia

Renal failure can lead to metabolic acidosis.⁹ Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m²—low, but not uremic.  

Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.

Diabetes

The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).¹⁰

There is another, less common cause of ketoacidosis: alcohol.¹¹ Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.¹¹ Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.¹¹

This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.

THE NEW MUD PILES

2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:

• The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
• There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
• Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
• Salicylates can paradoxically be associated both with elevated and low anion gaps.

Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.

Paraldehyde, isoniazid, lactate

The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.

UPDATING THE ‘P’ IN MUD PILES

Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).^12–20

Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.

5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen

Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).^21,22

Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.

Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,²³ the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.

No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.

Propylene glycol, a component of parenteral lorazepam

Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.^24,25

Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.²³

Isoniazid

Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,²⁶ either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.

The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.²⁷ A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.²⁸

Lactic acidosis

Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.²⁹ However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.²⁹

d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).³⁰ With short bowel syndrome, the neurologic manifestations occur after eating and clear later.³⁰

Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.

Salicylates

Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.

Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.

Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.³¹ Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.

WHAT ELSE MUST BE CONSIDERED?

3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)

• Methanol, ethylene, or diethylene glycol
• Excessive, chronic acetaminophen ingestion
• Salicylate toxicity
• Alcoholic ketoacidosis

All of the above can potentially contribute to metabolic acidosis.

A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.

Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.

The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.

GOLD MARK: ANOTHER WAY TO REMEMBER

Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).³²

ACID-BASE DISORDERS IN DIFFERENT DISEASES

Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:

Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.³³

Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.³⁴

Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.^35,36

Cancer^37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.

An expanding array of toxic ingestions

Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.

As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.